Subcutaneous administration of onfasprozil and method of administration for use in the treatment of depressive disorders

Abstract

The present disclosure relates to the subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof for treating diseases or disorders mediated by negative allosteric modulation or inhibition of NR2B-containing NMDA receptors, including but not limited to depressive disorders (e.g., major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, suicidal tendency, and seasonal affective disorder). The present disclosure also relates to the use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment of treatment-resistant depression in patients with major depressive disorder. 【Chemical 1】 TIFF2025518778000031.tif20170

Description

Technical Field

[0001] Claims of Priority This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 365,749, filed on June 2, 2022, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to the treatment of major depressive disorder (MDD), including treatment-resistant depression. The present disclosure further relates to the subcutaneous administration and / or regimen of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of depressive disorders (such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, and / or any combination of the foregoing). Some embodiments relate to the subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of the NR2B-containing NMDA receptor, such as depressive disorders (such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and / or any combination of the foregoing), but are not limited thereto. Some embodiments relate to the use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment of treatment-resistant depression in patients with major depressive disorder.

Background Art

[0003] Depression is a serious and life-threatening condition with a high prevalence and chronic course. It is a common disorder worldwide, affecting more than 264 million people (WHO (2020) World Health Organization: Depression (Depression. Key facts) (Internet), available from: https: / / crediblemeds.org / ). In cases of moderate or severe depression over a long period, it causes great suffering to the affected individuals and impairs their ability to work, take care of themselves, and maintain relationships.

[0004] Despite the widespread availability of antidepressants, approximately one-third of patients with major depressive disorder (MDD) do not respond adequately to antidepressant treatment for an appropriate period and dose, and most cannot maintain a long-term response to standard antidepressants (Rush AJ, Trivedi MH, Wisniewski SR, et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry; 163(11):1905 - 17). The chronicity of this symptom makes patients more likely to become treatment-resistant.

[0005] Treatment-resistant depression (TRD) is defined as the absence of clinically meaningful improvement after treatment with at least two different antidepressants prescribed for an appropriate period and at an appropriate dose.

[0006] Patients with TRD are at very high risk of suicidal thoughts and experience an excessive burden of the disease, which causes significant impairment and increased morbidity (Shelton RC, Osuntokun O, Heinloth AN, et al (2010) Therapeutic options for treatment resistant depression. CNS Drugs; 24(2):131 - 61).

[0007] Accordingly, there is a significant unmet medical need for more effective or better-tolerated rapid-acting antidepressants that can effectively interrupt depressive episodes and prevent future depressive episodes.

Summary of the Invention

Means for Solving the Problems

[0008] Ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been shown to be effective in treatment-resistant depression (TRD) in off-label use studies, but is limited by side effects that cause symptoms such as mental disorders. Furthermore, ketamine is rapid-acting and has been shown to reduce suicidal tendencies. The effectiveness of ketamine provides a theoretical basis for targeting N-methyl-D-aspartic acid (NMDA) receptor inhibition as a mechanism by which the antidepressant effect is rapidly manifested.

[0009] SPRAVATO® (esketamine), a non-competitive NMDA receptor antagonist, is approved for the treatment of TRD and has also been approved by the Food and Drug Administration (FDA) for major depressive disorder (MDD) with acute suicidal ideation or behavior. It has also been approved by the European Medicines Agency (EMA) for moderate to severe episodes of MDD as an acute short-term treatment, in accordance with clinical judgment, in combination with oral antidepressants for the rapid reduction of symptoms constituting a psychiatric emergency. Both ketamine and SPRAVATO® have demonstrated a certain level of effectiveness and a rapid mode of action, but their safety profiles are not without adverse effects and are meaningful for both patients and clinicians.

[0010] Targeting specific subsets of NMDA receptors is one approach to potentially mitigate the harmful effects of NMDA receptor inhibition while retaining the antidepressant effect. Infusion of traxoprodil (also known as CP-101,606), a selective negative allosteric modulator of the NR2B subtype of NMDA receptors, is effective in patients with TRD, and the magnitude and duration of response are comparable to those of ketamine, which is less likely to produce dissociative effects in patients. MK-0657 (also known as lisrenemdaz, MK-0657, or CERC-30), a selective NR2B antagonist, did not induce dissociative effects and was generally safe in patients with TRD.

[0011] Conventional pharmacotherapies for major depressive disorder (MDD) include antidepressants belonging to different classes. These include selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), norepinephrine-dopamine reuptake inhibitors (NDRI), tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants, but are not limited to these. Many patients start treatment with one and, after failure, may try another of these therapies and fail again, and are thus called "treatment-resistant."

[0012] The rationale for presenting a new dosing regimen for a given drug is that developing such a dosing regimen requires balancing patient compliance, treatment efficacy, and side effects of the drug, and considerable skill is required as the goal is not easily achieved.

[0013] Therefore, there is a large unmet medical need for faster-acting antidepressants that can effectively interrupt depressive episodes and prevent future depressive episodes, and are more effective or better tolerated.

[0014] In some embodiments, methods of treating a novel depressive disorder are provided herein. In some embodiments, the depressive disorder is major depressive disorder. In some embodiments, the depressive disorder is treatment-resistant depression. In some embodiments, the depressive disorder is one in which a potentially rapid-acting antidepressant effect may be beneficial (e.g., including, but not limited to, major depressive disorder, treatment-resistant depression, or other depressive disorders disclosed herein). In some embodiments, a rapid response is meaningful in people suffering from treatment-resistant depression, including populations that have not responded to conventional antidepressants used at appropriate periods and appropriate dosages. Depressive disorders often lead to suicidal thoughts or suicidal behaviors that put patients at risk. Furthermore, conventional antidepressants, even when they eventually act, may take several weeks to obtain a therapeutic benefit. Thus, there is a need for a rapidly acting and safe antidepressant treatment. Some embodiments disclosed herein solve the above or other problems disclosed herein. Compound (I) or a compound of formula (I), as used herein, is 6-((1S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol, the INN name of which is onfasaprodil, of the following formula [Chemical formula] :. Onfasaprodil is a non-allosteric modulator (NAM) of the NR2B-NMDA receptor and can be prepared as described in International Publication No. WO 2016 / 049165, which is hereby incorporated by reference in its entirety.

[0015] Compound (I) or a pharmaceutically acceptable salt thereof is a very potent, selective, and reversible low molecular weight NR2B-containing NMDA receptor NAM. The treatments disclosed herein are intended to provide a significant antidepressant effect rapidly in patients, particularly those having treatment-resistant depression.

[0016] Some embodiments disclosed herein provide a method of treating a depressive disorder, particularly a major depressive disorder, particularly treatment-resistant depression, using compound (I) and / or a novel formulation comprising compound (I). In some embodiments, advantageously, compound (I) is provided in a form with rapid onset of action and rapid manifestation of activity in a patient. In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder, treatment-resistant depression, etc.) has increased efficacy when compound (I) is provided as a formulation with rapid onset of action (e.g., a subcutaneous formulation). A rapid response (such as achieved using compound (I) disclosed herein) is meaningful in the treatment of resistant depression even in populations that did not respond to conventional antidepressants used at appropriate doses for an appropriate period. In some embodiments, as disclosed herein, the compositions of compound (I) disclosed herein are effective in treating a depressive disorder (e.g., major depressive disorder, treatment-resistant depression, etc.) in populations that did not respond to conventional antidepressants used at appropriate doses for an appropriate period. In some embodiments, the appropriate period is the period in which a conventional antidepressant is expected to exert sufficient efficacy in a patient.

[0017] Thus, there remains a need for a rapid onset of antidepressant effect as patients with major depression are at risk of suicide or self-harm, while conventional antidepressants can take several weeks to become effective.

[0018] Furthermore, patients with major depressive disorder with suicidal tendency often require hospitalization for 4 to 5 days. The compound (I) with rapid onset of efficacy can reduce (or completely eliminate) the number of days of hospitalization for patients, and thus can bring greater benefits than other antidepressants that take at least 4 weeks for patients to respond to treatment. In some embodiments, the treatment using the compound (I) disclosed herein shortens the hospitalization period by about 1 day or more, about 2 days or more, about 3 days or more, about 4 days or more, about 5 days or more, or a period within the range including and / or spanning the aforementioned number of days. For example, in some embodiments, the treatment using the compound (I) disclosed herein shortens the hospitalization period by 1 to 5 days, 2 to 5 days, 3 to 5 days, 4 to 5 days, 1 to 4 days, 2 to 4 days, 3 to 4 days, 1 to 3 days, 2 to 3 days, or 1 to 2 days.

[0019] In some embodiments, through the treatment using the compound (I), patients can rapidly achieve significant improvement in their depressive symptoms and suicidal tendency.

[0020] The present disclosure also aims to alleviate one or more depressive symptoms in patients with major depressive disorder, particularly treatment-resistant depression. The present disclosure is based in part on the treatment of major depressive disorder in patients who require adjuvant therapy for major depressive disorder, particularly treatment-resistant depression.

[0021] The present disclosure also aims to alleviate one or more depressive symptoms in patients with suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with suicidal behavior in major depressive disorder, self-harm in major depressive disorder, and seasonal affective disorder. In some embodiments, the present disclosure overcomes these drawbacks by providing subcutaneous administration of the compound (I).

[0022] In a first aspect, there is provided a method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0023] In a second aspect, there is provided a method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as the patient, a pharmaceutical composition comprising a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0024] In a third aspect, there is provided a method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0025] In a fourth aspect, there is provided a method of treating major depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0026] In a fifth aspect, there is provided a method of treating major depressive disorder in a subject, such as a patient, in need of such treatment, wherein the subject, such as the patient, meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0027] In a further aspect, there is provided a method of treating treatment-resistant depression in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0028] In a further aspect, there is provided a method of treating a major depressive episode in a subject, such as a patient, in need thereof, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0029] In a further aspect, there is provided a method of preventing a major depressive episode in a subject, such as a patient, in need thereof, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0030] In a further aspect, there is provided a method of treating recurrent and ongoing major depressive episodes in a subject, such as a patient, in need thereof, the method comprising administering subcutaneously to the subject, such as the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0031] In another aspect of the present disclosure, the method comprises adjunctive treatment with one or more antidepressants, the method comprising administering to a subject, such as a patient, in need thereof, a therapeutically effective amount of one or more antidepressants. Examples of the one or more antidepressants can include at least one member of lithium, conventional antidepressants, herbal antidepressants, mood stabilizers, antipsychotics, and benzodiazepines.

[0032] Examples of the one or more antidepressants can include selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine-dopamine reuptake inhibitors, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), multimodal antidepressants, or combinations thereof.

[0033] In another aspect, there is provided a method of treating major depressive disorder in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, does not respond to at least two antidepressant treatments, at least one of which has been used in the treatment of the current major depressive episode, the method comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0034] In a further aspect, there is provided a method of treating treatment-resistant depression in an adult patient in need thereof, the method comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof in combination with at least one oral antidepressant. BRIEF DESCRIPTION OF THE DRAWINGS

[0035]

Figure 1

Figure 2

Figure 3

Figure 4

BRIEF DESCRIPTION OF THE INVENTION

[0036] Some embodiments disclosed herein relate to the subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of the NR2B-NMDA receptor. In some embodiments, the disease or disorder mediated by negative allosteric modulation or inhibition of the NR2B-NMDA receptor is a depressive disorder. In some embodiments, the present disclosure relates to the subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of major depressive disorder (including, but not limited to, treatment-resistant depression). Further diseases or disorders mediated by negative allosteric modulation or inhibition of the NR2B-NMDA receptor (for which subcutaneous administration of the present disclosure may also be useful) include suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, and self-harm in major depressive disorder, seasonal affective disorder. Some embodiments disclosed herein relate to a method of treating a depressive disorder in a subject, such as a patient, in need thereof. In some embodiments, the method comprises subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof. In some embodiments, the depressive disorder is major depressive disorder. In some embodiments, the major depressive disorder is treatment-resistant depression. Some embodiments relate to the use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment of treatment-resistant depression in a patient having major depressive disorder.

[0037] The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) of the American Psychiatric Association provides a diagnostic tool for identifying the disorders described herein. Those skilled in the art will recognize that alternative nomenclatures, classifications, and classification systems exist for the mental disorders described herein and that these evolve with medical and scientific progress.

[0038] Definitions The headings used in this specification are for structural purposes only and should not be construed as limiting the subject matter being described. Features disclosed under one heading (such as a composition) can be used in combination with features disclosed under a different heading (such as a method of treatment). Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. It should be noted that the use of a particular term in describing a particular feature or aspect of the present disclosure should not be construed as meaning that the term is redefined herein to be limited to include the particular characteristics of the related feature or aspect of the present disclosure.

[0039] The terms and phrases used in this application, and their variations, particularly in the appended claims, are to be construed as open-ended and not limiting, unless otherwise expressly stated. By way of example, the term "including" should be construed to mean "including without limitation", "including but not limited to", etc.; the term "comprising" as used herein is synonymous with "including", "containing", or "characterized by", and does not exclude additional, unrecited elements or method steps; the term "having" is synonymous with "having at least", is inclusive or open-ended, and does not exclude additional, unrecited elements or methods; the term "include" should be construed to mean "including but not limited to"; the term "example" is used to provide an illustrative instance of the item under discussion, and is neither an exhaustive nor a limiting list; the use of terms such as "preferably", "preferred", "desired", or "desirable", and words of similar meaning, should not be understood to mean that a particular feature is critically important, essential, or important to the structure or function of the invention, but rather should be understood as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Further, the term "comprising" should be construed as synonymous with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may also include additional steps. When used in the context of a compound, composition, or apparatus, the term "comprising" means that the compound, composition, or apparatus includes at least the recited features or components, but may also include additional features or components.Similarly, a group of items connected by the conjunctive “and” should not be construed as requiring that each and every one of those items be present within the group; rather, absent any express contrary indication, it should be construed as “and / or”. Similarly, a group of items connected by the disjunctive “or” should not be construed as requiring mutual exclusivity among the group; rather, absent any express contrary indication, it should be construed as “and / or”.

[0040] Furthermore, the phrase “consisting essentially of” is understood to include specifically recited elements, as well as additional elements that do not materially affect the basic and novel characteristics of the technology recited in the claims. The phrase “consisting of” excludes unspecified elements.

[0041] With respect to the use of substantially any plural and / or singular terms herein, one of ordinary skill in the art can translate from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural substitutions may be explicitly set forth herein for clarity. The indefinite articles “a” or “an” do not exclude a plurality. The mere fact that certain evaluation criteria are recited in mutually different dependent claims does not indicate that a combination of these evaluation criteria cannot be used advantageously. No reference signs in the claims should be construed as limiting the scope.

[0042] Throughout this specification, references to "one embodiment" or "an embodiment" mean that the particular features, structures, or characteristics described in connection with that embodiment are included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0043] When referring to various features, the term "range including and / or spanning the aforementioned values" may be used. These terms (and their variations) mean including any range that includes or spans any of the aforementioned values. For example, with respect to the % improvement in mood, % may be expressed as "about 1% or more, about 5% or more, about 10% or more, about 20% or more, or a range including and / or spanning the aforementioned values". This language includes not only the specific % provided and ranges above that value (e.g., about 1% or more, about 5% or more, about 10% or more, and about 20% or more), but also % ranges spanning those values (e.g., 1% - 20%, 1% - 10%, 1% - 5%, 5% - 20%, 5% - 10%, and 10% - 20%). Similarly, with respect to the % improvement in mood, % may be expressed as "about 1% or less, about 5% or less, about 10% or less, about 20% or less, or a range including and / or spanning the aforementioned values". This language includes not only the specific % provided and ranges below that value (e.g., about 1% or less, about 5% or less, about 10% or less, and about 20% or less), but also % ranges spanning those values (e.g., 1% - 20%, 1% - 10%, 1% - 5%, 5% - 20%, 5% - 10%, and 10% - 20%).

[0044] Compound (I), the compound of formula (I), formula (I), as used herein, has the following formula, where the INN name is onfaspirone: [Chemical formula] It is 6-((1S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol. Onfaspoglutamate is a very potent, selective and reversible low molecular weight negative allosteric modulator (NAM) that targets the NR2B subunit of the N-methyl-D-aspartic acid receptor (NMDAR). Evidence suggests that MK-0657 (also known as CERC-301) and CP-101,606, which are NR2B-selective negative allosteric modulators (NAMs), have a low frequency of dissociative adverse events. The relative contribution of each individual subtype of NMDAR to the harmful effects of pan-NMDAR inhibition is not fully understood overall due to the lack of selective inhibitors for the various subtypes, but this suggests that achieving safe but rapid antidepressant efficacy is possible with compounds that selectively inhibit NR2B-containing NMDA receptors.

[0045] As used herein, the terms "salt", "salts" or "salt form" refer to the acid addition salts or base addition salts of the respective compounds, for example the compounds specified herein (e.g., compound (I), or for example further pharmaceutically active ingredients as defined herein). "Salt" includes in particular "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound and are generally not undesirable, either biologically or otherwise. The compounds specified herein (e.g., compound (I), or for example further pharmaceutically active ingredients as defined herein) can form acid salts and / or base salts due to the presence of amino groups and / or carboxyl groups or groups similar thereto. The compounds of the present disclosure can form acid addition salts, and thus, as used herein, the term pharmaceutically acceptable salt of compound (I) means the pharmaceutically acceptable acid addition salts of compound (I).

[0046] Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids.

[0047] Examples of inorganic acids capable of inducing salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.

[0048] Examples of organic acids capable of inducing salts include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0049] Pharmaceutically acceptable base addition salts can be formed by inorganic bases and organic bases.

[0050] Examples of inorganic bases capable of inducing salts include ammonium salts and metals in columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, and particularly preferred salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0051] Examples of organic bases capable of inducing salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Specific organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0052] Pharmaceutically acceptable salts can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (e.g., hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.) or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water or an organic solvent, or a mixture of the two. Generally, if feasible, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable. A further list of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 22 nd edition, Mack Publishing Company (2013); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2 nd edition).

[0053] Among the quantitative expressions described herein, there are some without the term “about” attached. Whether or not the term “about” is explicitly used, all the amounts shown herein are intended to refer to the actual values shown, and also to approximations to such shown values reasonably inferred based on ordinary techniques in the art, for example, approximations due to experimental and / or measurement conditions for such shown values. In embodiments, the term “about” refers to a range of ±10% of the specified value.

[0054] As used herein, the term "adjunct therapy," also known as adjuvant therapy, adjunctive therapy, additional therapy, or augmenting therapy, is a therapy given in addition to primary or initial therapy. In one embodiment, the primary or initial therapy in the context of the present disclosure is, for example, antidepressant therapy as disclosed herein. Non-pharmacological treatments such as psychotherapy and transcranial magnetic stimulation are also available and are options for adjunct therapy.

[0055] As used herein, unless otherwise specified, the terms "antidepressant", "antidepressant therapy", "conventional antidepressant", etc. mean any pharmaceutical that can be used for the treatment of depression. Antidepressants, antidepressant therapies, or conventional antidepressants also include those listed in the list of antidepressants of the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) (this document is incorporated herein by reference in its entirety). In certain examples, antidepressant therapy can be enhanced with antipsychotics. Suitable examples include selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine-dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible monoamine oxidase inhibitors (RIMA)), and multimodal antidepressants; natural products such as Kava-Kava, St. John's Wort; dietary supplements such as S-adenosylmethionine; neuropeptides such as thyrotropin-releasing hormone; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists; and hormones such as triiodothyronine, but are not limited thereto. Examples of selective serotonin reuptake inhibitors (SSRI) and selective serotonin and norepinephrine reuptake inhibitors (SNRI) include fluoxetine (e.g., Prozac®), duloxetine (e.g., Cymbalta®), desvenlafaxine (e.g., Pristiq®), venlafaxine (e.g., Effexor®), milnacipran (e.g., Savella®), citalopram (e.g., Celexa®), escitalopram (e.g., Lexapro®), fluvoxamine (e.g., Luvox®), paroxetine (e.g., Paxil®, Pexeva®), sertraline (e.g., Zoloft®), but are not limited thereto.Examples of monoamine oxidase inhibitors include isocarboxazid (e.g., Marplan®), phenelzine (e.g., Nardil®), tranylcypromine (e.g., Parnate®), and selegiline (e.g., Eldepryl®, Emsam®). Examples of reversible inhibitors of monoamine oxidase include moclobemide (e.g., Aurorix®), pirindole (e.g., Pirazidol®). Examples of norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Preferred examples of tricyclic antidepressants include amitriptyline (e.g., Elavil®, Endep®), clomipramine (e.g., Anafranil®), doxepin (e.g., Adapin®, Sinequan®, Quitaxon®, Aponal®), imipramine (e.g., Tofranil®), trimipramine (e.g., Surmontil®), amoxapine (e.g., Asendin®), desipramine (e.g., Norpramin®), maprotiline (e.g., Ludiomil®), nortriptyline (e.g., Pamelor®), protriptyline (e.g., Vivactil®), pipofezine (e.g., Azafen®), noxiptiline (e.g., Agedal®, Elronon®). Examples of multimodal antidepressants include vilazodone (e.g., Viibryd®), vortioxetine (e.g., Trintellix®, Brintellix®). A preferred norepinephrine-dopamine reuptake inhibitor includes bupropion (e.g., Wellbutrin®). In one embodiment, "antidepressant", "antidepressant therapy", "conventional antidepressant" are approved by the FDA as therapeutics for MDD.

[0056] The term "antipsychotic" includes, but is not limited to, the following: (a) For example, typical or traditional antipsychotics such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine), thioxanthenes (e.g., thiothixene, flupenthixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride); and (b) For example, atypical antipsychotics such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, bromocriptine, sertindole; and others such as sonapiprazole, aripiprazole, nemonapride. In one embodiment, the “atypical antipsychotic” is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. In another embodiment, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine, and risperidone; preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, and olanzapine.

[0057] Therapeutically effective or effective dosage levels and dosing regimens for antidepressants (e.g., SSRIs, SNRIs, TCAs, norepinephrine-dopamine reuptake inhibitors, norepinephrine reuptake inhibitors, MAOIs (including RIMAs), multimodal antidepressants, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, antipsychotics, and other pharmaceuticals disclosed herein) can be readily determined by those skilled in the art. For example, the therapeutic dosages and dosing regimens of approved-for-sale pharmaceuticals are publicly available, as described, for example, on the package label, in standard dosing guidelines, in standard dosing reference books such as the Physician’s Desk Reference (Medical Economics Company, or online at http: / / / www.pdrel.com), or from other sources.

[0058] As used herein, the term "AUClast" refers to the area under the plasma concentration-time curve from time zero to the last measurable time of concentration. "Time zero" in the general context refers to the time of subcutaneous injection of the intended dose.

[0059] Unless otherwise indicated herein, the term "baseline" or "baseline assessment" as used herein means the time immediately prior to the start of treatment with Compound I or a pharmaceutically acceptable salt thereof.

[0060] The terms "combination therapy", "combination", and "combined administration" mean the treatment of a patient in need thereof by administering compound (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents, for example as adjuvant therapy, and the additional therapeutic agents are administered by any suitable means. The agents can be administered simultaneously, or sequentially in any order, for the entire duration of treatment or a portion of the treatment period. The terms "combination therapy", "combination", and "combined administration" also encompass adjuvant therapy as defined herein. The terms "combination therapy", "combination", and "combined administration" also encompass treatment with compound (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents such as standard therapeutic agents prescribed for mental disorders such as depressive disorders as defined herein. In one embodiment, compound (I) is administered in combination with 1 to 5 additional therapeutic agents (e.g., 1, 2, 3, 4, or 5 additional therapeutic agents). In another embodiment, compound (I) is administered in combination with 1, 2, 3, 4, or 5 additional therapeutic agents. In another embodiment, compound (I) is administered in combination with 1 or 2 additional therapeutic agents. In another embodiment, compound (I) is administered in combination with 1 other therapeutic agent. In a further embodiment, compound (I) is administered in combination with additional therapeutic agents currently being administered to the patient, including the current antidepressant if the patient's response has been inadequate. In yet a further embodiment, compound (I) is administered in combination with one or more additional therapeutic agents not previously administered to the patient. In yet another further embodiment, compound (I) is administered in combination with one or more additional therapeutic agents previously administered to the patient. When compound (I) and the additional therapeutic agents are administered in separate dosage forms, the number of administrations per day for each compound may be the same or different, and more generally may be different. The additional therapeutic agents can be dosed according to the prescription of the attending physician and / or according to the prescription by the label, and compound (I) is administered as described herein. Typically, the patient is being co-treated with both an antidepressant and compound (I), and both are administered according to the prescribed dosing regimen.Compound (I) and the antidepressant can be administered simultaneously, either in a divided form or in a single form, at the same time or at different times during the course of treatment, according to a simultaneous or alternating regimen. In one embodiment, the additional therapeutic agent is selected from one or more antidepressants, antipsychotics such as atypical antipsychotics, mood stabilizers such as lithium, benzodiazepines, and combinations thereof. In certain embodiments, the one or more additional therapeutic agents are one or more antidepressants.

[0061] The terms "depressive episode" or "major depressive episode" as used herein refer to the characteristics of major depressive disorder as defined herein.

[0062] A "major depressive episode" can be defined as a depressed mood or loss of interest for at least two weeks, and can be accompanied by other symptoms of depression, particularly the symptoms of major depressive disorder as specified in the Diagnostic and Statistical Manual of Mental Disorders, 5th th Edition: DSM 5. The symptoms must persist continuously for at least two weeks, for most of the day (i.e., at least two-thirds of the patient's waking hours), and almost every day (i.e., at least 10 days out of 14). The "depressed mood" is often described by the patient as feeling sad, hopeless, weak, or worthless. Also, the patient may appear sad to an observer, for example, through facial expression, posture, voice, and tears. In children and adolescents, the mood may be irritable. The "loss of interest" is often described by the patient as a decrease in interest in hobbies or a loss of enjoyment in activities that were previously considered enjoyable.

[0063] A major depressive episode may be accompanied by other symptoms of depression, including significant weight loss or gain not due to diet (e.g., a change in weight of more than 5% in one month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness, or excessive or inappropriate guilt; diminished ability to think or concentrate; or indecisiveness; and recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or suicide attempt.

[0064] As used herein, the term "Cmax" refers to the maximum plasma concentration observed by assay after any administration, e.g., single or repeated administration. In some embodiments, the methods disclosed herein further comprise measuring the plasma levels of a patient.

[0065] As used herein, the term "depressive disorder" primarily means a clinical disorder that includes sadness or depression and is accompanied by psychological and / or physical symptoms. Depressive disorders can be mild depressive disorder, moderate depressive disorder, severe depressive disorder, clinical depressive disorder, or postpartum depressive disorder. Exemplary depressive disorders include major depressive disorder, (e.g., major depressive disorder with suicidal tendency, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, and self-harm in major depressive disorder), persistent depressive disorder, seasonal affective disorder, perinatal depression (e.g., postpartum depression), premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, late-life depression, depression due to identifiable stress factors, treatment-resistant depression, partial-resistant depression, and combinations thereof, but are not limited thereto, and each of these is contemplated to be treated using the methods and compositions described herein. There are many methods and techniques well known to those of skill in the art (including responses to treatment or therapy) for diagnosing depressive disorders, for assessing the state or severity of such conditions or their symptoms over time, and for monitoring changes in the state or severity of such conditions or their symptoms over time. In one embodiment, the depressive disorder is major depressive disorder. In a further embodiment, the depressive disorder is treatment-resistant depression. In another embodiment, the depressive disorder is seasonal affective disorder.

[0066] As used herein, the term "depressive symptoms" refers to one or more symptoms associated with depressive disorders, particularly major depressive disorder, and includes persistent anxiety or sad feelings, feelings of helplessness, hopelessness, pessimistic feelings, guilt, and / or worthlessness, low energy, restlessness, excitability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep or insomnia, overeating or loss of appetite, difficulty thinking, concentrating, or making decisions, suicidal thoughts, and suicidal attempts. The presence, number, severity, frequency, and duration of these symptoms can vary from person to person and also over time for a particular individual. Depressive symptoms can manifest as a depressive disorder, such as major depressive disorder.

[0067] The terms "drug", "active substance", "active ingredient", "pharmaceutically active ingredient", "active agent" or "therapeutic agent" should be understood to mean a compound in free form or in the form of a pharmaceutically acceptable salt, particularly a compound of the kind specified herein.

[0068] As used herein, the term "non-responsive" refers to a situation where, for example, a patient has shown little or no improvement in current symptoms, indicating that an adequate response has not been obtained to previous or current antidepressant treatment due to insufficient efficacy. The previous or current antidepressant treatment has been used for an appropriate period and at an appropriate dose, for example, a therapeutically effective amount. For example, the previous or current antidepressant treatment has been used for a period of at least 4 weeks, for example, at least 6 weeks. In some embodiments, a patient who is non-responsive to a medicament is a patient who has been treated with that medicament for a period of about 3 weeks or more, about 4 weeks or more, about 5 weeks or more, about 6 weeks or more, about 7 weeks or more, or a period within and / or spanning the ranges including the aforementioned values. An inadequate response can be evaluated by a clinician having skill in the art of treating the disorder in question.

[0069] As used herein, "inadequate response" refers to a patient in whom the reduction in the severity of depressive symptoms was less than about 50% from the start of treatment. Typically, an inadequate response is during the current / active episode of the depressive disorder. In some embodiments, an inadequate response refers to a patient in whom the reduction in the severity of depressive symptoms from the start of treatment was from about 26% to less than about 50%. In other embodiments, an inadequate response refers to a patient in whom the reduction in the severity of depressive symptoms from the start of treatment was about 26 to about 49%, about 26 to about 45%, about 26 to about 40, about 26 to about 35, about 26 to about 30, about 30 to about 49, about 30 to about 45, about 30 to about 40, about 30 to about 35, about 35 to about 49, about 35 to about 45, about 35 to about 40, about 40 to about 49, or about 40 to about 45%. In some embodiments, an inadequate response refers to a patient in whom the reduction in the severity of depressive symptoms from the start of treatment was 25% or less, the reduction in the severity of depressive symptoms from the start of treatment was 10% or less, the reduction in the severity of depressive symptoms from the start of treatment was 5% or less, or the reduction in the severity of depressive symptoms from the start of treatment was 0%. A patient's response can be measured by one or more of the scales described herein and / or by physician / clinical judgment. In some embodiments, an inadequate response is measured by the MGH-ATRQ, MADRS, or SHAPS. In further embodiments, an inadequate response is measured by the MGH-ATRQ.

[0070] As used herein, the term "major depressive disorder" or MDD is defined, for example, with reference to the DSM-5 criteria (the entire content of which is incorporated herein by reference). Major depressive disorder generally refers to a single or recurrent major depressive episode. It is a mental disorder that 1) exists during the same two-week period and meets five or more of the following symptoms that indicate a change from previous functioning (at least one of the symptoms is (i) a depressed mood or (ii) a loss of interest or pleasure): i) Depressed / sad mood; ii) Loss of interest and pleasure; iii) Significant weight loss not due to dieting, or weight gain, or decrease or increase in appetite; iv) Insomnia or hypersomnia; v) Psychomotor agitation or retardation; vi) Fatigue or loss of energy; vii) Feelings of worthlessness, or excessive or inappropriate guilt; viii) Diminished ability to think or concentrate, or indecisiveness; ix) Recurrent thoughts of death, or recurrent suicidal ideation, plans, or attempts; 2) The symptoms cause clinically significant distress, or impairment in social, occupational, or other important areas of functioning; 3) The episode cannot be better accounted for by a psychotic disorder; 4) The episode is not attributable to the physiological effects of a substance or another medical condition; 5) There has been no manic or hypomanic episode. (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association, 2013). The following table further defines the criteria for a major depressive episode / disorder.

[0071]

Table 1

[0072]

Table 2

[0073] In general, the term major depressive disorder as used in accordance with the present disclosure may refer to acute major depressive disorder or chronic major depressive disorder. In certain embodiments, the major depressive disorder is acute major depressive disorder.

[0074] The term "medication with a known risk of torsades de pointes" refers to any medication that prolongs the QT interval and has the potential to cause torsades de pointes. Examples of drugs known to cause torsades de pointes are listed at www.qtdrugs.org.

[0075] As used herein, the terms "non-responder" or "non-responsiveness" mean a patient in whom no clinically significant improvement is observed after treatment (e.g., a change from baseline of 50% or less in a given depression assessment test, a change from baseline of 25% or less in a given depression assessment test, a change from baseline of 10% or less in a given depression assessment test, a change from baseline of 5% or less in a given depression assessment test, a change from baseline of 0% (or a range including and / or spanning the foregoing values), or an improvement that is not statistically significant). In some embodiments, the depression assessment test is the MADRS. In some embodiments, the depression assessment test is the MGH-ATRQ. In some embodiments, the depression assessment test is the Hamilton Depression Scale (HAM-D). In some embodiments, the depression assessment test is the Clinical Global Impression-Severity Scale (CGI-S). To the extent that a patient is said to have a partial response to treatment, this refers to an improvement in symptoms from mild to moderate since the start of treatment, although some of the initial symptoms still remain and trouble the patient, and these persistent symptoms still affect behavior and function. For example, the patient's motivation, productivity, and interest in their normal activities may still be impaired. In one embodiment, the patient is better than baseline but still has symptoms and thus requires further antidepressant treatment. In another embodiment, the patient has a reduction in baseline depression scale score of <50% and ≧25%, including but not limited to, for example, MADRS, MGH-ATRQ, HAM-D, CGI-S.

[0076] As used herein, the term "patient" refers to an individual who has a disease and can benefit from treatment. In one embodiment, the individual, such as a patient, has major depressive disorder. Mild depressive disorder, moderate depressive disorder, and severe or major depressive disorder can be characterized by the total score of depressive symptom severity on the Montgomery-Åsberg Depression Rating Scale (MADRS). For example, the patient had a MADRS score of 24 or higher measured before treatment with compound (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the patient has been diagnosed with recurrent major depressive disorder (MDD) and has a current major depressive episode that has a duration of at least 4 weeks, such as at least 6 weeks, such as at least 8 weeks, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and confirmed by both the SCID-5 and appropriate clinical psychiatric evaluations. In certain embodiments of the present disclosure, the patient is in need of adjunctive therapy for treatment-resistant depression. In certain embodiments, the patient is an adult. As used herein, the term "adult" refers to a person who is about 18 years of age or older.

[0077] As used herein, the term "pharmaceutical composition" is defined to mean a mixture or solution containing at least one active ingredient or therapeutic agent that is administered to an individual, such as a patient, for treating a particular condition (i.e., a disease, disorder or medical condition, or at least one of their clinical symptoms) that the individual, such as a patient, is suffering from.

[0078] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, coloring agents, and the like, and combinations thereof, known to those of ordinary skill in the art (e.g., Remington’s Pharmaceutical Sciences, 22 nd(See Ed.Mack Printing Company, 2013, pp. 1049-1070). Conventional carriers are intended for use in therapeutic or pharmaceutical compositions, except when they are not compatible with the active ingredient.

[0079] As used herein, "pregnancy" is defined as the state of a female from conception until the end of the gestation period and is confirmed by a positive human chorionic gonadotropin (hCG) clinical test.

[0080] As used herein, the term "suicidal act" means an act or preparation to attempt suicide, but an act or preparation before the possibility of harm begins. This may include things beyond verbalization or thought, such as assembling a method (e.g., buying a gun, collecting pills), or preparing for death by suicide (e.g., writing a suicide note, giving away possessions).

[0081] As used herein, the term "psychotherapy" refers to the intentional application based on clinical methods and interpersonal postures of information derived from established psychological principles for the purpose of assisting participants in changing their behaviors, cognitions, emotions, and / or other personal characteristics in a direction they desire.

[0082] As used herein, the term "self-harm" means intentionally inflicting on oneself a destructive or injurious act that is painful and not intended to cause death.

[0083] As used herein, the term "standard treatment" refers to the treatment prescribed by a physician for patients suffering from major depressive disorder, including but not limited to patients with suicidal tendencies and / or suicidal thoughts who are assessed as having an imminent risk of suicide.

[0084] Typically, the standard treatment is provided as prescribed by a treating physician or other healthcare provider and is carried out in combination with treatment with compound (I). For example, the standard treatment is carried out during the same treatment period as the treatment with compound (I). The standard treatment may also precede the treatment with compound (I) and may continue after the treatment with compound (I) has been interrupted. With respect to the antidepressants used in the standard treatment, compound (I) and the antidepressant may be administered by the same route of administration or by different routes of administration.

[0085] "Subject" or "individual" are used interchangeably and refer to a human or non-human animal. The term includes mammals such as humans. In some embodiments, the subject is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, e.g., a subject who has, is at risk of having, or is likely to have a disease described herein. In some embodiments, the subject is a human who has, is at risk of having, or is likely to have a disease described herein. In some embodiments, the subject is a patient, i.e., a subject who has or is at risk of having a disease described herein or a subject in need of treatment for a disease described herein. In some embodiments, the patient is a human suffering from a depressive disorder. In some embodiments, the patient is a human suffering from major depressive disorder. In some embodiments, the patient is a human suffering from treatment-resistant depression.

[0086] The term "suicide" as used herein means death caused by a spontaneous harmful act with the intention of dying as a result of the act.

[0087] As used herein, the term "suicidal tendency" refers to thoughts of suicide (suicidal ideation) as well as suicide, suicide attempts, and preparatory acts (suicidal actions).

[0088] As used herein, the term "suicide attempt" means a non-fatal but potentially harmful spontaneous act with the intention of dying as a result of the act. A suicide attempt may or may not result in injury.

[0089] As used herein, the term "suicidal action" includes suicide, suicide attempts, and acts of preparing for suicide.

[0090] As used herein, the term "suicidal ideation" refers to passive thoughts of wanting to die or active thoughts of committing suicide, without accompanying preparatory acts. Suicidal ideation refers to thinking about or planning suicide. Thoughts can vary from making detailed plans to fleeting considerations, but do not include the final act of suicide. Passive suicidal ideation is the case where one is thinking about suicide or self-harm but has no plan to execute it. Active suicidal ideation is the case where one is thinking about suicide or self-harm and has a plan to execute it.

[0091] As used herein, the term "suicidal ideation with intent" or "suicidal ideation with suicidal intent" refers to passive thoughts of wanting to die, a desire, goal, purpose, or ultimate aim for self-destructive behavior leading to death, or active thoughts of committing suicide with such an aim. It refers to passive thinking. Suicidal ideation with intent or suicidal ideation with suicidal intent can be evaluated by a suicidal ideation assessment scale, which refers to any one of a number of standardized questionnaires, clinical instruments, or symptom lists used to measure the severity of suicidal ideation. Such suicidal ideation symptom assessment scales include, but are not limited to, the Suicidal Ideation Scale (SSI), the Suicide Situation Form (SSF), the Sheehan Suicide Tendency Tracking Scale (S-STS), or the Columbia Suicide Severity Rating Scale (C-SSRS).

[0092] As used herein, the term "suicidal ideation without intent" refers to passive thoughts of wanting to die or active thoughts of killing oneself, but without the intent to do so.

[0093] As used herein, the term "stable dose" means that there is no change in the dose or type of the drug.

[0094] As used herein, the terms "treating", "treatment", "treat" or "therapy" mean obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results include, but are not limited to, alleviation of one or more symptoms of a patient having major depressive disorder or treatment-resistant depression as defined herein. One aspect of treatment is, for example, that the harmful effects of the treatment on the patient are minimal, for example, the drug used has a high level of safety, for example, does not cause the side effects of previously known treatment regimens. For example, with respect to the symptoms of a disease state, the term "alleviation" as used herein refers to reducing at least one of the frequency and spread of the symptoms of the patient's disease state.

[0095] As used herein, the term "treating a depressive disorder" can refer to reducing the symptoms of a depressive disorder, such as major depressive disorder, as measured, for example, by a decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS) score. In some embodiments, the term "treating a depressive disorder" refers to a change from baseline as measured by the MADRS score. In some embodiments, the term "treating a depressive disorder" refers to remission as measured by a decrease in the MADRS score. In some embodiments, the term "treating a depressive disorder" refers to, for example, at least a 50% improvement when the MADRS score is measured. In some embodiments, treating a depressive disorder such as MDD refers to at least a 50% reduction in MDD severity in a standardized assessment scale, such as those disclosed herein, such as the MADRS. The term depressive disorder refers, in particular, to major depressive disorder, such as treatment-resistant depression. The MADRS scale is widely used herein as a scale for measuring depression, but the term "treating a depressive disorder" may also (or alternatively) refer to an improvement in the score of any scale of depression disclosed herein (e.g., the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, the Mini International Neuropsychiatric Interview, the Cambridge Automated Neuropsychological Test Battery, the Digit Symbol Substitution Task, the Affective Bias Task, etc.). In some embodiments, the improvement can be an increase in score if the scale provides a higher score for improvement in depressive assessment criteria. Alternatively, in some embodiments, the improvement in score can be a decrease in score if the scale provides a higher score for intensification of depressive symptoms.

[0096] The terms "treatment refractory" or "treatment resistant depression" or TRD, as used herein, are defined with reference to, for example, the DSM-5 criteria, the entire content of which is incorporated herein by reference. Treatment resistant depression refers to a type of major depressive disorder in which a patient has not responded (e.g., has not responded or has achieved only a partial response) to appropriate dosages of at least one antidepressant, particularly at least two different antidepressants, particularly two antidepressants (but five or less) in the current depressive episode. In other embodiments, TRD is defined as major depressive disorder in patients who have not responded to at least two oral antidepressants at appropriate dosages and durations (e.g., at least 6 weeks) in the current depressive episode. For example, treatment resistant depression can be a depressive disorder that is resistant or non-responsive to one or more antidepressants as described herein, such as, for example, selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), norepinephrine dopamine reuptake inhibitors (NDRI), tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants. The classes of antidepressants listed above are not exhaustive. Treatment resistant depression can be evaluated by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), a self-assessment scale used to determine treatment resistance in major depressive disorder.

[0097] One of ordinary skill in the art will recognize that whether a given antidepressant has failed to respond to appropriate treatment can be determined retrospectively and / or prospectively. In one embodiment, at least one of the failures to respond to appropriate treatment with an antidepressant is determined prospectively. In another embodiment, at least two of the failures to respond to appropriate treatment with an antidepressant are determined prospectively. In another embodiment, at least one of the failures to respond to appropriate treatment with an antidepressant is determined retrospectively. In another embodiment, at least two of the failures to respond to appropriate treatment with an antidepressant are determined retrospectively in the current depressive episode.

[0098] As used herein, the term "therapeutically effective amount" means the amount of an active compound or agent that elicits a biological or pharmaceutical response in a subject (including alleviation of one or more symptoms of the disease or disorder being treated) as desired by a physician or other clinician. In some embodiments of the present disclosure, a therapeutically effective amount of compound (I) is from about 0.1 mg to about 15 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 0.1 mg to about 1 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 0.3 mg to about 1 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 0.5 mg to about 1 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 1 mg to about 5 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 1 mg to about 10 mg. In other embodiments, a therapeutically effective amount of compound (I) is from about 1 mg to about 15 mg. In still other embodiments, a therapeutically effective amount of compound (I) is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mg. In still other embodiments, a therapeutically effective amount of compound (I) is 1 mg. In still other embodiments, a therapeutically effective amount of compound (I) is 4 mg. In still other embodiments, a therapeutically effective amount of compound (I) is 10 mg.

[0099] As used herein, "women of childbearing potential" refers to all women who are physiologically capable of becoming pregnant during the administration of Compound I and for one week after the last treatment, unless they are using a highly effective method of contraception. Highly effective methods of contraception include the following: · Complete abstinence (if this is consistent with the subject's preferred normal lifestyle). Periodic self-control (e.g., calendar method, ovulation method, symptothermal method, post-ovulation method), and withdrawal are not acceptable methods of contraception. · Female tubal ligation, female sterilization (with or without hysterectomy, if the subject has had an oophorectomy), or total hysterectomy at least 6 weeks before the administration of Compound I. In the case of oophorectomy alone, it is limited to the case where the female reproductive status has been confirmed by follow-up evaluation of hormone levels. · Male sterilization (at least 6 months before screening). For female participants in this study, the vasectomized male partner must be the only partner of the participant. · Use of an intrauterine contraceptive device (IUD) or intrauterine contraceptive system (IUS). When using an IUD or IUS, the device or system must be inserted into the patient at least 3 months before taking the test drug and must be well tolerated.

[0100] The use of hormonal contraception by oral (estrogen and progesterone), injection or implant, or other forms of hormonal contraception is not permitted for the purpose of contraception.

[0101] A woman is considered to have amenorrhea and no possibility of pregnancy if she has had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms), or if she has had an oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before treatment with Compound I. In the case of oophorectomy alone, it is considered that there is no possibility of pregnancy only when the female reproductive status has been confirmed by follow-up evaluation of hormone levels.

[0102] As used herein, the term "subject, e.g., patient" refers to a mammalian organism, preferably a human (male or female). In particular, the subject is a patient.

[0103] As used herein, a subject, e.g., a patient "in need of" treatment is when such subject, e.g., patient, would benefit biologically, medically or in terms of quality of life from such treatment.

[0104] The use of any examples or exemplary language (e.g., "such as") provided herein is merely intended to make the invention clearer and is not intended to limit the scope of the invention as otherwise claimed.

[0105] Method for treating depression The present disclosure provides a method for treating major depressive disorder (MDD). The method generally comprises subcutaneously administering a therapeutically effective amount of Compound I to an individual having MDD. In various embodiments, the treatment is combined with one or more antidepressant therapies, such as one or more oral antidepressants.

[0106] In some embodiments, the diagnosis of MDD is confirmed by meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for MDD (based on the Structured Clinical Interview for DSM-5 (SCID-5)). In some embodiments, the subject is characterized by having a Montgomery-Asberg Depression Rating Scale (MADRS) of ≧20, e.g., ≧21, ≧22, ≧23, ≧24, ≧25.

[0107] This specification discloses a method of treating a depressive disorder, such as major depressive disorder, in a patient in need thereof, the method comprising subcutaneously administering to the patient Compound I or a pharmaceutically acceptable salt thereof. The present disclosure also relates to a method of treating treatment-resistant depression in a patient in need thereof, the method comprising subcutaneously administering to the patient Compound I or a pharmaceutically acceptable salt thereof.

[0108] In particular, the present disclosure relates to a method of treating treatment-resistant depression in an adult patient in need thereof, the method comprising subcutaneously administering to the patient a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof in combination with at least one oral antidepressant.

[0109] The present disclosure provides a method of treating depressive symptoms in a subject, such as a patient, having depression, the method comprising subcutaneously administering to the subject, such as a patient, Compound I or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating depressive symptoms in a subject, such as a patient, having major depressive disorder, the method comprising subcutaneously administering to the subject, such as a patient, Compound I or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating depressive symptoms in a subject, such as a patient, having acute suicidal ideation, the method comprising subcutaneously administering to the subject, such as a patient, Compound I or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating depressive symptoms in a subject, such as a patient, having treatment-resistant depression, the method comprising subcutaneously administering to the subject, such as a patient, Compound I or a pharmaceutically acceptable salt thereof.

[0110] The present disclosure also provides a method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously to a subject, such as a patient, to alleviate one or more symptoms associated with a major depressive disorder.

[0112] The methods disclosed herein include administering subcutaneously to a patient a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition. The pharmaceutical composition may include at least one pharmaceutically acceptable excipient. In some embodiments, the methods disclosed herein include administering subcutaneously to a patient a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, whether in the form of a pharmaceutical composition or not.

[0113] In some embodiments, a subject, e.g., a patient, is characterized as having failed antidepressant treatment based on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) (Gregory M Chandler, Dan V Iosifescu, Mark H Pollack, Steven D Targum & Maurizio Fava. Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neuroscience & Therapeutics 16(2010)322-325). In some embodiments, a subject, e.g., a patient, is characterized as having a suboptimal response to at least one antidepressant treatment. For example, the subject has a <50% response to at least one antidepressant treatment (≥8 weeks at an appropriate and stable dose for at least 4 weeks) according to the MGH-ATRQ. In some embodiments, a subject, e.g., a patient, has a single episode major depressive disorder. In some embodiments, a subject, e.g., a patient, has a recurrent major depressive disorder. In some embodiments, a subject, e.g., a patient, has a chronic major depressive disorder. In some embodiments, a subject, e.g., a patient, is characterized as having treatment-resistant depression. In some embodiments, the diagnosis of TRD is confirmed by meeting the DSM-5 criteria for MDD, and the current depressive episode has not responded adequately to at least two different antidepressants at appropriate doses and durations. Typically, the methods disclosed herein further comprise administering to a subject, e.g., a patient, one or more additional antidepressant treatments, such as oral antidepressants.

[0114] In some embodiments, the present disclosure also provides a method of treating a subject, e.g., a patient, having recurrent or chronic depression, such as recurrent or chronic major depressive disorder, comprising administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to a subject, e.g., a patient, in need thereof. In some embodiments, the present disclosure also provides a method of treating a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode that has persisted for at least 8 weeks. In some embodiments, the present disclosure provides a method of treating a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode that has persisted for at least 8 weeks, wherein the subject, e.g., the patient, is treatment resistant.

[0115] In some embodiments, the present disclosure also provides a method of treating a subject, e.g., a patient, meeting the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), comprising administering subcutaneously to the subject, e.g., the patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject, e.g., the patient, has failed >1 and <8 trials in the current episode for the MGH ATRQ and / or has <50% response to current antidepressant treatment (for a major depressive episode of ≧8 weeks at an appropriate and stable dose for at least 4 weeks) for the MGH ATRQ.

[0116] In some embodiments, the subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof is used in an outpatient population of subjects, e.g., patients, with depression considered treatment resistant. The methods disclosed herein advantageously eliminate the need for the patient to go to a hospital or clinic for subcutaneous administration. As a result, a subject, e.g., a patient, can receive administration of a composition comprising compound (I) or a pharmaceutically acceptable salt thereof at home. In some embodiments, the methods disclosed herein do not require intensive monitoring of a subject, e.g., a patient, in a medically managed healthcare environment.

[0117] The dosage and dosing regimen include any of those described herein in any combination, for example, any of those described in the dosage and administration section. For example, in some preferred embodiments, the methods disclosed herein include subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof as a single subcutaneous injection to a subject, such as a patient. Each dose administered is such that compound (I) or a pharmaceutically acceptable salt thereof is in the range of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0118] In various embodiments, the present disclosure provides a method of subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, the method comprising selecting a subject, such as a patient, suffering from a depressive disorder.

[0119] In various embodiments, the present disclosure provides a method of subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject, such as a patient, has been or is diagnosed as having a depressive disorder.

[0120] In various embodiments, provided herein is a method of treating a depressive disorder in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof. As disclosed elsewhere herein, in some embodiments, the method comprises administering a dose of compound (I) of about 1 mg or less, about 2.5 mg or less, about 5 mg or less, about 7.5 mg or less, about 10 mg or less, about 12.5 mg or less, about 15 mg or less, or a range of doses including and / or spanning the foregoing values. For example, in some embodiments, the method comprises administering a dose of compound (I) in the range of 1 mg to 5 mg, 5 mg to 15 mg, 1 mg to 12.5 mg, or less than 15 mg. In some embodiments, the subject in need of treatment is a subject having a depressive disorder.

[0121] In various embodiments, provided herein is a method of treating a depressive disorder in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof and comprising selecting a subject, such as a patient, suffering from a depressive disorder.

[0122] In various embodiments, provided herein is a method of treating a depressive disorder in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, has been diagnosed as having or is diagnosed with a depressive disorder.

[0123] In certain embodiments, a method of treating a depressive disorder in a subject, such as a patient, in need thereof, comprising selecting a subject, such as a patient, suffering from a depressive disorder; and subcutaneously administering from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof, is provided herein.

[0124] In certain embodiments, a method of treating a depressive disorder in a subject, such as a patient, in need thereof, comprising subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, has been diagnosed as having or is diagnosed with a depressive disorder and compound (I) or a pharmaceutically acceptable salt thereof is subcutaneously administered in a dose of from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, is provided herein.

[0125] In some embodiments, as disclosed elsewhere herein, the depressive disorder is major depressive disorder. In certain embodiments, a method of treating major depressive disorder in a subject, such as a patient, in need thereof, comprising selecting a subject, such as a patient, suffering from major depressive disorder; and subcutaneously administering from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof, is provided herein.

[0126] In some embodiments, as disclosed elsewhere herein, the mood disorder is a major depressive disorder. In certain embodiments, a method of treating major depressive disorder in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, has been diagnosed or is diagnosed as having major depressive disorder; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof is provided herein.

[0127] In some embodiments, as disclosed elsewhere herein, the mood disorder is treatment-resistant depression. In certain embodiments, a method of treating treatment-resistant depression in a subject, such as a patient, in need thereof, comprising selecting a subject, such as a patient, suffering from treatment-resistant depression; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof is provided herein.

[0128] In some embodiments, as disclosed elsewhere herein, the mood disorder is treatment-resistant depression. In certain embodiments, a method of treating treatment-resistant depression in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, has been diagnosed or is diagnosed as having treatment-resistant depression; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof is provided herein.

[0129] In some embodiments, as disclosed elsewhere herein, the depressive disorder is treatment-resistant depression. In certain embodiments, a method of treating treatment-resistant depression in a subject, such as a patient, having a major depressive disorder, comprising administering subcutaneously a therapeutically effective amount, such as from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof is provided herein.

[0130] In various embodiments, a method of treating a subject, such as a patient, in need of long-term treatment of a depressive disorder, comprising administering subcutaneously to the subject, such as a patient, in need thereof, compound (I) or a pharmaceutically acceptable salt thereof in a dose of from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg is provided herein. In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in a regimen of at least 6 months, such as at least 1 year, up to 2 years.

[0131] In various embodiments, the present disclosure provides a method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0132] In various embodiments, the present disclosure provides a method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, comprising administering subcutaneously to the subject, such as a patient, compound (I) or a pharmaceutically acceptable salt thereof in a dose of from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

[0133] In various embodiments, the present disclosure provides a method for reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the subject, such as a patient, has not responded adequately to two or more antidepressant treatments prior to administration of compound (I) or a pharmaceutically acceptable salt thereof. In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0134] In various embodiments, the present disclosure provides a method for reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the subject, such as a patient, has been diagnosed or is diagnosed as having a depressive disorder. In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0135] In various embodiments, as disclosed elsewhere herein, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, or any combination of the foregoing. In certain embodiments, the depressive disorder is major depressive disorder. In another particular embodiment, the depressive disorder is treatment-resistant depression. In one embodiment, the major depressive disorder comprises a single major depressive episode. In one embodiment, the major depressive disorder comprises recurrent major depressive episodes.

[0136] In various embodiments, as disclosed elsewhere herein, a subject, such as a patient, is suffering from an episode of depression, such as a major depressive episode, and this episode of depression, such as a major depressive episode, is not responsive to treatment with at least one antidepressant, i.e., the subject, such as a patient, is not responsive to treatment with at least one antidepressant in the current major depressive episode. In one embodiment, the at least one antidepressant is an oral antidepressant. The antidepressant can be determined by the attending physician and / or can be administered to the patient in a suitable dosage that can be administered at the dosage described on its label. Similarly, the antidepressant has been administered for a suitable period, such as the period specified on its label. In one embodiment, the antidepressant has been administered for at least 4 weeks, such as at least 6 weeks.

[0137] In various embodiments, a subject, such as a patient, is suffering from an episode of depression, such as a major depressive episode, and this episode of depression, such as a major depressive episode, is not responsive to treatment with at least two antidepressants, i.e., the subject, such as a patient, is not responsive to treatment with at least two antidepressants in the current major depressive episode. In one embodiment, at least one of the at least two antidepressants is an oral antidepressant. The antidepressant can be determined by the attending physician and / or can be administered to the patient in a suitable dosage that can be administered at the dosage described on its label. Similarly, the antidepressant has been administered for a suitable period, such as the period specified on its label. In one embodiment, the antidepressant has been administered for at least 4 weeks, such as at least 6 weeks.

[0138] In certain embodiments, the present disclosure provides a method of reducing at least one depressive symptom in a subject, such as a patient, in need thereof, the method comprising selecting a subject, such as a patient, suffering from major depressive disorder; and subcutaneously administering from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the present disclosure provides a method of treating at least one depressive symptom in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, is diagnosed or diagnosed as having major depressive disorder; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the present disclosure provides a method of treating at least one depressive symptom in a subject, such as a patient, in need thereof, comprising selecting a subject, such as a patient, suffering from treatment-resistant depression; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the present disclosure provides a method of treating at least one depressive symptom in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, is diagnosed or diagnosed as having major depressive disorder; and administering subcutaneously from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0142] In various embodiments, the present disclosure provides a method for treating major depressive disorder, such as treatment-resistant depression, comprising administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to a subject in need thereof, such as a patient; wherein the subject in need thereof, such as a patient, has a major depressive episode and the subject in need thereof, such as a patient, has not responded to at least one antidepressant in the current major depressive episode.

[0143] In various embodiments, the present disclosure provides a method of treating a depressive disorder, such as a major depressive disorder, such as treatment-resistant depression, in a subject in need thereof, such as a patient: (a) determining or having determined a baseline MADRS score of the subject, such as a patient; (b) administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is such that the MADRS score is improved (e.g., decreased) by at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to the measured baseline MADRS score (wherein the baseline is the MADRS total score of the subject, such as a patient, prior to subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof); and optionally (c) re-evaluating the subject, such as a patient, at regular intervals after step (b) to determine relative efficacy (wherein the re-evaluation includes measuring the MADRS score of the subject, such as a patient) comprising the method.

[0144] In various embodiments, the methods disclosed herein further include regularly evaluating a subject, such as a patient, to obtain evidence of treatment efficacy to determine the need for continued treatment after treatment with compound (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject, such as a patient, is evaluated at about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks after treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0145] In various embodiments, the present disclosure provides a method of treating a major depressive disorder in a subject, such as a patient, in need thereof, where the patient has not responded to at least one, such as at least two, antidepressants in the current major depressive episode, comprising administering a first antidepressant to the subject, such as a patient, for at least 4 weeks, such as at least 6 weeks, and then subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to the patient, and optionally continuing treatment with the first antidepressant.

[0146] In various embodiments, the present disclosure provides a method of treating treatment-resistant depression in a subject, such as a patient, in need thereof, where the patient has not responded to at least one, such as at least two, antidepressants in the current major depressive episode, comprising administering a first antidepressant to the patient for at least 4 weeks, such as at least 6 weeks, and then subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to the patient, and optionally continuing treatment with the first antidepressant.

[0147] In various embodiments, the treatment method further includes determining or having determined the MADRS total score, and thereby evaluating the effectiveness of the treatment, compared to a baseline evaluation, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, such as 24 hours, 7, 14, 21, and / or 28 days later (where the baseline is the MADRS total score of the subject, such as a patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof).

[0148] In various embodiments, a subject, such as a patient, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, has a decreased MADRS total score as compared to a baseline assessment. For example, the subject, such as a patient, after 24 hours, 7 days, 14 days, 21 days, and / or 28 days of subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment, has a decreased MADRS total score as compared to the baseline assessment.

[0149] In various embodiments, a subject, such as a patient, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, has a MADRS total score that is improved (e.g., decreased) by more than 30%, such as more than 35%, more than 40%, more than 45%, more than 50%, particularly more than 50% as compared to a baseline assessment. For example, the subject, such as a patient, after 24 hours, 7 days, 14 days, 21 days, and / or 28 days of subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, has a MADRS total score that is improved by more than 30%, such as more than 35%, more than 40%, more than 45%, more than 50%, particularly more than 50% as compared to the baseline assessment.

[0150] In various embodiments, a subject, such as a patient, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, has a MADRS total score of less than 12, such as less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5 as compared to a baseline assessment. For example, the subject, such as a patient, after 24 hours, 7, 14, 21, and / or 28 days of subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, has a MADRS total score of less than 12, such as less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5 as compared to the baseline assessment.

[0151] In various embodiments, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, a subject (e.g., a patient) has a decrease in the MADRS total score of about 30 points, about 25 points, about 20 points, about 15 points, about 10 points, about 5 points (or a range spanning and / or including the aforementioned values) or more compared to the baseline assessment. In various embodiments, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, a subject (e.g., a patient) has a MADRS total score that is about 30 points, about 25 points, about 20 points, about 15 points, about 10 points, about 5 points (or a range spanning and / or including the aforementioned values) or less compared to the baseline assessment. In some embodiments, the MADRS score after treatment is evaluated 24 hours, 7 days, 14 days, 21 days, and / or 28 days after the first subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0152] In various embodiments, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, a subject (e.g., a patient) has an improvement (e.g., an increase or decrease in some cases) in the score of a depression scale disclosed herein (e.g., Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, Mini International Neuropsychiatric Interview, Cambridge Automated Neuropsychological Test Battery, Digit Symbol Substitution Task, Affective Bias Task, etc.) of about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 100% or more (or a range spanning and / or including the aforementioned values) compared to the baseline assessment. In some embodiments, the score after treatment is evaluated 24 hours, 7 days, 14 days, 21 days, and / or 28 days after the first subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0153] In various embodiments, a subject, such as a patient, does not have a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder.

[0154] In various embodiments, a subject, such as a patient, is between 18 and 65 years old and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0155] In various embodiments, a subject, such as a patient, does not have an acute depressive episode that lasts longer than 2 years and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0156] In various embodiments, a subject, such as a patient, does not have an acute alcohol disorder or a substance use disorder or withdrawal symptoms that require detoxification and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0157] In various embodiments, a subject, such as a patient, does not have a borderline personality disorder or an antisocial personality disorder and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0158] In various embodiments, a subject, such as a patient, does not have a clinical diagnosis of autism, dementia, or intellectual disability, and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, or self-harm in major depressive disorder.

[0159] In various embodiments, a subject, such as a patient, does not have a history of suicide attempt or suicidal behavior, and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, or self-harm in major depressive disorder.

[0160] In various embodiments, a subject, such as a patient, is neither pregnant nor lactating, and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, or self-harm in major depressive disorder.

[0161] In various embodiments, a subject, such as a patient, does not have a history of active HIV, COVID-19, and hepatitis B or C infection, and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, or self-harm in major depressive disorder.

[0162] In various embodiments, a subject, such as a patient, does not have a resting QTcF of ≥ 450 milliseconds (male) or ≥ 460 milliseconds (female), and has a depressive disorder, such as major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, or self-harm in major depressive disorder.

[0163] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 15 mg.

[0164] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 1 mg.

[0165] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg to about 1 mg.

[0166] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 1 mg.

[0167] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg.

[0168] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg.

[0169] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 10 mg.

[0170] In various embodiments, compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or about 15 mg.

[0171] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0172] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0173] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0174] Advantageously, the compound (I) or a pharmaceutically acceptable salt thereof can be administered once as a single dose.

[0175] In any embodiment of the methods disclosed herein, the compound (I) is administered as the free base.

[0176] In various embodiments, the present disclosure provides a method of subcutaneously administering the compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, the method comprising selecting a subject, such as a patient, suffering from a depressive disorder; and subcutaneously administering about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg of the compound (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder.

[0177] In various embodiments, the present disclosure provides a method of subcutaneously administering the compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, in need of treatment is a person diagnosed or to be diagnosed as having a depressive disorder, and the compound (I) or a pharmaceutically acceptable salt thereof is subcutaneously administered at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0178] In various embodiments, the present disclosure provides a method of subcutaneously administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, e.g., a patient, wherein the subject in need of treatment, e.g., the patient, is suffering from a major depressive episode and the subject in need of treatment, e.g., the patient, has not responded to at least one antidepressant treatment in the current major depressive episode.

[0179] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, e.g., a patient, wherein the subject in need of treatment, e.g., the patient, is suffering from a depressive disorder and does not have a major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features. In one embodiment, the subject in need of treatment, e.g., the patient, is diagnosed or to be diagnosed as having a major depressive disorder.

[0180] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, e.g., a patient, wherein the subject in need of treatment, e.g., the patient, is suffering from a depressive disorder and does not have an acute depressive episode that lasts longer than two years. In one embodiment, the subject in need of treatment, e.g., the patient, is diagnosed or to be diagnosed as having a major depressive disorder.

[0181] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, e.g., a patient, wherein the subject in need of treatment, e.g., the patient, is suffering from a depressive disorder and does not have an acute alcohol disorder or substance use disorder or withdrawal symptoms requiring detoxification. In one embodiment, the subject in need of treatment, e.g., the patient, is diagnosed or to be diagnosed as having a major depressive disorder.

[0182] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, wherein the subject in need of treatment, such as a patient, suffers from a depressive disorder and does not have borderline personality disorder or antisocial personality disorder. In one embodiment, the subject in need of treatment, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder.

[0183] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, wherein the subject, such as a patient, suffers from a depressive disorder and does not have a clinical diagnosis of autism, dementia, or intellectual disability. In one embodiment, the subject in need of treatment, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder.

[0184] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, wherein the subject, such as a patient, suffers from a depressive disorder and does not have a history of suicide attempt or suicidal behavior. In one embodiment, the subject in need of treatment, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder.

[0185] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, wherein the subject, such as a patient, suffers from a depressive disorder and is neither pregnant nor lactating. In one embodiment, the subject in need of treatment, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder.

[0186] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, suffers from a depressive disorder and has no history of active HIV, COVID-19, and hepatitis B or C infection. In one embodiment, the subject, such as a patient, in need of treatment is a person diagnosed with or being diagnosed with major depressive disorder.

[0187] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, suffers from a depressive disorder and has a resting QTcF of less than 450 milliseconds (for males) or less than 460 milliseconds (for females). In one embodiment, the subject, such as a patient, in need of treatment is a person diagnosed with or being diagnosed with major depressive disorder.

[0188] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, suffers from a depressive disorder and does not have a mean systolic blood pressure > 140 mmHg or a mean diastolic blood pressure > 90 mmHg. In some embodiments, after subcutaneous administration of compound (I), the patient's blood pressure does not increase to a mean systolic blood pressure > 140 mmHg or a diastolic blood pressure > 90 mmHg.

[0189] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, wherein the subject, such as a patient, suffers from a depressive disorder and is not pregnant.

[0190] In various embodiments, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, and / or any combination thereof. In certain embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

[0191] In some embodiments, as disclosed elsewhere herein, the reduction of depressive symptoms and / or depressive disorders by compound (I) is measured using any one or more of the test conditions provided herein (including those provided in the Examples section below) as disclosed elsewhere herein. In some embodiments, the reduction of depressive symptoms and / or depressive disorders is measured by self-report, the Montgomery-Åsberg Depression Rating Scale (MADRS), the Mini International Neuropsychiatric Interview (M.I.N.I.), e.g., version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia-Suicide Severity Rating Scale (C-SSRS), the Clinical Global Impression (CGI), or a single criterion for depression (e.g., a symptom) reported on the scales described above. In some embodiments, the reduction of depressive symptoms and / or depressive disorders is a reduction of about 50% or at least about 50% of the scales, criteria (e.g., any one or more criteria of the MADRS scale) or symptoms described above. In some embodiments, the reduction of depressive symptoms and / or depressive disorders is a reduction (from baseline) of the scales, criteria or symptoms described above, which is a reduction of about 10% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 100% or more, or a range including and / or spanning the values described above. In some embodiments, the reduction of depressive symptoms and / or depressive disorders is measured about 24 hours or more, about 7 days or more, about 14 days or more, about 21 days or more and / or about 28 days or more after subcutaneous administration of compound (I). In some embodiments, the reduction of depressive symptoms and / or depressive disorders can be measured as an improvement in the score of a positive outcome (such as an improvement in mood).

[0192] In some embodiments, CADSS, MOAA / S, and AAESI are used to demonstrate the safety of administration of compound (I). CADSS is a questionnaire for evaluating dissociative effects. Each item is scored from 0 to 4, and the individual scores are summed to obtain a total score ranging from a minimum of 0 to a maximum of 92. Trained staff who administer the scale also note the subjective interpretation of the participant's mental state and overall health, and whether any findings may be related to the test drug. MOAA / S is a scale from 0 (= does not respond to compression of the orbicularis oculi muscle with pain) to 5 (= responds immediately when called by name in a normal tone of voice [when awake]) and is used to evaluate the responsiveness of participants. Memory lapses / forgetfulness are AEs (AESI) that deserve particular attention. Memory assessment using recognition questions is evaluated by qualified individuals. In some embodiments, the patient safety scores before and after administration vary by about 10% or less, about 20% or less, about 30% or less, about 40% or less, or a range that includes and / or spans the aforementioned values.

[0193] In some embodiments, the patient population is selected based on classification of the participants' CYP2D6 metabolic phenotypes and / or CYP3A4 metabolic phenotypes. In some embodiments, patients taking a CYP2D6 inhibitor or patients with reduced CYP2D6 activity are excluded from the patient population. In some embodiments, patients taking a CYP3A4 inhibitor or patients with reduced CYP3A4 activity are excluded from the patient population.

[0194] In some embodiments, the local tolerability of subcutaneous injection is high (and injection of compound (I) results in a low incidence of lesions, low malignancy, or mild symptoms according to the aforementioned evaluation criteria). In some embodiments, subcutaneous injection of compound (I) results in mild to moderate AEs in patients or no AEs at all.

[0195] All of the foregoing embodiments and the following embodiments related to the method of treatment are equally applicable hereinafter: Compound (I) or a pharmaceutically acceptable salt thereof for use in a treatment method according to the present disclosure; Use of compound (I) or a pharmaceutically acceptable salt thereof in a treatment method according to the present disclosure; A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in a treatment method according to the present disclosure; and Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof in a treatment method according to the present disclosure.

[0196] Administration and Dosage In some embodiments, methods are provided herein for subcutaneous administration of a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof. In the context of the present disclosure, the dosage refers to the free base of compound (I). In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, as a fixed dose.

[0197] In various embodiments, methods are provided herein that include administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered as a fixed dose. In various embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is calculated based on the body weight of the patient. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg to about 0.32 mg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg per kg of the patient's body weight.

[0198] In various embodiments, the present disclosure provides methods for subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, in a dosage of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0199] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, at a dose of about 1 mg to about 15 mg, such as about 1 mg to about 10 mg. In some embodiments, the method comprises subcutaneously administering compound (I) at a dose of about 1 mg or less, about 2.5 mg or less, about 5 mg or less, about 7.5 mg or less, about 10 mg or less, about 12.5 mg or less, about 15 mg or less, or a dose within a range that includes and / or spans the foregoing values. For example, in some embodiments, the method comprises administering compound (I) at a dose within the range of 1 mg to 5 mg, 5 mg to 15 mg, 1 mg to 10 mg, 5 mg to 15 mg, 1 mg to 12.5 mg, or less than 15 mg. In some embodiments, the subject in need of treatment is a subject having a depressive disorder.

[0200] In various embodiments, as disclosed elsewhere herein, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg. In various embodiments, as disclosed elsewhere herein, compound (I) or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a dose of about 1 mg to about 15 mg.

[0201] In various embodiments, as disclosed elsewhere herein, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 10 mg. In various embodiments, as disclosed elsewhere herein, compound (I) or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a dose of about 1 mg to about 10 mg.

[0202] In various embodiments, the compound (I), or a pharmaceutically acceptable salt thereof, is administered by subcutaneous injection at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or about 15 mg.

[0203] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0204] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0205] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0206] In various embodiments, the method comprises subcutaneously administering the compound (I) or a pharmaceutically acceptable salt thereof as a single subcutaneous injection.

[0207] In various embodiments, the method comprises subcutaneously administering the compound (I) or a pharmaceutically acceptable salt thereof in the upper arm or abdominal region.

[0208] In various embodiments, the present disclosure provides a method of subcutaneously administering the compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, the method comprising selecting a subject, such as a patient, suffering from a treatment-resistant disorder; and subcutaneously administering about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg of the compound (I) or a pharmaceutically acceptable salt thereof.

[0209] In certain embodiments, the present disclosure provides a method of treating treatment-resistant depression, the method comprising administering compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient (wherein the subject, such as the patient, is diagnosed or to be diagnosed as having treatment-resistant depression), in a dose of from about 0.1 mg to about 15 mg, such as from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

[0210] In various embodiments, compound (I) is administered as the free base.

[0211] Administration schedule In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered as a single dose without repetition. In some embodiments, compound (I) is administered according to an administration schedule. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered once a week. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered twice a week. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered about once or less, about twice or less, about three times or less, about four times or less, about five times or less, about six times or less, about seven times or less per week, or in a range including and / or spanning the foregoing values. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered once every three weeks. In still other embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered once a month. In still other embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered once every six weeks. In various embodiments, the dose of compound (I) or a pharmaceutically acceptable salt thereof is administered once or more per week, once or more every two weeks, once or more every three weeks, once or more every four weeks, once or more every six weeks, once or more every eight weeks, or over a period in a range including and / or spanning the foregoing values.

[0212] In various embodiments, treatment with compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, or at least about 2 years. In some embodiments, treatment with compound (I) or a pharmaceutically acceptable salt thereof continues for about 2 weeks or more, about 3 weeks or more, about 4 weeks or more, about 5 weeks or more, about 6 weeks or more, about 7 weeks or more, about 8 weeks or more, about 9 weeks or more, about 10 weeks or more, about 11 weeks or more, about 12 weeks or more, about 13 weeks or more, about 14 weeks or more, about 15 weeks or more, about 16 weeks or more, about 17 weeks or more, about 18 weeks or more, about 19 weeks or more, about 20 weeks or more, about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, about 10 months or more, about 11 months or more, about 1 year or more, about 2 years or more, or a range that includes and / or spans the aforementioned values.

[0213] Package or pharmaceutical In further particular embodiments, the disclosure further relates to a package or pharmaceutical as described herein, wherein compound (I) is specifically the free base. In further embodiments of the package or pharmaceutical as described herein, the treatment instructions direct administration of compound (I) or a pharmaceutically acceptable salt thereof at about 0.1 mg and about 15 mg, for example, administration of compound (I) or a pharmaceutically acceptable salt thereof at about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0214] In a further embodiment of the package or pharmaceutical described herein, the treatment instructions direct administration of compound (I) or a pharmaceutically acceptable salt thereof at about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg or 15 mg.

[0215] In yet a further embodiment of the package or pharmaceutical described herein, the treatment instructions direct subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. Further, in a further specific embodiment of the package or pharmaceutical described herein, the treatment instructions direct administration of compound (I) or a pharmaceutically acceptable salt thereof once every two weeks, once every three weeks, once a month, or once every six weeks.

[0216] Subjects suitable for treatment The methods of the present disclosure are suitable for the treatment of individuals diagnosed with major depressive disorder. The methods of the present disclosure are particularly suitable for the treatment of individuals diagnosed with treatment-resistant or treatment-refractory depression. Subjects particularly suitable for treatment by the methods according to the present disclosure are those who have not responded to at least two conventional antidepressants. Also suitable for treatment are subjects who have not responded to more than two (not more than five) previous antidepressant treatments (where the two non-responsive treatments are treatments with two different antidepressants at appropriate doses and durations (e.g., ≧ 6 weeks) as identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ)). Also suitable for treatment are subjects who have a partial response to at least one antidepressant. Also suitable for treatment are subjects with a response of < 50% to at least one antidepressant treatment (for at least 4 weeks, at an appropriate and stable dose, lasting ≧ 8 weeks) according to the MGH-ATRQ.

[0217] The methods of the present disclosure are also suitable for subjects having major depressive disorder (MDD) and a current major depressive episode with a duration of at least 8 weeks, as defined, for example, by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The diagnosis can be further confirmed by both SCID-5 and clinical psychiatric evaluation.

[0218] In various embodiments, the individual is at risk of suicide.

[0219] In various embodiments, the individual is resistant to (e.g., non-responsive or having a negative response to) at least one antidepressant other than compound (I) or a pharmaceutically acceptable salt thereof. In still other embodiments, the individual partially responds to at least one antidepressant other than compound (I) or a pharmaceutically acceptable salt thereof.

[0220] In various embodiments, the subject, e.g., a patient, is characterized as having treatment-resistant or treatment-refractory depression. In various embodiments, the subject, e.g., a patient, is characterized as having treatment-resistant or treatment-refractory depression and is at risk of suicide.

[0221] In various embodiments, the subject, e.g., a patient, has a MADRS score of at least 20, e.g., at least 21, at least 22, at least 23, at least 24 at baseline.

[0222] In various embodiments, the subject, e.g., a patient, is between 18 and 65 years of age.

[0223] In various embodiments, the subject, e.g., a patient, has no history of treatment failure with esketamine, ketamine, or arketamine.

[0224] In various embodiments, a subject, such as a patient, is suffering from an episode of depression, such as a major depressive episode, and this episode of depression, such as a major depressive episode, has not responded to treatment with at least one antidepressant (e.g., a conventional antidepressant), i.e., the subject, such as the patient, has not responded to treatment with at least one antidepressant in the current major depressive episode. In one embodiment, the at least one antidepressant is an oral antidepressant. The antidepressant can be determined by the attending physician and / or can be administered to the patient in an appropriate dosage that can be administered at the dosage described on its label. Similarly, the antidepressant has been administered for a suitable period, e.g., the period specified on its label. In one embodiment, the antidepressant has been administered for at least 4 weeks, e.g., at least 6 weeks.

[0225] In various embodiments, a subject, such as a patient, is suffering from an episode of depression, such as a major depressive episode, and this episode of depression, such as a major depressive episode, has not responded to treatment with at least two antidepressants (e.g., one or more of which can be a conventional antidepressant), i.e., the subject, such as the patient, has not responded to treatment with at least two antidepressants in the current major depressive episode. In one embodiment, at least one of the at least two antidepressants is an oral antidepressant. The antidepressant can be determined by the attending physician and / or can be administered to the patient in an appropriate dosage that can be administered at the dosage described on its label. Similarly, the antidepressant has been administered for a suitable period, e.g., the period specified on its label. In one embodiment, the antidepressant has been administered for at least 4 weeks, e.g., at least 6 weeks.

[0226] In various embodiments, the subject, such as the patient, is male or female.

[0227] In various embodiments, the subject, such as the patient, does not have an acute depressive episode that has persisted for more than 2 years.

[0228] In various embodiments, a subject, such as a patient, has not received electroshock therapy during the current depressive episode or within one year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0229] In various embodiments, a subject, such as a patient, has not received transcranial magnetic stimulation therapy during the current depressive episode or within one year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0230] In various embodiments, a subject, such as a patient, has not received vagus nerve stimulation therapy during the current depressive episode or within one year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0231] In various embodiments, a subject, such as a patient, has not received deep brain stimulation therapy during the current depressive episode or within one year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0232] In various embodiments, a subject, such as a patient, has never received a diagnosis of major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features, as determined, for example, by SCID-5, either previously or currently.

[0233] In various embodiments, a subject, such as a patient, does not have an acute alcohol disorder or substance use disorder requiring detoxification or withdrawal symptoms.

[0234] In various embodiments, a subject, such as a patient, has not received detoxification treatment within one month prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0235] In various embodiments, a subject, such as a patient, does not have borderline personality disorder or antisocial personality disorder, for example, based on DSM-5 criteria.

[0236] In various embodiments, a subject, such as a patient, has not received a clinical diagnosis of autism, dementia, or intellectual disability.

[0237] In various embodiments, the subject, e.g., a patient, does not have a history of suicide attempt or suicidal behavior within one year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0238] In various embodiments, the subject, e.g., a patient, does not exhibit suicidal ideation with intent, as determined by the CSSRS, e.g., by a positive response to Q4 or Q5 at baseline.

[0239] In various embodiments, the subject, e.g., a patient, does not show evidence of severe renal impairment as indicated by an estimated glomerular filtration rate (eGFR) of <40 mL / min / 1.73m 2 at baseline.

[0240] In various embodiments, the subject, e.g., a patient, does not have a history of hypersensitivity to compound (I) or a pharmaceutically acceptable salt thereof, or a drug having a similar mechanism of action, i.e., a drug that affects the NMDA receptor.

[0241] In various embodiments, the subject, e.g., a patient, does not have active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

[0242] In various embodiments, the subject, e.g., a patient, does not have a history of seizures, except for febrile seizures in children.

[0243] In various embodiments, the subject, e.g., a patient, does not have any of the following cardiac or cardiac repolarization abnormalities: a) A history of myocardial infarction, angina pectoris, or coronary artery bypass graft within six months prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, b) A history of clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, advanced atrioventricular (AV) block (e.g., 2 bundle branch block, Mobitz type II third-degree AV block) within six months prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof.

[0244] In various embodiments, a subject, such as a patient, does not have a baseline resting QTcF of ≧450 milliseconds (for males) or ≧460 milliseconds (for females).

[0245] In various embodiments, a subject, such as a patient, does not present any of the following: a risk factor for torsades de pointes (TdP) including untreated hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or a) a family history of QT prolongation syndrome, idiopathic sudden death, or congenital QT prolongation syndrome, b) a concomitant medicine with a "known risk of TdP" that cannot be discontinued or replaced with a safe alternative.

[0246] In various embodiments, a subject, such as a patient, does not have a baseline mean systolic blood pressure >140 mmHg or a mean diastolic blood pressure >90 mmHg; or does not have a past history of hypertensive crisis.

[0247] In various embodiments, a subject, such as a patient, does not have a history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other locations (e.g., aorta).

[0248] In some embodiments, a subject, such as a patient, is not a pregnant woman or a nursing (lactating) female.

[0249] In some embodiments, a subject, such as a patient, is not a potentially pregnant female who is not using an effective method of contraception.

[0250] In some embodiments, a subject, such as a patient, is not a sexually active male who does not wish to use a condom during intercourse while being administered Compound I or a pharmaceutically acceptable salt thereof and for one week after discontinuation of the dosing treatment with Compound I or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, a subject, such as a patient, is not administered any of the following agents defined in Table 1 during treatment with Compound I or a pharmaceutically acceptable salt thereof:

[0252] [Table 3]

[0253] Response evaluation criteria Several scales are known in the art that can be used to diagnose or monitor patients with MDD. Examples of these scales include, but are not limited to, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Montgomery-Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) scale, the Clinical Global Impression-Improvement (CGI-I) scale, the Patient Global Impression of Change (PGIC), the Structured Clinical Interview for DSM-5 (SCID-5), the Columbia Suicide Severity Rating Scale (C-SSRS), the Hamilton Depression Rating Scale (HAM-D), and the Mini International Neuropsychiatric Interview (M.I.N.I.).

[0254] Improvement of an index or scale known in the art, such as those described below, indicates that Compound (I) is effective in the treatment of MDD. Such improvement can be determined by comparing the pre-treatment and post-treatment scores of a subject, such as a patient, with MDD.

[0255] Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) In various embodiments, the MGH-ATRQ is utilized to diagnose and / or monitor a patient's depression. The MGH-ATRQ examines the appropriateness of past and current antidepressant treatment durations and dosages in a stepwise procedure (Chandler 2010). When evaluating the antidepressant administration duration and dosage, the investigator must always question compliance with each treatment. Additionally, the MGH-ATRQ evaluates the degree of improvement on a scale from 0% (no improvement at all) to 100% (completely improved).

[0256] Montgomery-Åsberg Depression Rating Scale (MADRS) In some embodiments, the MADRS is utilized to diagnose and / or monitor a patient. The Montgomery-Åsberg Depression Rating Scale (MADRS, SIGMA version) is a clinician-rated scale designed to measure the severity of depressive disorders and detect changes due to antidepressant treatment: the examination consists of 10 items, each scored from 0 (the item is absent or normal) to 6 (severe or persistent symptoms are present), and the total score is 60. The higher the score, the more severe the condition. The MADRS evaluates outward sadness, reported sadness, inner tension, sleep, appetite, concentration, fatigue, level of interest, pessimistic thoughts, and suicidal thoughts.

[0257] In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of depressive disorders as disclosed herein, for example, and the treatment of depression is determined by improvement in the total MADRS score of a subject, such as a patient.

[0258] Hamilton Depression Rating Scale (HAM-D) In some embodiments, the HAM-D is utilized to diagnose and / or monitor a patient. The Hamilton Depression Rating Scale (HAM-D) (Journal of Neurology Neurosurgery and Psychiatry 23:56-62, 1960) is incorporated herein by reference. The 24-item HAM-D questionnaire is used to evaluate the severity of a patient's depression and the effectiveness of antidepressant therapy. The HAM-D score is generally interpreted as follows: very severe, >23; severe, 19-22; moderate, 14-18; mild, 8-13; and no depression, 0-7. Response to treatment can be defined as a patient with a ≥50% decrease in the HAM-D score. Remission is defined as a HAM-D score of ≤7.

[0259] Clinical Global Impression-Severity (CGI-S) In some embodiments, the CGI-S is utilized to diagnose and / or monitor a patient. The CGI-S (Guy 1976) is a clinician-rated scale that measures the overall severity of a patient's disease in comparison to the severity of other patients observed by the clinician. The patient is rated on a scale of 1-7, where 1 indicates "normal" and 7 indicates "the most severely ill patient". The CGI-S is administered by an investigator, sub-investigator, or rater who has extensive specialized training and experience in the evaluation of mental disorders.

[0260] In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of a depressive disorder as disclosed herein, for example, and treatment of the depression is determined by improvement in the CGI-S score of a subject, such as a patient.

[0261] Clinical Global Impression-Improvement (CGI-I) In some embodiments, CGI-I is utilized to diagnose and / or monitor patients. The Clinical Global Impression - Improvement (CGI-I) scale (Guy 1976) is a clinician - rated scale used to assess the overall improvement or worsening of a mental disorder, regardless of whether the treating physician considered it to be a result of drug treatment. Patients are rated on a scale of 1 - 7, where 1 indicates that the patient has improved significantly and 7 indicates that the patient has worsened significantly.

[0262] In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of depressive disorders, such as those disclosed herein, and the treatment of depression is determined by improvement in the CGI-I score of a subject, such as a patient.

[0263] Patient Global Impression of Change (PGIC) In some embodiments, PGIC is utilized to diagnose and / or monitor patients. The PGIC scale is intended to quantify disease activity compared to baseline. Participants are asked to calculate the difference between their current and previous health status based on a Likert scale. The PGIC includes multiple items that demonstrate optimal patient preference, discriminative ability, and test - retest reliability, tailored to specific pathologies and disease parameters.

[0264] Structured Clinical Interview for DSM - 5 SCID - 5 In various embodiments, SCID - 5 is utilized to diagnose and / or monitor a patient's depression. SCID - 5 is a semi - structured interview guide for making primary DSM - 5 diagnoses (formerly diagnosed on Axis I). This clinician - rated diagnosis is performed by a principal investigator, study sub - investigator, or evaluator with extensive specialized training and experience in the diagnosis of mental disorders.

[0265] Pharmaceutical composition In some embodiments, a pharmaceutical composition comprising compound (I) is provided. In some embodiments, the pharmaceutical formulation is suitable for administration to a subject in need of treatment. In some embodiments, the pharmaceutical composition of the present disclosure suitable for subcutaneous administration comprises compound (I) combined with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, antioxidants, buffers, bacteriostatic agents, agents to render the formulation isotonic with the blood of the recipient of the subject, or solutes, or suspending or thickening agents (e.g., Remington Essentials of Pharmaceutics, edited by Linda Felton, published by Pharmaceutical Press in 2012, 2013, 1 st Edition, ISBN 978 0 85711 105 0; particularly described in Chapter 30) may contain one or more (or all) of them. In some embodiments, pharmaceutical additives that can be used in combination with compound (I) include, for example, those described in "Handbook of Pharmaceutical Excipients, 2012, 7 th Edition, ISBN 978 0 85711 027 5", edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, and one or more of cyclodextrins. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants.

[0266] After being formulated, the pharmaceutical composition can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dry or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (e.g., similar to an EpiPen®)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0267] In some embodiments, the pharmaceutical composition is aqueous. In some embodiments, the pharmaceutical composition contains water for injection. In some embodiments, compound (I) is provided in a dry form (e.g., powder, solid, etc.). In some embodiments, the dry form of compound (I) is constituted or reconstituted with a carrier (e.g., a liquid). In some embodiments, the dry form of compound (I) is constituted or reconstituted with a carrier before use, including at the time of care.

[0268] Specific pharmaceutical compositions for use according to the present disclosure include lyophilized formulations containing compound (I) or a pharmaceutically acceptable salt thereof mixed with water. In one embodiment, the lyophilized formulation contains compound (I) as the free base. In some embodiments, compound (I) is reconstituted before use.

[0269] Combination therapy In various embodiments, the present disclosure provides a method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the compound is administered in combination with at least one additional therapeutic agent, such as antidepressant therapy.

[0270] In some embodiments, a subject, such as a patient, can receive combination therapy of both an antidepressant and compound (I) or a pharmaceutically acceptable salt thereof, in which case both are administered according to their prescribed dosing regimens.

[0271] In various embodiments, a "subject in need of such treatment, e.g., a patient" can be a subject, e.g., a patient, who has been prescribed or is currently receiving at least one other therapeutic agent, a "background therapy", prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof. The background therapy can be, for example, a standard care agent prescribed for a mental disorder, e.g., a depressive disorder. The background therapy can be, for example, at least one additional antidepressant disclosed herein. The background therapy can be, for example, a conventional antidepressant. The background therapy can be, for example, at least one additional antidepressant and a mood stabilizer, e.g., lithium, disclosed herein. The background therapy can be, for example, at least one additional antidepressant and an antipsychotic, e.g., an atypical antipsychotic, disclosed herein. The background therapy can also include other concomitant medications, e.g., benzodiazepines, without precluding any psychotherapy. In some embodiments, a subject in need of such treatment, e.g., a patient, continues the background therapy after the subject, e.g., the patient, has been administered compound (I) or a pharmaceutically acceptable salt thereof. In further embodiments, a subject in need of such treatment, e.g., a patient, discontinues receiving the background therapy before (e.g., immediately before or gradually) receiving compound (I) or a pharmaceutically acceptable salt thereof. In further embodiments, a subject, e.g., a patient, has received the background therapy for at least 4 weeks, e.g., at least 6 weeks, prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof. In further embodiments, a subject, e.g., a patient, has received the background therapy for at least 4 weeks, e.g., at least 6 weeks, prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof and continues the background therapy after receiving compound (I) or a pharmaceutically acceptable salt thereof.

[0272] Treatment with compound (I) or a pharmaceutically acceptable salt thereof, and the background therapies described herein, may be useful as an enhancement strategy for the treatment of depressive disorders described herein. The enhancement strategy is particularly useful for the treatment of treatment-resistant depression.

[0273] In some embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with other antidepressants currently administered to a subject, such as a patient (including current antidepressants to which the subject, such as a patient, has shown an inadequate response). In other embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, in combination with an antidepressant not previously administered. In still other embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, in combination with an antidepressant previously administered.

[0274] In some embodiments, the other antidepressant therapy may include one antidepressant. In other embodiments, the other antidepressant therapy includes two or more antidepressants. In further embodiments, the other antidepressant therapy includes two antidepressants. In still other embodiments, the other antidepressant therapy includes three antidepressants.

[0275] Accordingly, in one aspect of the present disclosure, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with at least one other therapeutic agent for the treatment of a depressive disorder (wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously). The depressive disorder can be any of those disclosed herein. In one embodiment, the depressive disorder is MDD. In particular, the depressive disorder is TRD. In one embodiment, the at least one other therapeutic agent is at least one antidepressant, such as an oral antidepressant.

[0276] In some embodiments, compound (I) and at least one other therapeutic agent, such as antidepressants (including conventional and herbal antidepressants), antipsychotics, mood stabilizers, benzodiazepines, can be administered via the same or different routes of administration. Examples of suitable methods of administration of antidepressants include, but are not limited to, oral, intravenous, intranasal, intramuscular, subcutaneous, transdermal, buccal, or rectal. In certain embodiments, the at least one other therapeutic agent is at least one other antidepressant, and this antidepressant is administered orally.

[0277] Accordingly, compound (I) or a pharmaceutically acceptable salt thereof can be administered as combination therapy, for example as adjunctive or add-on therapy, to one or more other treatments or therapies for mental disorders, such as depressive disorders. Compound (I) or a pharmaceutically acceptable salt thereof can be administered in combination with one or more additional therapeutic agents, for example in combination with 1 to 3 additional therapeutic agents, for example in combination with 1 to 2 additional therapeutic agents, for example in combination with 1 additional therapeutic agent. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, in combination with at least one other therapeutic agent that is currently being administered. In one embodiment, the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, such as an oral antidepressant. In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, such as an oral antidepressant, to which the subject, such as the patient, has not shown a sufficient response.

[0278] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered as combination therapy with one or more additional antidepressants, and compound (I) or a pharmaceutically acceptable salt thereof is administered as acute treatment. In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered as combination therapy with one or more additional antidepressants, compound (I) or a pharmaceutically acceptable salt thereof is administered as acute treatment, and the one or more antidepressants are administered as chronic treatment.

[0279] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered as additional therapy to a subject, such as a patient, undergoing background therapy for a specified period (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, or more) as described above.

[0280] In various embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of a patient's depressive disorder, and the compound (I) or a pharmaceutically acceptable salt thereof is administered as additional therapy to a patient undergoing background therapy for a specified period (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, or more) as described above. In some embodiments, treatment with the compound (I) or a pharmaceutically acceptable salt thereof is carried out for a specified period of about 4 weeks or more, about 5 weeks or more, about 6 weeks or more, about 7 weeks or more, about 8 weeks or more, about 9 weeks or more, about 10 weeks or more, about 11 weeks or more, about 12 weeks or more, about 13 weeks or more, about 14 weeks or more, about 15 weeks or more, about 16 weeks or more, about 17 weeks or more, about 18 weeks or more, about 19 weeks or more, about 20 weeks or more, about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, about 10 months or more, about 11 months or more, about 1 year or more, about 2 years or more, or a specified period within a range that includes and / or spans the aforementioned values when the patient is undergoing background therapy as described above.

[0281] For example, the therapeutically effective amounts / dosing levels and dosing regimens for additional therapeutic agents as defined herein, such as antidepressants, antipsychotics, mood stabilizers, benzodiazepines, can be readily determined by one of ordinary skill in the art and are administered in accordance with the prescribed dosing regimens, such as those prescribed by a treating physician and / or as set forth on its label. For example, the therapeutic dosages and dosing regimens of commercially approved pharmaceuticals are publicly available, for example, on the package label, in standard dosing guidelines, in standard reference books such as the Physician’s Desk Reference (Medical Economics Company, or online at http: / / / www.pdrel.com), or from other sources.

[0282] Examples of antidepressants that can be used in the combination therapies or background therapies according to the present disclosure are those that have received FDA approval for major depressive disorder.

[0283] As disclosed elsewhere herein, examples of antidepressants that can be used in the combination therapies or background therapies according to the present disclosure include, but are not limited to, selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine-dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants such as those described herein.

[0284] In one embodiment, the antidepressant is selected from the group consisting of fluoxetine, duloxetine, desvenlafaxine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, pirindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofezine, noxiptiline, vilazodone, vortioxetine, and bupropion.

[0285] In certain embodiments, the antidepressant is selected from the group consisting of serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), or combinations thereof.

[0286] In certain embodiments, the antidepressant is selected from the group consisting of SSRI, SNRI, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof. For example, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline, and combinations thereof.

[0287] In various embodiments, at least one antidepressant treatment, for example one of the antidepressants described above, is being used or prescribed to treat the current major depressive episode in a subject, e.g., a patient, suffering from major depressive disorder, e.g., treatment-resistant depression.

[0288] As disclosed herein, compound (I) or a pharmaceutically acceptable salt thereof can be administered in combination with another antidepressant (listed above) and / or an antipsychotic and / or a mood stabilizer. Examples of antipsychotics or mood stabilizers include, but are not limited to, lithium, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

[0289] In various embodiments, as disclosed elsewhere herein, during the process of administering compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, no other antidepressants are administered.

[0290] In various embodiments, as disclosed elsewhere herein, compound (I) is administered as the free base.

[0291] In various embodiments, as disclosed elsewhere herein, depressive disorders are selected from major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. In certain embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

[0292] As disclosed elsewhere herein, all of the foregoing embodiments and the following embodiments regarding the combination therapies of the present disclosure are equally applicable hereinafter: Compound (I) or a pharmaceutically acceptable salt thereof for use in combination therapy according to the present disclosure; Use of compound (I) or a pharmaceutically acceptable salt thereof in combination therapy according to the present disclosure; A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in combination therapy according to the present disclosure; and Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof in combination therapy according to the present disclosure.

[0293] Further embodiments of the present disclosure In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive disorders, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0294] In another aspect, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, wherein the compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

[0295] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0296] In one embodiment, the depressive disorder is selected from major depressive disorder, particularly treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. In certain embodiments, the depressive disorder is major depressive disorder. In a further embodiment, the major depressive disorder is treatment-resistant depression.

[0297] In another aspect, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms of major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. The present disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms in major depressive disorder with acute suicidal ideation or acute suicidal behavior, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms of treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0298] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, wherein the major depressive disorder does not respond to at least two antidepressant treatments, at least one of which has been used to treat the current major depressive episode, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. In one embodiment, the at least two antidepressants are two different antidepressants.

[0299] In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, for example by subcutaneous injection, at a dose of about 0.0048 mg to about 0.32 mg per kg of the patient's body weight, in particular 0.0048 mg, 0.016 mg, 0.048 mg, 0.16 mg or 0.32 mg of the patient's body weight.

[0300] In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, for example by subcutaneous injection, at a dose of about 0.1 mg to about 15 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg to about 1 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg to about 1 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg to about 1 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 10 mg. In one embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 15 mg. In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

[0301] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 4 mg or about 10 mg.

[0302] In certain embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, such as treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is subcutaneously administered at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0303] In certain embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, such as treatment-resistant depression, wherein the major depressive disorder does not respond to therapy with at least one antidepressant in the current major depressive episode, and the compound (I) or a pharmaceutically acceptable salt thereof is subcutaneously administered at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0304] In certain embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, wherein the major depressive disorder does not respond to therapy with at least two antidepressants in the current major depressive episode, and the compound (I) or a pharmaceutically acceptable salt thereof is subcutaneously administered at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0305] In another aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, wherein the major depressive disorder does not respond to treatment with at least two antidepressants, at least one of which is used to treat the current major depressive episode, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg. In one embodiment, the at least two antidepressants are two different antidepressants.

[0306] In certain embodiments, the disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of recurrent major depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0307] In certain embodiments, the disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of recurrent major depressive disorder and a current major depressive episode having a duration of at least 8 weeks in a subject, such as a patient, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg. In certain embodiments, the major depressive episode has a duration of at least 8 weeks but does not exceed 24 months.

[0308] In one embodiment, the depressive disorder is characterized as treatment-resistant depression. In one embodiment, the diagnosis of TRD is confirmed by meeting the DSM-5 criteria for MDD, and the current depressive episode has not responded adequately to at least two different antidepressants at appropriate dosages and durations. In certain embodiments, a subject, such as a patient, has not responded to treatment with two or more (but no more than five) previous antidepressants (where the two non-responsive treatments were conducted with two different antidepressants at appropriate dosages and durations, such as ≥ 6 weeks, according to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ)).

[0309] In one embodiment, a subject, such as a patient, is characterized by having a response of < 50% to treatment with at least one antidepressant. For example, the subject has a current major depressive episode of ≥ 8 weeks and has received antidepressant treatment at a sufficient and stable dosage, i.e., an effective dosage, for at least 4 weeks according to the MGH-ATRQ. In one embodiment, a subject, such as a patient, has single-episode major depressive disorder. In one embodiment, a subject, such as a patient, has recurrent major depressive disorder.

[0310] In certain embodiments, the subject is a human patient.

[0311] In certain embodiments, the subject is an adult patient.

[0312] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered as a single dose without repetition. In a further embodiment, the compound (I) is administered according to a dosing schedule. In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered once a week. In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered twice a week. In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks. In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered once every three weeks. In yet a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered once a month. In yet a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered once every six weeks.

[0313] In certain embodiments, the compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks or less frequently.

[0314] In a further embodiment, the treatment further comprises administration of one or more additional therapeutic agents, for example, one or more standard care medications prescribed for the treatment of mental disorders such as depressive disorders. In one embodiment, the treatment further comprises administration of one or more additional therapeutic agents for at least about 4 weeks, for example, at least about 6 weeks, prior to subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof. In one embodiment, treatment with one or more additional therapeutic agents is continued after treatment with the compound (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, for example, an oral antidepressant.

[0315] In one embodiment, the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. In one embodiment, the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof.

[0316] In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with other antidepressants currently administered to a subject, such as a patient (including current antidepressants to which the subject, such as the patient, has shown an insufficient response). In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with an antidepressant not previously administered to a subject, such as a patient. In yet another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with an antidepressant previously administered to a subject, such as a patient.

[0317] In certain embodiments, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder in a subject, such as a patient, wherein the subject, such as the patient, has not responded to at least one antidepressant therapy in the current major depressive episode, and the treatment comprises administering to the subject, such as the patient, a first antidepressant for at least 4 weeks, such as at least 6 weeks, and then administering to the subject, such as the patient, compound (I) or a pharmaceutically acceptable salt thereof subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, and further optionally continuing the treatment with the first antidepressant.

[0318] In certain embodiments, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder in a subject, e.g., a patient, wherein the subject, e.g., the patient, has not responded to at least two antidepressant therapies in the current major depressive episode, and the treatment comprises administering a first antidepressant to the subject, e.g., the patient, for at least 4 weeks, e.g., at least 6 weeks, and then administering the compound (I) or a pharmaceutically acceptable salt thereof to the subject, e.g., the patient, subcutaneously at a dose of about 0.1 mg to about 15 mg, e.g., about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, and further optionally comprises continuing the treatment with the first antidepressant.

[0319] In further embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, e.g., about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, and the treatment further comprises administering one or more additional therapeutic agents such as an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, or a combination thereof.

[0320] As described herein, compound (I) can be used as adjuvant therapy, i.e., in combination with one or more therapeutic agents, for example one or more antidepressants, as additional therapy, or in combination, for example a patient can already be administered or can further be administered one or more antidepressants. Thus, in further particular embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof for use as described herein, comprising subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as adjuvant therapy with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In further particular embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof for use as described herein, comprising subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In further particular embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof for use as described herein, comprising subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more therapeutic agents, for example one or more antidepressants.

[0321] In further particular embodiments, the present disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct subcutaneous administration of an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as adjuvant therapy with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In further particular embodiments, the present disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of compound (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In further particular embodiments, the present disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of compound (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of one or more therapeutic agents, for example one or more antidepressants. Such one or more antidepressants can be selected from any antidepressants disclosed herein.

[0322] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents for treating a depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0323] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents for treating a major depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0324] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents for treating treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0325] In certain embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more oral antidepressants for treating a major depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0326] In a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more oral antidepressants for treating treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0327] In certain embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more oral antidepressants for treating treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg.

[0328] In a further embodiment, the present disclosure also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression in a patient, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 0.1 mg to about 15 mg, such as about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, and the treatment further comprises administering one or more oral antidepressants. In one embodiment, the patient is an adult.

[0329] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg.

[0330] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg.

[0331] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg.

[0332] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg.

[0333] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg.

[0334] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.6 mg.

[0335] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.7 mg.

[0336] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg.

[0337] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.9 mg.

[0338] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0339] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg.

[0340] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg.

[0341] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0342] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 mg.

[0343] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 6 mg.

[0344] In a further embodiment, the compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 7 mg.

[0345] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 8 mg.

[0346] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 9 mg.

[0347] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0348] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 11 mg.

[0349] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 mg.

[0350] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 13 mg.

[0351] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 14 mg.

[0352] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 15 mg.

[0353] In a further embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 4 mg or about 10 mg.

[0354] In one embodiment, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants.

[0355] In one embodiment, the antidepressant is selected from the group consisting of fluoxetine, duloxetine, desvenlafaxine, venlafaxine, milnacipram, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, pirindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofezine, noxiptiline, vilazodone, vortioxetine, and bupropion.

[0356] In certain embodiments, the antidepressant therapy is selected from the group consisting of serotonin reuptake inhibitors (SSRI), selective serotonin, norepinephrine reuptake inhibitors (SNRI), and combinations thereof.

[0357] In certain embodiments, the antidepressant therapy is selected from the group consisting of SSRI, SNRI, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof.

[0358] In certain embodiments, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline, and combinations thereof.

[0359] In certain embodiments, the antidepressant is an oral antidepressant.

[0360] Further embodiments of the present disclosure are outlined below.

[0361] Embodiment a A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a depressive disorder, wherein the treatment comprises (a) determining or having determined a baseline MADRS score of a subject, such as a patient; and (b) subcutaneously administering to the subject, such as a patient, a compound (I) or a pharmaceutically acceptable salt thereof, wherein the amount of the compound (I) or a pharmaceutically acceptable salt thereof is at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% improving the MADRS score as compared to the measured baseline MADRS score (wherein the baseline is the total MADRS score of the subject, such as a patient, prior to subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof). A compound or a pharmaceutically acceptable salt thereof comprising. A compound or a pharmaceutically acceptable salt thereof for use as described in Embodiment 3a, wherein the subject, such as a patient, is evaluated at regular intervals after step (b) to determine relative efficacy (wherein the evaluation comprises measuring the MADRS score of the subject, such as a patient). Embodiment 5a. The depressive disorder is selected from major depressive disorder, particularly treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder, and is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 4a. Embodiment 6a. The depressive disorder is a major depressive disorder such as acute MDD, and is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 5a. Embodiment 7a. The depressive disorder is treatment-resistant depression, and is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 6a. Embodiment 8a. The treatment-resistant depression includes partial resistance, and is a compound or a pharmaceutically acceptable salt thereof for use according to Embodiment 7a. Embodiment 9a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, the compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 10a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms in major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, the compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 11a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms in major depressive disorder with acute suicidal ideation or acute suicidal behavior, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, the compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 12a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms in treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, the compound of formula (I) or a pharmaceutically acceptable salt thereof. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of reducing at least one depressive symptom in a subject suffering from a depressive disorder, such as a patient, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prevention of a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound or a pharmaceutically acceptable salt thereof according to embodiment 14a or 15a for use as described above, wherein the duration of a major depressive episode is at least 4 weeks, such as at least 6 weeks, at least 8 weeks. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, particularly acute MDD, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a single episode major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 20a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of recurrent major depressive disorder and a current major depressive episode having a duration of at least 4 weeks, such as at least 6 weeks, such as at least 8 weeks, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, a compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 21a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 14a to 20a, wherein the duration of the major depressive episode is at least 6 weeks, such as at least 8 weeks, but less than 24 months. Embodiment 22a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 21a, wherein the depressive disorder or depressive episode, for example in the current depressive episode, has not responded sufficiently to at least one antidepressant treatment. Embodiment 23a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 22a, wherein the depressive disorder or depressive episode, for example in the current depressive episode, has responded partially to at least one antidepressant treatment. Embodiment 24a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 23a, wherein the depressive disorder or depressive episode, for example in the current depressive episode, has not responded sufficiently to at least two antidepressant treatments. Embodiment 25a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 24a, wherein the depressive disorder or depressive episode, for example in the current depressive episode, has responded partially to at least two antidepressant treatments. Embodiment 26a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 25a, wherein the depressive disorder or depressive episode, for example in the current depressive episode, has not responded sufficiently to at least two (but no more than five) antidepressant treatments. Embodiment 27a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 24a to 26a, wherein at least two antidepressant treatments are by two different antidepressants. Embodiment 28a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 22a to 27a, wherein the antidepressant treatment is carried out for at least 4 weeks, for example at least 6 weeks. Embodiment 29a. The antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 22a to 28a. Embodiment 30a. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 22a to 29a. Embodiment 31a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, a compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 32a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder in a subject, such as a patient, wherein the subject, such as a patient, meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), and the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, a compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 33a. The treatment further comprises the step of regularly evaluating a subject, such as a patient, to obtain evidence of treatment efficacy to determine the need for continued treatment after treatment with the compound (I) or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 32a. Embodiment 34a. The subject, such as a patient, is evaluated about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks after treatment with the compound (I) or a pharmaceutically acceptable salt thereof, a compound or a pharmaceutically acceptable salt thereof for use according to Embodiment 33a. Embodiment 35a. The compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg to about 0.32 mg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg per kg of the patient's body weight, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 34a. Embodiment 36a. The compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.1 mg to about 15 mg, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 35a. Embodiment 37a. The compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.1 mg to about 1 mg, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 36a. Embodiment 38a. The compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.3 mg to about 1 mg, a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 37a. Embodiment 39a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 38a, administered at a dose of about 0.5 mg to about 1 mg. Embodiment 40a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 39a, administered at a dose of about 1 mg to about 5 mg. Embodiment 41a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 40a, administered at a dose of about 1 mg to about 10 mg. Embodiment 42a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 41a, administered at a dose of about 1 mg to about 15 mg. Embodiment 43a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 42a, administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. Embodiment 44a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 43a, administered at a dose of about 1 mg, about 4 mg or about 10 mg. Embodiment 45a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 44a, administered once without repetition, once a week, twice a week, once every two weeks, once every three weeks, once a month, or once every six weeks. Embodiment 46a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 45a, which is administered once without repetition. Embodiment 47a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 46a, which is administered once every two weeks or less frequently. Embodiment 48a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 47a, which is administered once every three weeks or less frequently. Embodiment 49a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 48a, which is administered once a month or less frequently. Embodiment 50a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 49a, which is administered once every six weeks or less frequently. Embodiment 51a. Treatment with the compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, or at least about 2 years, and is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 50a. After treatment with the compound (I) or a pharmaceutically acceptable salt thereof, an improvement in score is observed in one or more depression assessment tools selected from the group consisting of the Montgomery-Åsberg Depression Rating Scale (MADRS), the Mini International Neuropsychiatric Interview (M.I.N.I.), for example version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicide Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI). The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 51a. Embodiment 53a. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, having recurrent major depressive disorder and a current major depressive episode with a duration of at least 4 weeks, for example at least 6 weeks, at least 8 weeks. The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 52a. Embodiment 54a. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is treatment-resistant. The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 53a. Embodiment 55a. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is partially resistant. The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 54a. Embodiment 56a. The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who had an insufficient response or no response to other antidepressant therapies, for example, prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof, in the current major depressive episode. The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 55a. Compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not responded adequately or has not responded to at least one antidepressant, for example, in the current major depressive episode, for use as described in any one of Embodiments 1a to 56a. Compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not responded adequately or has not responded to at least two antidepressants, for example, in the current major depressive episode, for use as described in any one of Embodiments 1a to 57a. Compound of formula (I) or a pharmaceutically acceptable salt thereof for use as described in any one of Embodiments 56a to 58a, wherein inadequate response or no response includes partial response. Compound of formula (I) or a pharmaceutically acceptable salt thereof for use as described in any one of Embodiments 56a to 59a, wherein the current major depressive episode has a duration of at least about 4 weeks, such as at least about 6 weeks, at least about 8 weeks, particularly at least about 8 weeks, but does not exceed 24 months. Compound of formula (I) or a pharmaceutically acceptable salt thereof for use as described in any one of Embodiments 56a to 60a, wherein the antidepressant is the antidepressant described in Embodiment 29a or 30a. Compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose MADRS score at baseline is at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, for use as described in any one of Embodiments 1a to 61a. Embodiment 63a. The treatment further includes determining or having determined the total MADRS score, compared to the baseline evaluation, for example, 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, thereby evaluating the effectiveness of the treatment (wherein the baseline is the total MADRS score of the subject, for example, the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 62a. Embodiment 64a. The total MADRS score of the subject, for example, the patient, decreases compared to the baseline evaluation after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. For example, the total MADRS score of the subject, for example, the patient, decreases compared to the baseline evaluation 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof (wherein the baseline is the total MADRS score of the subject, for example, the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 63a. Embodiment 65a. The total MADRS score of the subject, for example, the patient, improves by more than 30%, for example, more than 35%, more than 40%, more than 45%, more than 50% compared to the baseline evaluation after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. For example, the total MADRS score of the subject, for example, the patient, improves by more than 30%, for example, more than 35%, more than 40%, more than 45%, more than 50% compared to the baseline evaluation 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof (wherein the baseline is the total MADRS score of the subject, for example, the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). The compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 64a. Embodiment 66a. For use according to any one of Embodiments 1a - 65a, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject, e.g., a patient, has a MADRS total score of less than 12 after subcutaneous administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to the baseline assessment; e.g., the subject, e.g., a patient, has a MADRS total score of less than 12 at 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to the baseline assessment (wherein the baseline is the MADRS total score of the subject, e.g., a patient, before subcutaneous administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof). Embodiment 67a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents for the treatment of mental disorders, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 68a. Use according to Embodiment 67a, wherein the compound or a pharmaceutically acceptable salt thereof is for use according to any one of Embodiments 1a - 66a. Embodiment 69a. Use according to any one of Embodiments 1a - 66a, wherein the treatment further comprises administration of one or more additional therapeutic agents. Embodiment 70a. Use according to Embodiment 69a, wherein treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof is carried out in addition to one or more standard care medications prescribed for use in the treatment of mental disorders. Embodiment 71a. Use according to any one of Embodiments 67a - 70a, wherein the mental disorder is a depressive disorder. Embodiment 72a. Use according to Embodiment 71a, wherein the depressive disorder is a major depressive disorder. Embodiment 73a. Use according to Embodiment 72a, wherein the major depressive disorder is treatment - resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and intent, major depressive disorder with suicidal behavior, self - harm in major depressive disorder, or seasonal affective disorder. Embodiment 74a. The treatment involves administering one or more additional therapeutic agents for at least about 4 weeks, for example at least about 6 weeks, prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 67a - 73a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 75a. The treatment with one or more additional therapeutic agents continues after treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 67a - 74a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 76a. The one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof, for use according to any one of embodiments 67a - 75a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 77a. At least one of the one or more additional therapeutic agents is an antidepressant, for example an oral antidepressant, for use according to any one of embodiments 67a - 76a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 78a. The one or more additional therapeutic agents are one or more antidepressants, for use according to any one of embodiments 67a - 77a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 79a. The disorder is, for example, during the current major depressive episode, not sufficiently responsive or non - responsive to at least one, for example at least two, of the one or more additional therapeutic agents or standard care medications, for use according to any one of embodiments 76a - 78a of the compound or a pharmaceutically acceptable salt thereof. Embodiment 80a. The antidepressant is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 76a to 79a, selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), multimodal antidepressants, and combinations thereof. Embodiment 81a. The antidepressant is selected from the group consisting of SSRI, SNRI, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof. For example, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline, and combinations thereof. It is a compound or a pharmaceutically acceptable salt thereof for use according to Embodiment 80a. Embodiment 82a. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, vortioxetine, and combinations thereof. It is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 76a to 81a. Embodiment 83a. The antipsychotic or mood stabilizer is selected from the group consisting of lithium, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone. It is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 76a to 82a. Embodiment 84a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 83a, which is administered subcutaneously in the upper arm or abdominal region. Embodiment 85a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 84a, which is administered as a single subcutaneous injection. Embodiment 86a. The compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 85a, which is in the form of a pharmaceutical composition optionally containing at least one pharmaceutically acceptable excipient. Embodiment 87a. The compound (I) is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 86a, which is administered as a free base. Embodiment 88a. The compound (I) is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 87a, which is formulated to be delivered from a subcutaneous injection device. Embodiment 89a. The compound (I) is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 88a, which is formulated to be delivered from a subcutaneous injection device as a single subcutaneous injection. Embodiment 90a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not responded to two or more (but five or less) previous antidepressant treatments (where the two non-responsive treatments are, for example, with two different antidepressants identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), at appropriate doses and for a period, such as at least 6 weeks). It is a compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 89a. In Embodiment 91a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has a response of <50% to at least one antidepressant treatment at an effective and stable dose for at least 4 weeks, for example, during a major depressive episode of ≧8 weeks, according to MGH-ATRQ. The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 90a. In Embodiment 92a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has been diagnosed with recurrent major depressive disorder (MDD) and has a current major depressive episode with a duration of at least 8 weeks, for example, as defined by the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 91a. In Embodiment 93a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is characterized as having treatment-resistant or treatment-refractory depression. The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 92a. In Embodiment 94a, the compound or a pharmaceutically acceptable salt thereof is administered to a human patient. The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 93a. In Embodiment 95a, the compound or a pharmaceutically acceptable salt thereof is administered to an adult patient. The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 94a. In Embodiment 96a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of treatment failure with esketamine, ketamine, or arketamine. The compound or a pharmaceutically acceptable salt thereof is for use as described in any one of Embodiments 1a to 95a. In Embodiment 97a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, suffering from a depressive episode, such as a major depressive episode (wherein the subject, such as the patient, has not responded to treatment with at least one antidepressant in the current depressive episode), the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 96a. In Embodiment 98a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, suffering from a depressive episode, such as a major depressive episode (wherein the subject, such as the patient, has not responded to treatment with at least two antidepressants in the current depressive episode), the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 97a. In Embodiment 99a, at least one antidepressant is an oral antidepressant, the compound or a pharmaceutically acceptable salt thereof for use according to Embodiment 97a or 98a. In Embodiment 100a, the antidepressant has been administered for at least 4 weeks, such as at least 6 weeks, the compound for use according to any one of Embodiments 97a to 99a. In Embodiment 101a, the compound or a pharmaceutically acceptable salt thereof is administered to a male or female subject, such as a patient, the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 100a. In Embodiment 102a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, not having an acute depressive episode lasting longer than 2 years, the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 101a. In Embodiment 103a, the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received electroshock therapy during the current depressive episode or within 1 year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 102a. Embodiment 104a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received transcranial magnetic stimulation therapy during the current depressive episode or within 1 year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1a to 103a. Embodiment 105a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received vagus nerve stimulation therapy during the current depressive episode or within 1 year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1a to 104a. Embodiment 106a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received deep brain stimulation therapy during the current depressive episode or within 1 year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1a to 105a. Embodiment 107a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has never received a diagnosis of major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features, as determined by, for example, SCID-5, for use according to any one of Embodiments 1a to 106a. Embodiment 108a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have acute alcohol disorder or substance use disorder requiring detoxification or withdrawal symptoms, for use according to any one of Embodiments 1a to 107a. Embodiment 109a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received detoxification treatment within 1 month prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1a to 108a. Embodiment 110a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have borderline personality disorder or antisocial personality disorder based on, for example, DSM-5 criteria, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 109a. Embodiment 111a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received a clinical diagnosis of autism, dementia, or intellectual disability, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 110a. Embodiment 112a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have a history of suicide attempt or suicidal behavior within 1 year prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 111a. Embodiment 113a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not show suicidal ideation with intent, as determined by the CSSRS, for example, by a positive response to Q4 or Q5 at baseline, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 112a. Embodiment 114a. The compound or a pharmaceutically acceptable salt thereof has a calculated glomerular filtration rate (eGFR) of <40 mL / min / 1.73m 2 at baseline and is administered to a subject, such as a patient, who does not show evidence of severe renal insufficiency, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 113a. Embodiment 115a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have a history of hypersensitivity to compound (I) or a pharmaceutically acceptable salt thereof, or a drug having a similar mechanism of action, that is, a drug that affects the NMDA receptor, and is the compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 114a. Embodiment 116a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, having no active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or active COVID-19 infection, for use as described in any one of Embodiments 1a to 115a. Embodiment 117a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, having no history of seizures except for febrile seizures in children, for use as described in any one of Embodiments 1a to 116a. Embodiment 118a. The compound or a pharmaceutically acceptable salt thereof is as follows, namely, a) A history of myocardial infarction, angina pectoris or coronary artery bypass graft within 6 months before treatment with compound (I) or a pharmaceutically acceptable salt thereof, b) A history of clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, advanced atrioventricular (AV) block (e.g., 2 bundle branch block, Mobitz type II third-degree AV block) within 6 months before treatment with compound (I) or a pharmaceutically acceptable salt thereof The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, having no abnormalities of the heart or cardiac repolarization, including any of the above, for use as described in any one of Embodiments 1a to 117a. Embodiment 119a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose baseline resting QTcF is not ≥450 milliseconds (male) or ≥460 milliseconds (female), for use as described in any one of Embodiments 1a to 118a. Embodiment 120a. The compound or a pharmaceutically acceptable salt thereof is risk factors for torsades de pointes (TdP) including untreated hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or the following, namely, a) A family history of QT prolongation syndrome, idiopathic sudden death or congenital QT prolongation syndrome, b) A concomitant medicine having a "known risk of TdP" that cannot be discontinued or replaced with a safe alternative A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 119a, which is not administered to a subject, such as a patient, who presents any of Embodiment 121a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 120a, which is not administered to a subject, such as a patient, whose baseline mean systolic blood pressure is >140 mmHg or mean diastolic blood pressure is >90 mmHg; or who has no history of hypertensive crisis. Embodiment 122a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 121a, which is not administered to a subject, such as a patient, who has no history of hemorrhagic stroke or known cerebrovascular disorder (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other locations (e.g., aorta). Embodiment 123a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 122a, which is not administered to a pregnant woman or a subject, such as a patient, who is nursing (not a lactating woman). Embodiment 124a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 123a, which is not administered to a female subject, such as a patient, who is not using an effective contraceptive method and has a possibility of pregnancy. Embodiment 125a. A compound or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 124a, which is not administered to a sexually active male subject, such as a patient, who does not desire to use a condom during sexual intercourse while being administered Compound I or a pharmaceutically acceptable salt thereof and for one week after discontinuation of the dosing treatment with Compound I or a pharmaceutically acceptable salt thereof. Embodiment 126a. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not been administered any of the following agents defined in Table 1 during treatment with compound I or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1a to 125a. Embodiment 127a. A therapeutic agent for use in the treatment of mental disorders, such as depressive disorders, such as major depressive disorder, such as treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 128a. The therapeutic agent according to Embodiment 127a, which is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. Embodiment 129a. The therapeutic agent according to Embodiment 127a or 128a, which is an antidepressant, such as an oral antidepressant. Embodiment 130a. The therapeutic agent according to any one of Embodiments 127a to 129a, which is administered for a period of at least about 4 weeks, such as at least about 6 weeks, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 131a. The therapeutic agent according to any one of Embodiments 127a to 130a, wherein treatment with the therapeutic agent continues after treatment with compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 132a. The antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants, for use according to any one of Embodiments 128a to 131a. Embodiment 133a. The antidepressant is a therapeutic agent for use according to any one of Embodiments 128a to 132a, selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine. Embodiment 134a. The antipsychotic or mood stabilizer is a therapeutic agent for use according to any one of Embodiments 128a to 133a, selected from the group consisting of lithium members such as lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone. Embodiment 135a. Treatment with compound (I) or a pharmaceutically acceptable salt thereof is a therapeutic agent for use according to any one of Embodiments 127a to 134a, according to any one of Embodiments 1a to 66a and 84a to 126a. Embodiment 136a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression in adult patients, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously and the treatment is combined with at least one oral antidepressant. Embodiment 137a. The use is a compound or a pharmaceutically acceptable salt thereof for use according to Embodiment 136a, according to any one of Embodiments 33a to 66a, 80a to 82a, and 84a to 126a.

[0362] Regarding other embodiments, the specific features described in this disclosure in connection with a single embodiment can also be implemented in combination in a single embodiment. Conversely, the various features described in connection with a single embodiment can also be implemented separately in multiple embodiments or in any suitable sub-combination. Further, although the features have been described above as acting in a particular embodiment, one or more features from the claimed combination can, in some cases, be deleted from that combination, and the claimed combination can be directed to a sub-combination or a variation of a sub-combination.

[0363] Embodiment b: Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for use in the treatment of a depressive disorder, wherein the pharmaceutical composition is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a depressive disorder, wherein the treatment comprises: (a) determining or having determined a baseline MADRS score for a subject, such as a patient; and (b) subcutaneously administering to the subject, such as a patient, a compound (I) or a pharmaceutically acceptable salt thereof, wherein the amount of the compound (I) or a pharmaceutically acceptable salt thereof is such that the MADRS score is improved by at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to the measured baseline MADRS score (wherein the baseline is the total MADRS score of the subject, such as a patient, prior to subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof). comprising. Embodiment 4b. For determining relative effectiveness, a subject, e.g., a patient, is evaluated at regular intervals after step (b) (where the evaluation includes measuring the MADRS score of the subject, e.g., the patient), the use as described in Embodiment 3b. Embodiment 5b. The use as described in any one of Embodiments 1b to 4b, wherein the depressive disorder is selected from major depressive disorder, particularly treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. Embodiment 6b. The use as described in any one of Embodiments 1b to 5b, wherein the depressive disorder is a major depressive disorder such as acute MDD. Embodiment 7b. The use as described in any one of Embodiments 1b to 6a, wherein the depressive disorder is treatment-resistant depression. Embodiment 8b. The use as described in any one of Embodiments 1b to 7b, wherein the treatment-resistant depression includes partial resistance. Embodiment 9b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depressive symptoms, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 10b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depressive symptoms in major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 11b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depressive symptoms in major depressive disorder with acute suicidal ideation or acute suicidal behavior, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 12b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of depressive symptoms in treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in reducing at least one depressive symptom in a subject suffering from a depressive disorder, such as a patient, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the prevention of a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use according to embodiment 14b or 15b, wherein the duration of the major depressive episode is at least 4 weeks, such as at least 6 weeks, at least 8 weeks, such as about 8 weeks. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of major depressive disorder, particularly acute MDD, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a single episode major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of recurrent major depressive injury, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of recurrent major depressive disorder and a current major depressive episode having a duration of at least 6 weeks, such as at least 8 weeks, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Use according to any one of Embodiments 14b to 20b, wherein the duration of the major depressive episode is at least 6 weeks, for example at least 8 weeks, but less than 24 months. Use according to any one of Embodiments 1b to 21b, wherein the depressive disorder or depressive episode, for example in the current depressive episode, does not respond sufficiently to at least one antidepressant treatment. Use according to any one of Embodiments 1b to 22b, wherein the depressive disorder or depressive episode, for example in the current depressive episode, responds partially to at least one antidepressant treatment. Use according to any one of Embodiments 1b to 23b, wherein the depressive disorder or depressive episode, for example in the current depressive episode, does not respond sufficiently to at least two antidepressant treatments. Use according to any one of Embodiments 1b to 24b, wherein the depressive disorder or depressive episode, for example in the current depressive episode, responds partially to at least two antidepressant treatments. Use according to any one of Embodiments 1b to 25b, wherein the depressive disorder or depressive episode, for example in the current depressive episode, does not respond sufficiently to at least two (but 5 or less) antidepressant treatments. Use according to any one of Embodiments 24b to 26b, wherein at least two antidepressant treatments are by two different antidepressants. Use according to any one of Embodiments 22b to 27b, wherein the antidepressant treatment has been carried out for at least 4 weeks, for example at least 6 weeks. Embodiment 29b. The antidepressant is selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (e.g., bupropion), a norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor (MAOI) (including a reversible inhibitor of monoamine oxidase (RIMA)), and a multimodal antidepressant, for use according to any one of Embodiments 22b to 28b. Embodiment 30b. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine, for use according to any one of Embodiments 22b to 29b. Embodiment 31b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 32b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of major depressive disorder in a subject, e.g., a patient, wherein the subject, e.g., a patient, meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), and the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 33b. The treatment further comprises the step of regularly evaluating the subject, e.g., a patient, to obtain evidence of treatment efficacy to determine the need for continued treatment after treatment with the compound (I) or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1b to 32b. Use according to embodiment 33b, wherein the subject, e.g., a patient, is evaluated about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks after treatment with compound (I) or a pharmaceutically acceptable salt thereof. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 34b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg to about 0.32 mg, in particular 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg, per kg of the patient's body weight. Use according to any one of embodiments 1b to 35b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.1 mg to about 15 mg. Use according to any one of embodiments 1b to 36b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.1 mg to about 1 mg. Use according to any one of embodiments 1b to 37b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.3 mg to about 1 mg. Use according to any one of embodiments 1b to 38b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 0.5 mg to about 1 mg. Use according to any one of embodiments 1b to 39b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 5 mg. Use according to any one of embodiments 1b to 40b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 10 mg. Use according to any one of embodiments 1b to 41b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 15 mg. Use according to any one of Embodiments 1b to 42b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg. Use according to any one of Embodiments 1b to 43b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 4 mg or about 10 mg. Use according to any one of Embodiments 1b to 44b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once without repetition, once a week, twice a week, once every two weeks, once every three weeks, once a month, or once every six weeks. Use according to any one of Embodiments 1b to 45b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once without repetition. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1b to 46b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks or less frequently. Use according to any one of Embodiments 1b to 47b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once every three weeks or less frequently. Use according to any one of Embodiments 1b to 48b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once a month or less frequently. Use according to any one of Embodiments 1b to 49b, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once every six weeks or less frequently. Use according to any one of Embodiments 1b to 50b, wherein treatment with compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, or at least about 2 years. Use according to any one of Embodiments 1b to 51b, wherein improvement in scores is observed in one or more depression assessment tools selected from the group consisting of the Montgomery - Åsberg Depression Rating Scale (MADRS), Mini International Neuropsychiatric Interview (M.I.N.I.), e.g., version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH - ATRQ), Columbia - Suicide Severity Rating Scale (C - SSRS), and Clinical Global Impression (CGI) after treatment with compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 52b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode with a duration of at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks. Use according to any one of Embodiments 1b to 53b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is treatment - resistant. Use according to any one of Embodiments 1b to 54b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is partially resistant. Embodiment 56b. The use according to any one of Embodiments 1b to 55b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has had an insufficient response or no response to other antidepressant therapies, for example, in the current major depressive episode, prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 57b. The use according to any one of Embodiments 1b to 56b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has had an insufficient response or no response to at least one antidepressant, for example, in the current major depressive episode. Embodiment 58b. The use according to any one of Embodiments 1b to 57b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has had an insufficient response or no response to at least two antidepressants, for example, in the current major depressive episode. Embodiment 59b. The use according to any one of Embodiments 56b to 58b, wherein the insufficient response includes a partial response. Embodiment 60b. The use according to any one of Embodiments 56b to 59b, wherein the current major depressive episode has a duration of at least about 4 weeks, such as at least about 6 weeks, at least about 8 weeks, particularly at least about 8 weeks, but does not exceed 24 months. Embodiment 61b. The use according to any one of Embodiments 56b to 60b, wherein the antidepressant is the antidepressant described in Embodiment 29b or 30b. Embodiment 62b. The use according to any one of Embodiments 1b to 61b, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose MADRS score at baseline is at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25. Embodiment 63b. The treatment further includes determining or determining the total MADRS score compared to the baseline assessment, for example, 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, thereby evaluating the effectiveness of the treatment (where the baseline is the total MADRS score of the subject, such as a patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof), the use according to any one of Embodiments 1b to 62b. Embodiment 64b. The total MADRS score of the subject, such as a patient, decreases compared to the baseline assessment after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. For example, the total MADRS score of the subject, such as a patient, decreases 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof compared to the baseline assessment (where the baseline is the total MADRS score of the subject, such as a patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof), the use according to any one of Embodiments 1b to 63b. Embodiment 65b. The total MADRS score of the subject, such as a patient, improves by more than 30%, for example, more than 35%, for example, more than 40%, more than 45%, more than 50% compared to the baseline assessment after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. For example, the total MADRS score of the subject, such as a patient, improves by more than 30%, for example, more than 35%, more than 40%, more than 45%, more than 50% 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof compared to the baseline assessment (where the baseline is the total MADRS score of the subject, such as a patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof), the use according to any one of Embodiments 1b to 64b. Embodiment 66b. The subject, for example a patient, has a total MADRS score of less than 12 after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment. For example, the subject, for example a patient, has a total MADRS score of less than 12 at 24 hours, 7 days, 14 days, 21 days, and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment (wherein the baseline is the total MADRS score of the subject, for example a patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof), use according to any one of Embodiments 1b to 65b. Embodiment 67b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in combination with one or more additional therapeutic agents for the treatment of a mental disorder, depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. Embodiment 68b. The use according to Embodiment 67b, wherein the compound or a pharmaceutically acceptable salt thereof is for the use according to any one of Embodiments 1b to 66b. Embodiment 69b. The use according to any one of Embodiments 1b to 66b, wherein the treatment further comprises administration of one or more additional therapeutic agents. Embodiment 70b. The use according to Embodiment 69b, wherein the treatment with compound (I) or a pharmaceutically acceptable salt thereof is carried out in addition to one or more standard care medications prescribed for use in the treatment of mental disorders. Embodiment 71b. The use according to any one of Embodiments 67a to 70a, wherein the mental disorder is a depressive disorder. Embodiment 72b. The use according to Embodiment 71b, wherein the depressive disorder is a major depressive disorder. Embodiment 73b. The use according to Embodiment 72b, wherein the major depressive disorder is treatment-resistant depression, major depressive disorder with suicidal tendency, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, or seasonal affective disorder. Embodiment 74b. The use according to any one of embodiments 67b - 74b, wherein the treatment comprises administering one or more additional therapeutic agents for at least about 4 weeks, for example at least about 6 weeks, prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 75b. The use according to any one of embodiments 67b - 75b, wherein the treatment with one or more additional therapeutic agents continues after treatment with compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 76b. The use according to any one of embodiments 67b - 76b, wherein the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. Embodiment 77b. The use according to any one of embodiments 67b - 77b, wherein at least one of the one or more additional therapeutic agents is an antidepressant, for example an oral antidepressant. Embodiment 78b. The use according to any one of embodiments 67b - 78b, wherein the one or more additional therapeutic agents are one or more antidepressants. Embodiment 79b. The use according to any one of embodiments 76b - 78b, wherein the disorder, for example during the current major depressive episode, does not respond or does not respond adequately to at least one, for example at least two, of the one or more additional therapeutic agents or standard care medications. Embodiment 80b. The use according to any one of embodiments 76b - 79b, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine - dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), multimodal antidepressants, and combinations thereof. Embodiment 81b. The antidepressant is selected from the group consisting of SSRIs, SNRIs, tricyclic antidepressants, norepinephrine-dopamine reuptake inhibitors, and combinations thereof. For example, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline, and combinations thereof, for use according to Embodiment 80b. Embodiment 82b. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, vortioxetine, and combinations thereof, for use according to any one of Embodiments 76b to 81b. Embodiment 83b. The antipsychotic or mood stabilizer is selected from the group consisting of lithium, such as lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone, for use according to any one of Embodiments 76b to 82b. Embodiment 84b. Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously in the upper arm or abdominal region, for use according to any one of Embodiments 1b to 83b. Embodiment 85b. Compound (I) or a pharmaceutically acceptable salt thereof is administered as a single subcutaneous injection, for use according to any one of Embodiments 1b to 84b. Embodiment 86b. Compound (I) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition optionally containing at least one pharmaceutically acceptable excipient, for use according to any one of Embodiments 1b to 85b. Embodiment 87b. Compound (I) is administered as the free base, for use according to any one of Embodiments 1b to 86b. Embodiment 88b. Compound (I) is formulated to be delivered from a subcutaneous injection device, for use according to any one of Embodiments 1b to 87b. Embodiment 89b. The use according to any one of Embodiments 1b to 88b, wherein the compound (I) is formulated to be delivered from a subcutaneous injection device as a single subcutaneous injection. Embodiment 90b. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not responded to two or more (but five or less) previous antidepressant treatments (wherein the two non-responsive treatments are, for example, two different antidepressants identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), administered at appropriate doses and for a period, such as at least 6 weeks), the use according to any one of Embodiments 1b to 89b. Embodiment 91b. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has a response of < 50% to at least one antidepressant treatment at an effective and stable dose for at least 4 weeks according to the MGH-ATRQ, for example, during a major depressive episode of ≧ 8 weeks, the use according to any one of Embodiments 1b to 90b. Embodiment 92b. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has been diagnosed with recurrent major depressive disorder (MDD) and has a current major depressive episode with a duration of at least 8 weeks, defined, for example, according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the use according to any one of Embodiments 1b to 91b. Embodiment 93b. The compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, characterized as having treatment-resistant or treatment-refractory depression, the use according to any one of Embodiments 1b to 92b. Embodiment 94b. The compound or a pharmaceutically acceptable salt thereof is administered to a human patient, the use according to any one of Embodiments 1b to 93b. Embodiment 95b. The compound or a pharmaceutically acceptable salt thereof is administered to an adult patient, the use according to any one of Embodiments 1b to 94b. Use according to any one of Embodiments 1b to 95b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of treatment failure with esketamine, ketamine, or arketamine. Use according to any one of Embodiments 1b to 96b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, suffering from a depressive episode, such as a major depressive episode (wherein the subject, such as the patient, has not responded to treatment with at least one antidepressant in the current depressive episode). Use according to any one of Embodiments 1b to 97b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, suffering from a depressive episode, such as a major depressive episode (wherein the subject, such as the patient, has not responded to treatment with at least two antidepressants in the current depressive episode). Use according to Embodiment 97b or 98b, wherein at least one antidepressant is an oral antidepressant. Use according to any one of Embodiments 97b to 99b, wherein the antidepressant has been administered for at least 4 weeks, such as at least 6 weeks. Use according to any one of Embodiments 1b to 100b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a male or female subject, such as a patient. Use according to any one of Embodiments 1b to 101b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have an acute depressive episode that has persisted for more than 2 years. Use according to any one of Embodiments 1b to 102b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received electroshock therapy during the current depressive episode or within 1 year prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 103b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received transcranial magnetic stimulation therapy during the current depressive episode or within 1 year prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 104b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received vagus nerve stimulation therapy during the current depressive episode or within 1 year prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 105b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received deep brain stimulation therapy during the current depressive episode or within 1 year prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 106b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has never been diagnosed with major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features, as determined, for example, by SCID-5. Use according to any one of Embodiments 1b to 107b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have acute alcohol disorder or substance use disorder requiring detoxification or withdrawal symptoms. Use according to any one of Embodiments 1b to 108b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received detoxification treatment within 1 month prior to treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 109b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have borderline personality disorder or antisocial personality disorder, for example, based on DSM-5 criteria. Use according to any one of Embodiments 1b to 110b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received a clinical diagnosis of autism, dementia, or intellectual disability. Use according to any one of Embodiments 1b to 111b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of suicide attempt or suicidal behavior within one year before treatment with the compound (I) or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 112b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not show suicidal ideation with intent, as determined by the CSSRS, for example, by a positive response to Q4 or Q5 at baseline. Embodiment 114b. The compound or a pharmaceutically acceptable salt thereof 2 Use according to any one of Embodiments 1b to 113b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who shows no evidence of severe renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) of <40 mL / min / 1.73m Use according to any one of Embodiments 1b to 114b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of hypersensitivity to the compound (I) or a pharmaceutically acceptable salt thereof, or a drug having a similar mechanism of action, i.e., a drug that affects the NMDA receptor. Use according to any one of Embodiments 1b to 115b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection. Use according to any one of Embodiments 1b to 116b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of seizures except for febrile seizures in children. Embodiment 118b. The compound or a pharmaceutically acceptable salt thereof is the following, namely, a) A history of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, b) A history of clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, advanced atrioventricular (AV) block (e.g., 2-bundle branch block, Mobitz type II third-degree AV block) within 6 months prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof The use according to any one of embodiments 1b to 117b, which is administered to a subject, such as a patient, having no abnormalities of the heart or cardiac repolarization and including any one of the above. Embodiment 119b. The use according to any one of embodiments 1b to 118b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose baseline resting QTcF is not ≧450 milliseconds (male) or ≧460 milliseconds (female). Embodiment 120b. The compound or a pharmaceutically acceptable salt thereof is a risk factor for torsades de pointes (TdP) including untreated hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or the following, namely, a) A family history of QT prolongation syndrome, idiopathic sudden death, or congenital QT prolongation syndrome, b) A concomitant medicine having a "known risk of TdP" that cannot be discontinued or replaced with a safe alternative The use according to any one of embodiments 1b to 119b, which is administered to a subject, such as a patient, presenting none of the above. Embodiment 121b. The use according to any one of embodiments 1b to 120b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose baseline mean systolic blood pressure is not >140 mmHg or mean diastolic blood pressure is not >90 mmHg; or having no history of hypertensive crisis. Embodiment 122b. The use according to any one of embodiments 1b to 121b, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, such as a patient, having no history of hemorrhagic stroke or known cerebrovascular disorder (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other locations (e.g., aorta). Use according to any one of Embodiments 1b to 122b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject who is not a pregnant woman or a nursing (lactating) woman, such as a patient. Use according to any one of Embodiments 1b to 123b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject who is not a woman with a possible pregnancy who is not using an effective contraceptive method, such as a patient. Use according to any one of Embodiments 1ab to 124b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject who is not a sexually active male who does not wish to use a condom during sexual intercourse during the administration of Compound I or a pharmaceutically acceptable salt thereof and for one week after discontinuation of the drug treatment with Compound I or a pharmaceutically acceptable salt thereof. Use according to any one of Embodiments 1b to 125b, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not been administered any of the following drugs defined in Table 1 during treatment with Compound I or a pharmaceutically acceptable salt thereof. Use of a therapeutic agent in the manufacture of a medicament for the treatment of mental disorders, such as depressive disorders, such as major depressive disorder, such as treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof. The therapeutic agent according to Embodiment 127b, wherein the therapeutic agent is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof. The therapeutic agent according to Embodiment 127b or 128b, wherein the therapeutic agent is an antidepressant, such as an oral antidepressant. Embodiment 130b. A therapeutic agent for use according to any one of Embodiments 127b to 129b, wherein the therapeutic agent is administered for a period of at least about 4 weeks, for example at least about 6 weeks, before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 131b. A therapeutic agent for use according to any one of Embodiments 127b to 130b, wherein the treatment with the therapeutic agent continues after treatment with Compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 132b. The antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants, for use according to any one of Embodiments 128b to 131b. Embodiment 133b. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine, for use according to any one of Embodiments 128b to 132b. Embodiment 134b. The antipsychotic or mood stabilizer is selected from the group consisting of lithium members, such as lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone, for use according to any one of Embodiments 128b to 133b. Embodiment 135b. Treatment with Compound (I) or a pharmaceutically acceptable salt thereof is a therapeutic agent for use according to any one of Embodiments 127b to 134b, according to any one of Embodiments 1b to 66b and 84b to 126b. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of treatment-resistant depression in adult patients, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously and the treatment is combined with at least one oral antidepressant, the compound or a pharmaceutically acceptable salt thereof. Embodiment 137b. The use is a compound or a pharmaceutically acceptable salt thereof for the use according to Embodiment 136a according to any one of Embodiments 33a to 66a, 80a to 82a, and 84a to 126a.

[0364] Embodiment c Embodiment 1c. A method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 2c. A method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a pharmaceutical composition comprising a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Embodiment 3c. A method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 4c. A method of treating a long-term depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, in need thereof, a compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 5c. A method of treating treatment-resistant depression in a subject, such as a patient, having major depressive disorder, the method comprising administering subcutaneously a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof. Embodiment 6c. A method of administering a compound (I) or a pharmaceutically acceptable salt thereof to a subject, such as a patient, in need thereof, the method comprising administering subcutaneously the compound (I) under the skin of the subject. Embodiment 7c. A method of treating a depressive episode in a subject, such as a patient, in need thereof, comprising: a. determining or having determined a baseline MADRS score of the subject, such as a patient; and b. subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof is such that the MADRS score is improved by at least about 30%, such as at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to the measured baseline MADRS score (wherein the baseline is the total MADRS score of the subject, such as a patient, prior to subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). A method comprising the steps. Embodiment 8c. Use of Embodiment 7c, wherein the subject, such as a patient, is evaluated at regular intervals after step (b) to determine relative effectiveness (wherein the evaluation comprises measuring the MADRS score of the subject, such as a patient). Embodiment 9c. The method according to any one of Embodiments 1c to 8c, wherein the subject, such as a patient, is diagnosed or to be diagnosed as having a depressive disorder. Embodiment 10c. The method according to any one of Embodiments 1c to 9c, wherein the subject, such as a patient, is diagnosed or to be diagnosed as having major depressive disorder. Embodiment 11c. The method according to any one of Embodiments 1c to 10c, wherein the subject, such as a patient, is diagnosed or to be diagnosed as having treatment-resistant depression (TRD). In the method according to any one of Embodiments 1c to 11c, an improvement in score is observed in one or more depression evaluation tools selected from the group consisting of the Montgomery - Åsberg Depression Rating Scale (MADRS), the Mini - International Neuropsychiatric Interview (M.I.N.I.), for example Version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH - ATRQ), the Columbia - Suicide Severity Rating Scale (C - SSRS), and the Clinical Global Impression (CGI). In the method according to any one of Embodiments 1c to 12c, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 1 mg to about 15 mg (wherein the dose refers to the free base of compound (I)). In the method according to any one of Embodiments 1c to 13c, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 1 mg to about 10 mg (wherein the dose refers to the free base of compound (I)). In the method according to any one of Embodiments 1c to 14c, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of about 1 mg, about 4 mg or about 10 mg (wherein the dose refers to the free base of compound (I)). In the method according to any one of Embodiments 1c to 15c, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, for example a patient, once a week. In the method according to any one of Embodiments 1c to 16c, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, for example a patient, twice a week. In the method according to any one of Embodiments 1c to 17c, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, for example a patient, once every two weeks. In the method according to any one of Embodiments 1c to 18c, compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, for example a patient, once every three weeks. Embodiment 20c. The method according to any one of Embodiments 1c to 19c, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, once a month; or b) once every six weeks to a subject, such as a patient. Embodiment 21c. Treatment with the compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, or at least about 2 years, according to the method according to any one of Embodiments 1c to 20c. Embodiment 22c. The method according to any one of Embodiments 1c to 21c, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, and self-harm in major depressive disorder. Embodiment 23c. The method according to any one of Embodiments 1c to 23c, wherein the depressive disorder is major depressive disorder. Embodiment 24c. The method according to any one of Embodiments 1c to 23c, wherein the depressive disorder is treatment-resistant depression. Embodiment 25c. The method according to any one of Embodiments 1c to 24c, wherein a subject, such as a patient, has not responded adequately to two or more antidepressant treatments before subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 26c. The antidepressant treatment is the method according to Embodiment 25c, which is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants. Embodiment 27c. The antidepressant treatment is the method according to Embodiment 26c, which is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine. Embodiment 28c. The method according to any one of Embodiments 1c to 27c, wherein the subject, such as a patient, is experiencing a major depressive episode. Embodiment 29c. The method according to any one of Embodiments 25c to 28c, wherein at least one of the two or more antidepressants is used to treat the current major depressive episode. Embodiment 30c. The method according to Embodiment 29c, wherein the subject, such as a patient, does not respond to at least one antidepressant in the current major depressive episode. Embodiment 31c. The method of Embodiment 30c, wherein at least one antidepressant is an oral antidepressant. Embodiment 32c. The method according to Embodiment 29c, wherein the subject, such as a patient, does not respond to at least two antidepressants in the current major depressive episode. Embodiment 33c. The method of Embodiment 32c, wherein at least two antidepressants are not the same. Embodiment 34c. ...

Claims

1. A method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof.

2. A method of treating a depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a pharmaceutical composition comprising a therapeutically effective amount of compound (I) 【Chemical Formula 2】 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

3. A method of reducing at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof.

4. A method of treating a major depressive disorder in a subject, such as a patient, in need of such treatment, the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4, wherein the major depressive disorder is acute.

6. A method of treating a major depressive disorder in a subject, such as a patient, in need of such treatment, wherein the subject, such as a patient, meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), the method comprising administering subcutaneously to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical Formula 5】 A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 7** A method of treating treatment-resistant depression in a subject, e.g., a patient, in need thereof, comprising administering to said subject, e.g., patient, a therapeutically effective amount of compound (I) **Formula 6** A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 8** A method of treating depressive symptoms of major depressive disorder in a subject, e.g., a patient, in need thereof, comprising administering to said subject, e.g., patient, a therapeutically effective amount of compound (I) **Formula 7** A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 9** A method of treating a major depressive episode in a subject, e.g., a patient, in need thereof, comprising administering to said subject, e.g., patient, a therapeutically effective amount of compound (I) **Formula 8** A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 10** A method of preventing a major depressive episode in a subject, e.g., a patient, in need thereof, comprising administering to said subject, e.g., patient, a therapeutically effective amount of compound (I) **Formula 9** A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 11** A method of treating recurrent major depressive disorder and a current major depressive episode in a subject, e.g., a patient, in need thereof, comprising administering to said subject, e.g., patient, a therapeutically effective amount of compound (I) **Formula 10** A method comprising subcutaneous administration of (I) or a pharmaceutically acceptable salt thereof. **Claim 12** The method according to any one of claims 9 to 11, wherein the major depressive episode has a duration of at least 4 weeks, for example at least 6 weeks, for example at least 8 weeks.

13. The method according to any one of claims 9 to 12, wherein the major depressive episode has a duration of at least 8 weeks but does not exceed 24 months.

14. A method of treating a subject, such as a patient, in need of such treatment for major depressive disorder, wherein the subject, such as a patient, does not respond to at least two antidepressant treatments, at least one of which is being used for the treatment of the current major depressive episode, and administering to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical Formula 11】 or a pharmaceutically acceptable salt thereof by subcutaneous administration.

15. The method according to claim 14, wherein the at least two antidepressant treatments are two different antidepressant treatments.

16. The method according to any one of claims 1 to 15, wherein the treatment further comprises administering to the subject, such as a patient, one or more additional therapeutic agents.

17. The method according to any one of claims 1 to 16, wherein the treatment further comprises administering to the subject, such as a patient, one or more pharmacologically standard care treatments.

18. The method according to any one of claims 1 to 17, wherein the subject, such as a patient, is treatment-resistant.

19. The method according to any one of claims 1 to 18, wherein the subject, such as a patient, is partially resistant.

20. The method according to any one of claims 1 to 19, wherein the subject, such as a patient, did not respond adequately to at least one antidepressant treatment.

21. The method according to any one of claims 1 to 20, wherein the subject, such as a patient, did not respond adequately to at least two antidepressant treatments.

22. The method according to any one of claims 1 to 21, wherein the subject, such as a patient, is at risk of suicide.

23. The method according to any one of claims 16 to 22, wherein the one or more additional therapeutic agents or standard care treatments include an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, or a combination thereof.

24. The method according to any one of claims 16 to 23, wherein the one or more additional therapeutic agents or standard care treatments are one or more additional antidepressants.

25. The method according to any one of claims 16 to 24, wherein at least one of the one or more additional therapeutic agents or standard care treatments is an oral antidepressant.

26. The method according to any one of claims 23 to 25, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium, such as lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

27. A method of treating treatment-resistant depression in adult patients in need thereof, comprising administering to the subject, such as a patient, a therapeutically effective amount of compound (I) 【Chemical 12】 or a pharmaceutically acceptable salt thereof, in combination with at least one oral antidepressant, by subcutaneous administration.

28. The antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), selective serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOI) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants, according to the method of any one of claims 14 to 27.

29. The antidepressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, vilazodone, and vortioxetine, according to the method of claim 28.

30. The subject, e.g., a patient, continues treatment with the one or more additional therapeutic agents or standard care treatment even after treatment with the compound (I) or a pharmaceutically acceptable salt thereof, according to the method of any one of claims 16 to 29.

31. (a) determining or having determined the baseline MADRS score of the subject, e.g., a patient; and (b) subcutaneously administering a therapeutically effective amount of the compound (I) or a pharmaceutically acceptable salt thereof to the subject, e.g., a patient, wherein the amount of the compound (I) or a pharmaceutically acceptable salt thereof is such that the MADRS score is improved by at least about 30%, e.g., at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to the measured baseline MADRS score (wherein the baseline is the total MADRS score of the subject, e.g., a patient, before subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof) The method according to any one of claims 1 to 30, comprising **Claim 32** The method according to claim 31, wherein, in order to determine the relative effectiveness, the subject, e.g., the patient, is evaluated at regular intervals after step (b) (wherein the evaluation comprises measuring the MADRS score of the subject, e.g., the patient). **Claim 33** The method according to any one of claims 1 to 32, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1 mg to 15 mg (wherein the dose refers to the free base of the compound (I)). **Claim 34** The method according to any one of claims 1 to 33, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.1 mg to 1 mg (wherein the dose refers to the free base of the compound (I)). **Claim 35** The method according to any one of claims 1 to 34, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.3 mg to 1 mg (wherein the dose refers to the free base of the compound (I)). **Claim 36** The method according to any one of claims 1 to 35, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.5 mg to 1 mg (wherein the dose refers to the free base of the compound (I)). **Claim 37** The method according to any one of claims 1 to 36, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg to 5 mg (wherein the dose refers to the free base of the compound (I)). **Claim 38** The method according to any one of claims 1 to 37, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 1 mg to 10 mg (wherein the dose refers to the free base of the compound (I)). **Claim 39** The compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 1 mg to 15 mg (wherein the said dose refers to the free base of the compound (I)), the method according to any one of claims 1 to 38.

40. The compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg or 15 mg (wherein the said dose refers to the free base of the compound (I)), the method according to any one of claims 1 to 39.

41. The compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of 1 mg, 4 mg or 10 mg (wherein the said dose refers to the free base of the compound (I)), the method according to any one of claims 1 to 40.

42. The compound (I) or a pharmaceutically acceptable salt thereof is administered to the said subject, for example a patient, once a week, the method according to any one of claims 1 to 41.

43. The compound (I) or a pharmaceutically acceptable salt thereof is administered to the said subject, for example a patient, twice a week, the method according to any one of claims 1 to 42.

44. The compound (I) or a pharmaceutically acceptable salt thereof is administered to the said subject, for example a patient, once every two weeks, the method according to any one of claims 1 to 43.

45. The compound (I) or a pharmaceutically acceptable salt thereof is administered to the said subject, for example a patient, once every three weeks, the method according to any one of claims 1 to 44.

46. The compound (I) or a pharmaceutically acceptable salt thereof is administered to the said subject, for example a patient, a) once a month; or b) once every six weeks, the method according to any one of claims 1 to 45.

47. The method according to any one of claims 1 to 46, wherein treatment with the compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, or at least about 2 years.

48. The method according to any one of claims 1 to 47, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidal tendency in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder.

49. The method according to claim 48, wherein the depressive disorder is major depressive disorder.

50. The method according to claim 49, wherein the major depressive disorder is acute.

51. The method according to claim 48, wherein the depressive disorder is treatment-resistant depression.

52. The method according to claim 51, wherein the treatment-resistant depression includes partial resistance.

53. In one or more depression assessment tools selected from the group consisting of the Montgomery-Asberg Depression Rating Scale (MADRS), the Mini International Neuropsychiatric Interview (M.I.N.I.), for example version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia-Suicide Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI), the method according to any one of claims 1 to 52, wherein an improvement in score is observed as compared to the baseline.

54. The subject, such as a patient, has a MADRS baseline score of at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the method according to any one of claims 1 to 53.

55. Further comprising determining or having determined the total MADRS score as compared to the baseline assessment, for example about 24 hours after, about 7 days after, about 14 days after, about 21 days after, and / or about 28 days after subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof, thereby evaluating the effectiveness of the treatment (wherein the baseline is the total MADRS score of the subject, such as a patient, before subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof), the method according to any one of claims 1 to 54.

56. The total MADRS score of the subject, such as a patient, decreases as compared to the baseline assessment after subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof, for example, the total MADRS score of the subject, such as a patient, decreases as compared to the baseline assessment about 24 hours after, about 7 days after, about 14 days after, about 21 days after, and / or about 28 days after subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof (wherein the baseline is the total MADRS score of the subject, such as a patient, before subcutaneous administration of the compound (I) or a pharmaceutically acceptable salt thereof), the method according to any one of claims 1 to 55.

57. The subject, e.g., the patient, has an improvement of more than about 30%, e.g., more than about 35%, more than about 40%, more than about 45%, more than about 50% in the total MADRS score after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment. For example, the subject, e.g., the patient, has an improvement of more than about 30%, e.g., more than about 35%, more than about 40%, more than about 45%, more than about 50% in the total MADRS score about 24 hours, about 7 days, about 14 days, about 21 days, and / or about 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment (wherein the baseline is the total MADRS score of the subject, e.g., the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). The method according to any one of claims 1 to 56. Claim 58 The subject, e.g., the patient, has a total MADRS score of less than 12 after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment. For example, the subject, e.g., the patient, has a total MADRS score of less than 12 about 24 hours, about 7 days, about 14 days, about 21 days, and / or about 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof as compared to the baseline assessment (wherein the baseline is the total MADRS score of the subject, e.g., the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof). The method according to any one of claims 1 to 57. Claim 59 Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously in the upper arm or abdominal region. The method according to any one of claims 1 to 58. Claim 60 Compound (I) or a pharmaceutically acceptable salt thereof is administered as a subcutaneous injection. The method according to any one of claims 1 to 59. Claim 61 Compound (I) or a pharmaceutically acceptable salt thereof is administered as a single subcutaneous injection. The method according to any one of claims 1 to 60. Claim 62 The method according to any one of claims 1 to 61, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered as a free base. **Claim 63** The method according to any one of claims 1 to 62, wherein the compound (I) or a pharmaceutically acceptable salt thereof is formulated to be delivered from a subcutaneous injection device. **Claim 64** The method according to any one of claims 1 to 63, wherein the compound (I) or a pharmaceutically acceptable salt thereof is formulated to be delivered from a subcutaneous injection device as a single subcutaneous injection.

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