Methods of subcutaneous administration and administration of olfadil for use in treatment of depressive disorders

Abstract

The present disclosure relates to subcutaneous doses of Compound (I), or a pharmaceutically acceptable salt thereof, for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of NMDA receptors containing NR2B, including, but not limited to, depressive disorders, such as, for example, neurological disorders. Comprising major depressive disorder, treatment of resistant depression, suicide tendency in major depressive disorder, major depressive disorder with suicide thought, major depressive disorder with suicide thought and suicide intention, suicide tendency and seasonal affective disorder. The disclosure also relates to the use of Compound (I) or a pharmaceutically acceptable salt thereof in the treatment of resistant depression in the treatment of patients suffering from severe depressive disorder. Formula (I) imgabs0 #

Description

[0001] Priority claim

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 365,749, filed on June 2, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to the treatment of major depressive disorder (MDD) (including treatment-resistant depression). The present disclosure further relates to the subcutaneous dose and / or scheme of compound (I) or its pharmaceutically acceptable salt, for treating depressive disorder (for example, 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 intention, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder and / or any aforementioned combination). Several embodiments relate to the subcutaneous dose of compound (I) or its pharmaceutically acceptable salt, for treating the disease or obstacle mediated by the negative allosteric regulation of the NMDA receptor containing NR2B or inhibition, including but not limited to depressive disorder (for example, 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 intention, major depressive disorder with suicidal behavior, self-harm in major depressive disorder and / or any aforementioned combination). Several embodiments relate to the use of Compound (I) or a pharmaceutically acceptable salt thereof for treating treatment-resistant depression in a patient suffering from major depressive disorder. Background Art

[0004] Depression is a serious and life-threatening condition with high morbidity and a chronic course. It is a common illness worldwide, affecting over 264 million people (WHO (2020) World Health Organization: Depression (Depression. Key facts) [World Health Organization: Depression (Depression. Key facts)] (Internet, available at: https: / / crediblemeds.org / ). If depression lasts for a long time and is moderate or severe in intensity, it can cause significant suffering to those affected, impairing their ability to work, care for themselves, and maintain relationships.

[0005] Despite the widespread availability of antidepressant medications, approximately one-third of patients with major depressive disorder (MDD) fail to respond adequately to antidepressant treatment of adequate duration and dose, and most patients fail to maintain a long-term response to standard antidepressant medications (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). This chronic symptom predisposes patients to treatment resistance.

[0006] Treatment-resistant depression (TRD) is defined as the lack of clinically meaningful improvement after treatment with at least two different antidepressants at adequate doses and durations.

[0007] Patients with TRD are likely to have suicidal ideation and experience a disproportionate burden of disease, leading to 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).

[0008] Therefore, there is a substantial 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

[0009] Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective for TRD in off-label studies, but is limited by psychotomimetic side effects. Furthermore, ketamine has been shown to have a rapid onset of action and reduce suicidality. Ketamine's efficacy provides a rationale for targeting NMDA receptor inhibition as a rapid-onset antidepressant mechanism.

[0010] (Esketamine) is a noncompetitive NMDA receptor antagonist approved by the U.S. Food and Drug Administration (FDA) for the treatment of TRD, also approved for the treatment of MDD with acute suicidal ideation or behavior, and approved by the European Medicines Agency (EMA) for moderate to severe MDD episodes as an acute short-term treatment in combination with oral antidepressants to rapidly reduce symptoms that constitute a psychiatric emergency based on clinical judgment. Although ketamine and All have demonstrated some degree of efficacy and displayed a rapid mode of action, but their safety profile is not without side effects, which is of interest to both patients and clinicians.

[0011] Targeting specific subsets of NMDA receptors is an approach to potentially mitigate the side effects of NMDA receptor inhibition while retaining antidepressant efficacy. Infusions of traxoprodil (a negative allosteric modulator selective for the NR2B subtype of the NMDA receptor, also known as CP-101,606) are effective in patients with TRD, with a magnitude and duration of response comparable to ketamine, but with a lower potential for dissociative effects in patients. MK-0657 (Rislenemdaz), a selective NR2B antagonist, also known as MK-0657 or CERC-30, does not cause dissociative effects in patients with TRD and is generally safe.

[0012] Conventional pharmacotherapy for major depressive disorder (MDD) includes antidepressants belonging to different classes. These include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), serotonin neuroreceptor reuptake inhibitors (SNRIs), norepinephrine dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants. Many patients begin treatment with one therapy, fail, and then try another, only to fail again, hence the term "treatment resistance."

[0013] The rationale for proposing a new dosage regimen for a given drug is that the development of such a dosage regimen requires balancing patient compliance, therapeutic efficacy, and side effects of the drug; a non-trivial goal and therefore requiring considerable skill.

[0014] Therefore, there is a substantial unmet medical need for more effective or better tolerated rapid-acting antidepressants that can effectively interrupt depressive episodes and prevent future depressive episodes.

[0015] In several embodiments, the present invention provides a novel method for treating depressive disorders. In several embodiments, the depressive disorder is major depressive disorder. In several embodiments, the depressive disorder is treatment-resistant depression. In several embodiments, the depressive disorder is a depressive disorder (including but not limited to, for example, major depressive disorder, treatment-resistant depression, or other depressive disorders disclosed herein) for which a potential fast-acting antidepressant effect may be beneficial. In several embodiments, rapid response is meaningful for those patients suffering from treatment-resistant depression, including groups that do not respond to conventional antidepressants used with sufficient duration and sufficient dosage. Depressive disorders often lead to suicidal thoughts or behaviors, putting patients at risk. In addition, even if conventional antidepressants are ultimately effective, conventional antidepressant treatments may take several weeks to achieve therapeutic benefits. Therefore, there is a need for fast-acting, safe antidepressant treatments. Several embodiments disclosed herein solve the above-mentioned or other problems disclosed herein. As used herein, compound (I) or a compound of formula (I) is 6-((1S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol, which has the following formula:

[0016]

[0017] It has the INN name of onfasprodil. Ofafadil is a NR2B-NMDA receptor non-allosteric modulator (NAM) that can be prepared as described in WO 2016 / 049165 (which is incorporated herein by reference in its entirety).

[0018] Compound (I) or a pharmaceutically acceptable salt thereof is a highly effective, selective and reversible low molecular weight NAM containing NR2B NMDA receptor. One or more treatments disclosed herein are intended to allow patients to quickly achieve significant antidepressant effects, especially patients with treatment-resistant depression.

[0019] Several embodiments disclosed herein provide methods for treating depressive disorders, particularly major depressive disorder, and especially treatment-resistant depression using compound (I) and / or novel formulations comprising compound (I). In several embodiments, advantageously, compound (I) is provided in a fast-acting form and is active quickly in patients. In several embodiments, the method for treating depressive disorders (e.g., major depressive disorder, treatment-resistant depression, etc.) has increased efficacy, wherein compound (I) is provided as a fast-acting formulation (e.g., subcutaneous formulation). Rapid responses (e.g., rapid responses achieved using compound (I) disclosed herein) are meaningful for treatment-resistant depression, even in groups that do not respond to conventional antidepressants used with sufficient duration and sufficient dosage. In several embodiments, as disclosed herein, the compositions of compound (I) disclosed herein can effectively treat depressive disorders (e.g., major depressive disorder, treatment-resistant depression, etc.) in groups that do not respond to conventional antidepressants used with sufficient duration and sufficient dosage. In several embodiments, sufficient duration is the time it is expected that conventional antidepressants will achieve full efficacy in patients.

[0020] Therefore, there remains a need to achieve rapid antidepressant effects, as patients with major depression are at risk for suicide or self-harm, and conventional antidepressant medications may take several weeks to be effective.

[0021] In addition, patients with major depressive disorder and suicidal tendencies typically require hospitalization for 4-5 days. Compound (I) has a fast-acting effect that can reduce the number of days a patient is hospitalized (or eliminate hospitalization entirely), and therefore provides benefits relative to other antidepressants that require at least 4 weeks for the patient to respond to treatment. In several embodiments, treatment with compound (I) as disclosed herein reduces the length of hospital stay by equal to or at least about: 1 day, 2 days, 3 days, 4 days, 5 days, or a range including and / or spanning the above values. For example, in several embodiments, treatment with compound (I) as disclosed herein reduces the length of hospital stay 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.

[0022] In several examples, treatment with Compound (I) allowed patients to rapidly achieve significant improvements in their depressive symptoms and suicidality.

[0023] The present disclosure is also directed to alleviating one or more depressive symptoms in patients with major depressive disorder, particularly treatment-resistant depression. The present disclosure is based, in part, on treating major depressive disorder in patients in need of adjunctive therapy for major depressive disorder, particularly treatment-resistant depression.

[0024] The present disclosure is also intended to alleviate one or more depressive symptoms in patients suffering from the following: suicidality 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. In several embodiments, the present disclosure overcomes these shortcomings by providing a subcutaneous dose of compound (I).

[0025] In a first aspect, a method of treating a depressive disorder in a subject (eg, patient) in need thereof is provided, comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0026] In a second aspect, a method for treating a depressive disorder in a subject (e.g., a patient) in need thereof is provided, the method comprising subcutaneously administering to the subject (e.g., 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.

[0027] In a third aspect, a method of alleviating at least one depressive symptom in a subject (eg, patient) suffering from a depressive disorder is provided, the method comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0028] In a fourth aspect, provided is a method for treating major depressive disorder in a subject (eg, patient) in need thereof, the method comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0029] In a fifth aspect, a method for treating major depressive disorder in a subject (e.g., a patient) in need thereof is provided, wherein the subject (e.g., the patient) meets the DSM-5 criteria for MDD based on the Formulated Clinical Examination for DSM-5 (SCID-5), the method comprising subcutaneously administering to the subject (e.g., the patient) a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

[0030] In a further aspect, provided is a method of treating treatment-resistant depression in a subject (eg, patient) in need thereof, the method comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0031] In a further aspect, provided is a method of treating a major depressive episode in a subject (eg, patient) in need thereof, the method comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0032] In a further aspect, provided is a method for preventing a major depressive episode in a subject (eg, patient) in need thereof, the method comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0033] In a further aspect, provided is a method for treating recurrent major depressive disorder and current major depressive episode in a subject (e.g., patient) in need thereof, the method comprising subcutaneously administering to the subject (e.g., patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0034] In other aspects of the present disclosure, the methods include adjunctive treatment with one or more antidepressants, comprising administering to a subject (e.g., a patient) in need thereof a therapeutically effective amount of one or more antidepressants. The one or more antidepressants may include, for example, lithium, conventional antidepressants, herbal antidepressants, mood stabilizers, antipsychotics, and benzodiazepines. At least one of these drugs.

[0035] The one or more antidepressants may include, for example, a selective serotonin reuptake inhibitor (SSRI), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor (MAOI) including a reversible inhibitor of monoamine oxidase (RIMA), a multimodal antidepressant, or a combination thereof.

[0036] In another aspect, a method for treating major depressive disorder in a subject (e.g., a patient) in need thereof is provided, wherein the subject (e.g., the patient) has not responded to at least two antidepressant therapies (at least one of which is used to treat the current major depressive episode), the method comprising subcutaneously administering to the subject (e.g., the patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0037] In a further aspect, provided is a method of treating treatment-resistant depression in an adult patient in need thereof, the method comprising subcutaneously administering to the subject (e.g., patient) a therapeutically effective amount of a combination of Compound (I) or a pharmaceutically acceptable salt thereof and at least one oral antidepressant. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The cycles in the study protocol described in Example 3 are depicted.

[0039] Figure 2The reversal activity of Compound (I) in haloperidol-induced catalepsy in rats treated with subcutaneous injection of vehicle (negative control), Compound (I) (1, 3, 10, and 30 mg / kg), or ketamine (1, 3, 10, and 30 mg / kg, positive control) is shown. Data are expressed as mean ± SEM (N = 10). Data were analyzed by one-way ANOVA. *p < 0.05 compared to haloperidol (hal) + vehicle.

[0040] Figure 3 Shown are the locomotor activities of rats treated with subcutaneous injection of vehicle (negative control), Compound (I) (1, 3, 10, and 30 mg / kg), or ketamine (1, 3, 10, and 30 mg / kg, positive control).

[0041] Figure 4 The effects of ketamine and compound (I) on rat motor activity using quantitative electroencephalography (qEEG) are shown. In this test, rats were treated with subcutaneous injections of vehicle (negative control) or compound (I) (0.1, 0.3, and 1 mg / kg). Data are expressed as mean ± SEM (N = 10). Data were analyzed by one-way analysis of variance. DETAILED DESCRIPTION

[0042] Several embodiments disclosed herein relate to a subcutaneous dose of compound (I) or a pharmaceutically acceptable salt thereof, for treating a disease or disorder mediated by the negative allosteric regulation or inhibition of NR2B-NMDA receptors. In several embodiments, the disease or disorder mediated by the negative allosteric regulation or inhibition of NR2B-NMDA receptors is a depressive disorder. In several embodiments, the disclosure relates to a subcutaneous dose of compound (I) or a pharmaceutically acceptable salt thereof, for treating major depressive disorder (including but not limited to treatment-resistant depression). The subcutaneous dose of the disclosure may also be used for other diseases or disorders mediated by the negative allosteric regulation or inhibition of NR2B-NMDA receptors, including suicidal tendencies 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, seasonal affective disorder in major depressive disorder. Several embodiments disclosed herein relate to a method for treating a depressive disorder in a subject (e.g., patient) in need thereof. In several embodiments, the method comprises 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. In several embodiments, the depressive disorder is major depressive disorder. In several embodiments, the major depressive disorder is treatment-resistant depression. Several embodiments relate to the use of compound (I) or a pharmaceutically acceptable salt thereof in treating treatment-resistant depression in a patient with major depressive disorder.

[0043] The disorder of the American Psychiatric Association (DSM-V) provides a diagnostic tool for identifying the disorders described herein. Those skilled in the art will recognize that there are alternative nomenclatures, nosologies and classification systems for the mental disorders described herein, and these develop as medicine and science advance.

[0044] definition

[0045] The section headings used herein are for organizational purposes only and should not be interpreted as limiting the subject matter described. Features disclosed under one heading (e.g., composition) can be used in combination with features disclosed under different headings (e.g., methods of treatment). Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as understood by those of ordinary skill in the art. It should be noted that when describing certain features or aspects of the present disclosure, the use of a particular term should not be considered as implying that the term is redefined herein to be limited to including any specific features of the features or aspects of the present disclosure associated with the term.

[0046] Unless otherwise expressly stated, the terms and phrases used in this application (especially in the appended claims) and their variations should be interpreted as open-ended and not restrictive. As an example of the foregoing, the term "including" should be understood as "including, but not limited to", "including but not limited to", etc.; as used herein, the term "comprising" is synonymous with "including", "containing" or "characterized by", and is inclusive or open-ended and does not exclude additional, unlisted elements or method steps; the term "having" should be interpreted as "having at least"; the term "including" should be interpreted as "including but not limited to"; the term "example" is used to provide an exemplary case of the item in question, rather than an exhaustive or limiting list thereof; the use of terms such as "preferred", "preferred", "desirable" or "expected" and words of similar meaning should not be understood to imply that certain features are critical, necessary or even important to the structure or function of the invention, but are merely intended to highlight alternative or additional features that may or may not be used in a particular embodiment of the invention. In addition, the term "comprising" should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the steps recited, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the features or components recited, but may also include additional features or components. Likewise, a group of items connected with the conjunction "and" should not be understood as requiring that each and every one of these items be present in the group, but rather should be understood as "and / or" unless expressly stated otherwise. Likewise, a group of items connected with the conjunction "or" should not be understood as requiring mutual exclusion between the group, but rather should be understood as "and / or" unless expressly stated otherwise.

[0047] Additionally, the phrase "consisting essentially of will be understood to include those elements specifically recited as well as those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of excludes any unspecified elements.

[0048] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can convert from the plural to the singular and / or from the singular to the plural, as appropriate, depending on the context and / or application. For the sake of clarity, various singular / plural arrangements may be explicitly set forth herein. The indefinite article "a" or "an" does not exclude plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0049] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the 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.

[0050] When referring to various features, the term "or including and / or spanning a range of the aforementioned values" may be used. These terms (and variations thereof) are intended to encompass any range including or spanning any of the aforementioned values. For example, with respect to a % of improvement in mood, the % may be expressed as "equal to or at least about: 1%, 5%, 10%, 20% or including and / or spanning a range of the aforementioned values." This language includes not only the specific % provided and ranges exceeding that value (e.g., equal to or at least about 1%, equal to or at least about 5%, equal to or at least about 10%, and equal to or at least about 20%), but also includes ranges of % spanning these values ​​(e.g., from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, 10% to 20%). Similarly, with respect to a % improvement in mood, the % may be expressed as "equal to or less than about: 1%, 5%, 10%, 20% 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., equal to or less than about 1%, equal to or less than about 5%, equal to or less than about 10%, and equal to or less than about 20%), but also includes ranges of % spanning these values ​​(e.g., from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, 10% to 20%).

[0051] As used herein, compound (I), a compound having formula (I), formula (I) is 6-((1S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-1-hydroxyethyl)pyridin-3-ol, which has the following formula:

[0052]

[0053] and has the INN name of ofadil. Ofadil is a highly potent, selective and reversible low molecular weight negative allosteric modulator (NAM) that targets the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR). Evidence suggests that the NR2B selective negative allosteric modulators (NAMs) MK-0657 (also known as CERC-301) and CP-101,606 have a lower frequency of dissociative adverse events. Although the relative contribution of each individual subtype of NMDAR to the adverse effects of pan-NMDAR inhibition is poorly understood due to the lack of selective inhibitors for each subtype, taken together, this suggests that it is feasible to achieve safe but rapidly acting antidepressant efficacy using compounds that selectively inhibit NR2B-containing NMDA receptors.

[0054] As used herein, the term "salt" or "salt form" refers to an acid addition salt or base addition salt of the corresponding compound, e.g., a compound specified herein, e.g., Compound (I) or another pharmaceutically active ingredient, e.g., as defined herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound and are typically not biologically or otherwise undesirable. The compounds specified herein, e.g., Compound (I) or another pharmaceutically active ingredient, e.g., as defined herein, can form acid salts and / or base salts by the presence of amino and / or carboxyl groups or groups similar thereto. The compounds of the present disclosure are capable of forming acid addition salts, and therefore, as used herein, the term pharmaceutically acceptable salt of Compound (I) means a pharmaceutically acceptable acid addition salt of Compound (I).

[0055] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0056] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0057] Organic acids from which salts can be derived include, for example, 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, and the like.

[0058] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0059] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0060] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0061] Pharmaceutically acceptable salts can be synthesized by alkaline or acidic moieties by conventional chemical methods. Usually, such salts can be prepared in the following manner: the free acid form of the compound is reacted with the appropriate alkali (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate etc.) of stoichiometric amount, or by reacting the free base form of the compound with the appropriate acid of stoichiometric amount. Typically, such reactions are carried out in water or in an organic solvent or in a mixture of the two. Usually, where feasible, it is desirable to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Lists of other suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 22nd ed., Mack Publishing Company (2013); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2nd ed.).

[0062] Some quantitative expressions given herein are not qualified with the term "about." It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein refers to the actual given value, as well as an approximation of the given value that can be reasonably inferred based on ordinary skill in the art, including approximations resulting from experimental and / or measurement conditions of the given value. In the Examples, the term "about" refers to a value that is within a range of ±10% of the specified value.

[0063] As used herein, the term "adjunctive therapy," also referred to as auxiliary therapy, adjunctive therapy, additional therapy, or augmentation therapy, is a therapy administered in addition to a primary or initial therapy. In embodiments, the primary or initial therapy in the context of the present disclosure is an antidepressant therapy, for example, as disclosed herein. Non-drug treatments, such as psychotherapy and transcranial magnetic stimulation, may also be options for adjunctive therapy.

[0064] As used herein, unless otherwise indicated, the terms "antidepressant," "antidepressant therapy," "conventional antidepressant," and the like shall refer to any agent that can be used to treat depression. Antidepressants, antidepressant therapy, or conventional antidepressants also include those listed under the list of antidepressants in the MGH Antidepressant Treatment Response Questionnaire (ATRQ), which is incorporated herein by reference in its entirety. In some cases, antidepressant therapy can be augmented with an antipsychotic medication. Suitable examples include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), or multimodal antidepressants; natural products, such as Kava-Kava, St. John's wort, etc.; dietary supplements, such as S-adenosylmethionine, etc.; neuropeptides, such as thyrotropin-releasing hormone, etc.; compounds targeting neuropeptide receptors, such as neurokinin receptor antagonists, etc.; and hormones, such as triiodothyronine, etc. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) include, but are not limited to, fluoxetine (e.g., ), duloxetine (e.g., ), desvenlafaxine (e.g., ), venlafaxine (e.g., ), milnacipran (e.g., ), Citalopram (e.g., ), escitalopram (e.g., ), fluvoxamine (e.g., ), paroxetine (e.g., ), sertraline (e.g., Examples of monoamine oxidase inhibitors include isocarboxazid (e.g., ), phenelzine (e.g., ), tranylcypromine (e.g., ) and selegiline (e.g., Examples of reversible inhibitors of monoamine oxidase include moclobemide. (e.g., ), pyrindole (e.g., ). Norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tricyclic antidepressants include amitriptyline (e.g., ), clomipramine (e.g., ), doxepin (e.g., ), imipramine (e.g., ), trimipramine (e.g., ), amoxapine (e.g., ), desipramine (e.g., ), maprotiline (e.g., ), nortriptyline (e.g., ), protriptyline (e.g., ), pipofiazine (e.g., ), nocitriptyline (e.g., Suitable examples of multimodal antidepressants include vilazodone (e.g., ), vortioxetine. (For example, Suitable norepinephrine dopamine reuptake inhibitors include bupropion (e.g., In the embodiments, "antidepressants," "antidepressant therapy," and "conventional antidepressants" are FDA-approved for the treatment of MDD.

[0065] The term "antipsychotic drugs" includes, but is not limited to:

[0066] (a) Typical or traditional antipsychotics, such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzazepines (e.g., loxapine), indolinones (e.g., morpholinone), substituted benzamides (e.g., sulpiride, amisulpride), etc.; and

[0067] (b) Atypical antipsychotics, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, and others; and others such as sonepiprazole, aripiprazole, nemoprid, and the like. In an 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.

[0068] Those of ordinary skill in the art can readily determine therapeutically effective or efficacious dosage levels and dosage 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 agents disclosed herein). For example, therapeutic dosages and regimens for approved marketed agents are publicly available, for example, as listed on package labels, in standard dosage guides, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / www.pdrel.com), or other sources.

[0069] As used herein, the term "AUClast" refers to the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration. Typically, "time zero" refers to the time of subcutaneous injection of the intended dose.

[0070] Unless otherwise indicated herein, the term "baseline" or "baseline assessment" herein refers to the time immediately prior to initiation of treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0071] The terms "combination therapy", "accompanying" and "simultaneous administration" shall mean that a patient in need is treated by administering compound (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents (e.g., as adjuvant therapy), wherein the one or more additional therapeutic agents are administered by any suitable means. The agents may be administered sequentially, simultaneously or in any order, during the entire or partial period of treatment. The terms "combination therapy", "accompanying" and "concomitant administration" also encompass adjuvant therapy as defined herein. The terms "combination therapy", "accompanying" and "concomitant administration" also encompass treatment with compound (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agents (e.g., standard care medications prescribed for mental disorders (e.g., depressive disorders) as defined herein). In an embodiment, compound (I) is administered in combination with one to five additional therapeutic agents (e.g., 1, 2, 3, 4 or 5 additional therapeutic agents). In another embodiment, compound (I) is administered in combination with one, two, three, four or five additional therapeutic agents. In another embodiment, compound (I) is administered in a regimen with one or two additional therapeutic agents. In another embodiment, compound (I) is administered in a regimen with one other therapeutic agent. In another embodiment, compound (I) is administered in a regimen with another therapeutic agent currently administered to the patient (including one or more current antidepressants to which the patient has insufficient response). In yet further embodiments, compound (I) is administered in a regimen with one or more other therapeutic agents not previously administered to the patient. In yet other embodiments, compound (I) is administered in a regimen with one or more other therapeutic agents previously administered to the patient. When compound (I) and one or more other therapeutic agents are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different, more typically different. One or more other therapeutic agents may be administered according to the attending physician's prescription and / or its label, and compound (I) is administered as described herein. Typically, the patient receives treatment with an antidepressant and compound (I) simultaneously, both of which are administered according to their prescribed dosing regimen. Compound (I) and one or more antidepressants can be administered simultaneously according to a simultaneous or alternating schedule, at the same or different times during the course of therapy, in divided or single forms. In embodiments, the one or more additional therapeutic agents are selected from one or more antidepressants, antipsychotics (e.g., atypical antipsychotics), mood stabilizers (e.g., lithium), benzodiazepines In certain embodiments, the one or more additional therapeutic agents are one or more antidepressants.

[0072] As used herein, the term "depressive episode" or "major depressive episode" refers to the features of major depressive disorder as defined herein.

[0073] A "major depressive episode" can be defined as a depressed mood or loss of interest lasting at least two weeks, possibly accompanied by other depressive symptoms, particularly symptoms of major depressive disorder, sufficient to meet the criteria for major depressive disorder as specified in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition: DSM 5. Symptoms must persist for most of the day (i.e., at least two-thirds of the patient's waking hours) and nearly every day (i.e., at least ten out of fourteen days) for at least two consecutive weeks. Patients often describe "depressed mood" as feeling sad, hopeless, helpless, or worthless. To an observer, patients may also appear sad, for example, through facial expressions, posture, voice, and tears. Children and adolescents may have an irritable mood. Patients often describe "loss of interest" as having less interest in hobbies or not taking any pleasure in activities that they previously found pleasurable.

[0074] A major depressive episode may be accompanied by other symptoms of depression, including significant weight loss or weight gain (eg, greater than 5 percent weight change in a month) when not dieting, or decreased or increased appetite; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; decreased ability to think or concentrate; or indecisiveness; and recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or suicide attempts.

[0075] As used herein, the term "Cmax" shall refer to the maximum observed plasma concentration determined after any administration (eg, single or repeated administration). In some embodiments, the methods disclosed herein further comprise measuring the patient's plasma level.

[0076] As used herein, the term "depressive disorder" is intended to include clinical disorders that are mainly sadness or depressed mood and are accompanied by psychological and / or physical symptoms.Depressive disorder can be mild depressive disorder, moderate depressive disorder, major depressive disorder, clinical depressive disorder or postpartum depression.Exemplary depressive disorder includes, but is not limited to, major depressive disorder, including suicidal tendencies in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intention, self-harm in major depressive disorder with suicidal behavior and major depressive disorder, persistent depressive disorder, seasonal affective disorder, perinatal depression (such as postpartum depression), premenstrual dysphoric disorder, situational depression, lack of pleasure, melancholy, middle-aged depression, late-life depression, depression caused by identifiable stressors, treatment-resistant depression, partially resistant depression and combinations thereof, each of which is expected to be treated using the methods and compositions described herein. There are many methods and techniques well known to those skilled in the art for diagnosing depressive disorder, for assessing the state or severity of such disorders or their symptoms over time and for monitoring the state or severity of such disorders or symptoms over time, including the response to treatment or therapy. In an embodiment, the depressive disorder is major depressive disorder. In another embodiment, the depressive disorder is treatment-resistant depression. In another embodiment, the depressive disorder is seasonal affective disorder.

[0077] As used herein, the term "depressive symptoms" refers to one or more symptoms associated with: depressive disorder, particularly major depressive disorder, which includes persistent anxiety or sad feelings, helplessness, despair, pessimism, guilt and / or worthlessness, lack of energy, restlessness, irritability, fatigue, loss of interest in pleasant activities or hobbies, excessive sleep or insomnia, overeating or loss of appetite, difficulty thinking, concentrating or making decisions, suicidal thoughts, and suicide attempts. The existence, quantity, severity, frequency, and duration of these symptoms may vary from individual to individual, and may change over time for a particular individual. Depressive symptoms can be manifested as depressive disorder, major depressive disorder.

[0078] The terms "drug", "active substance", "active ingredient", "pharmaceutically active ingredient", "active agent" or "therapeutic agent" are understood to mean a compound, particularly a compound of the type specified herein, in free form or in pharmaceutically acceptable salt form.

[0079] As used herein, the term "no response" refers to an inadequate response to a previous or current antidepressant treatment due to insufficient efficacy, for example, if the patient indicates little to no improvement in their current symptoms. The previous or current antidepressant treatment has been used for a sufficient duration and at a sufficient dose, for example, a therapeutically effective dose. For example, the previous or current antidepressant treatment has been used for at least 4 weeks, for example, at least 6 weeks. In several embodiments, a patient who has not responded to a drug is a patient who has been treated with the drug for a period of time equal to or at least about 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or a range including and / or spanning the above values. A lack of response can be assessed by a clinician skilled in treating the relevant disease.

[0080] As used herein, "inadequate response" refers to a patient experiencing less than about a 50% reduction in depression symptom severity since the start of treatment. Typically, an inadequate response is during a current / active episode of depression. In some embodiments, an inadequate response refers to a patient experiencing a reduction in depression symptom severity of about 26% to less than about 50% since the start of treatment. In other embodiments, an inadequate response refers to a patient experiencing a reduction in depression symptom severity of 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 experiencing a 25% or less reduction in depression symptom severity from the start of treatment, a 10% or less reduction in depression symptom severity from the start of treatment, a 5% or less reduction in depression symptom severity from the start of treatment, or a 0% reduction in depression symptom severity from the start of treatment. The patient's response can be measured by one or more 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.

[0081] As used herein, the term "major depressive disorder" or MDD is defined, for example, with reference to the DSM-5 criteria (the entire contents of which are incorporated herein by reference). Major depressive disorder generally refers to a single or recurrent major depressive episode. It is characterized by 1) a mental disturbance that meets the following five or more symptoms, which occur within the same 2-week period and represent a change from previous functioning; at least one of the symptoms is (i) depressed mood or (ii) loss of interest or pleasure:

[0082] i) depressed / sad mood; ii) loss of interest and pleasure; iii) significant weight loss or weight gain or decreased or increased appetite when not dieting; 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) decreased or indecisive ability to think or concentrate; ix) recurrent thoughts of death or suicidal ideation, plans, or attempts; 2) symptoms cause clinically significant distress or impairment in social, occupational, or other functioning; 3) the episode is not better explained by a psychotic disorder; 4) the episode is not due to the physiological effects of a substance or other medical condition; 5) a history of a manic or hypomanic episode (Diagnostic and Statistical Manual of Mental Disorders, 5th ed., American Psychiatric Association, 2013). The criteria for a major depressive episode / disorder are further defined below:

[0083]

[0084]

[0085] In principle, 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 a specific embodiment, the major depressive disorder is acute major depressive disorder.

[0086] The term “drug with a known risk of torsades de pointes” refers to any drug that can prolong the QT interval and cause torsades de pointes. Examples of drugs known to cause torsades de pointes are listed at www.qtdrugs.org.

[0087] As used herein, the term "non-responder" or "no response" refers to a patient who does not experience clinically meaningful improvement after treatment (e.g., a change of 50% or less from baseline for a given depression assessment test, a change of 25% or less from baseline for a given depression assessment test, a change of 10% or less from baseline for a given depression assessment test, a change of 5% or less from baseline for a given depression assessment test, a change of 0% from baseline for a given depression assessment test (or a range including and / or spanning the foregoing values)), or the improvement is not statistically significant. In several embodiments, the depression assessment test is the MADRS. In several embodiments, the depression assessment test is the MGH-ATRQ. In several embodiments, the depression assessment test is the Hamilton Depression Rating Scale (HAM-D). In several embodiments, the depression assessment test is the Clinical Global Impression-Severity Scale (CGI-S). To the extent that a patient has a partial response to treatment, this means that some mild to moderate symptoms have improved since the start of treatment, but some of the initial symptoms still persist and bother the patient, and these persistent symptoms still affect behavior and function. For example, the patient's motivation, productivity, and interest in their daily activities may still be impaired. In one embodiment, the patient is better than baseline, but still has symptoms, thereby requiring further antidepressant treatment. In another embodiment, the patient experiences a reduction of <50% but ≥25% compared to baseline depression scale scores (including, for example, but not limited to, MADRS, MGH-ATRQ, HAM-D, CGI-S).

[0088] As used herein, the term "patient" refers to a subject who is ill and will benefit from treatment. In an embodiment, the subject (e.g., patient) suffers from major depressive disorder. Mild depressive disorder, moderate depressive disorder, and major depressive disorder can be rated according to the Montgomery-Asberg Depression Rating Scale (MTAS). In some embodiments, the present invention provides a method for treating a depression symptom of a patient with a major depressive disorder (MDD) or a pharmaceutically acceptable salt thereof. The method of treating a depression symptom of a patient with a major depressive disorder (MDD) is characterized by the total score of the severity of the depressive symptoms of the Depression disorder Rating Scale (MADRS). For example, before treatment with compound (I) or a pharmaceutically acceptable salt thereof, the MADRS score of the patient's measurement was 24 or higher. In a specific embodiment, the patient is diagnosed with recurrent major depressive disorder (MDD), and the current major depressive episode continues for at least 4 weeks, for example, at least 6 weeks, for example, at least 8 weeks, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and determined by SCID-5 and sufficient clinical psychiatric assessment. In a specific embodiment of the present disclosure, the patient needs an adjunctive therapy for treatment-resistant depression. In a specific embodiment, the patient is an adult. As used herein, the term "adult" refers to a person of about 18 years of age or older.

[0089] The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject (e.g., a patient) for the treatment of a particular condition (i.e., a disease, disorder or condition or at least one clinical symptom thereof) affecting the subject (e.g., a patient).

[0090] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 22nd ed., Mack Printing Company, 2013, pp. 1049-1070). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0091] As used herein, "pregnancy" is defined as the state of a female following conception until the termination of pregnancy, as determined by a positive human chorionic gonadotropin (hCG) laboratory test.

[0092] As used herein, the term "preparatory behavior" means actions or preparations for a suicide attempt, but before potential harm has occurred. This may include anything beyond verbal expression or thought, such as assembling a method (e.g., buying a gun, collecting pills) or preparing for suicide (e.g., writing a suicide note, giving away items).

[0093] As used herein, the term "psychotherapy" refers to the informed and intentional application of clinical methods and interpersonal approaches derived from established psychological principles with the goal of helping people change their behaviors, cognitions, emotions, and / or other personal characteristics (in the directions identified by the participants).

[0094] As used herein, the term "self-injury" means intentional self-inflicted painful, destructive, or injurious actions, without the intent to die.

[0095] As used herein, the term "standard of care treatment" refers to physician-prescribed treatment for patients with a mental disorder (e.g., major depressive disorder), including but not limited to patients with suicidal tendencies and / or suicidal ideation who have been assessed as being at imminent risk of suicide.

[0096] Typically, standard care treatment is provided by the treating physician or other health care professional as prescribed and is administered concomitantly with Compound (I) treatment, for example, during the same treatment period as Compound (I) treatment. Standard care treatment may also precede treatment with Compound (I) and may continue after treatment with Compound (I) has ceased. For antidepressants used in standard care treatment, Compound (I) and one or more antidepressants may be administered by the same or different routes of administration.

[0097] "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. A subject also refers to, for example, a primate (e.g., a human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, 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, i.e., a patient suffering from, at risk of, or likely to suffer from a disease as described herein. In some embodiments, the subject is a human suffering from, at risk of, or likely to suffer from a disease as described herein. In some embodiments, the subject is a patient, i.e., a subject suffering from, at risk of, or likely to suffer from a disease as described herein or in need of treatment for a disease as 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.

[0098] As used herein, the term "suicide" means death resulting from self-directed injurious behavior with any intent to die as a result of that behavior.

[0099] As used herein, the term "suicidal tendencies" refers to thoughts about suicide (suicidal ideation) as well as suicide, suicide attempts, and preparatory actions (suicidal behavior).

[0100] As used herein, the term "suicide attempt" means a non-fatal, self-directed, potentially harmful act with any intent to die as a result of the act. A suicide attempt may or may not result in harm.

[0101] As used herein, the term "suicidal behavior" includes suicide, suicide attempts, and actions in preparation for suicide.

[0102] As used herein, the term "suicidal ideation" refers to passive thoughts about wanting to die or active thoughts about committing suicide, not accompanied by preparatory actions. Suicidal ideation refers to thinking about or planning suicide. Thoughts can range from making a detailed plan to considering it, but not including final suicidal actions. Passive suicidal ideation refers to thoughts about suicide or self-harm without a plan to carry it out. Active suicidal ideation refers to thoughts about suicide or self-harm with a plan to carry it out.

[0103] As used herein, the term "suicidal ideation with intent" or "suicidal ideation with suicidal intention" refers to passive thoughts about wanting to die or active thoughts about suicide, with a desire, aim, purpose, or goal to take self-destructive action culminating in death. Suicidal ideation with intent or suicidal ideation with suicidal intention can be assessed by a suicide ideation rating scale, which refers to any of a variety of standardized questionnaires, clinical instruments, or symptom lists for measuring the severity of suicidal ideation. Such suicidal ideation symptom rating scales include, but are not limited to, the Suicidal Ideation Inventory (SSI), the Suicide State Form (SSF), the Sheehan Suicide Tracking Scale (S-STS), or the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0104] As used herein, the term "suicidal ideation without intent" refers to passive thoughts about wanting to die or active thoughts about committing suicide without the intention to do so.

[0105] As used herein, the term "stable dose" means that there is no change in the dose or type of pharmaceutical agent.

[0106] As used herein, the terms "treat," "treating," "treatment," or "therapy" mean obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results can include, but are not limited to, alleviating one or more symptoms of a patient suffering from major depressive disorder or treatment-resistant depression, such as those defined herein. For example, one aspect of treatment is that the treatment should have minimal adverse effects on the patient, such as the agent used should have a high level of safety, such as not producing the side effects of previously known treatment regimens. As used herein, for example, with respect to symptoms of a disorder, the term "alleviate" refers to reducing at least one of the frequency and magnitude of the symptoms of the disorder in a patient.

[0107] As used herein, the term "treatment depressive disorder" can refer to the alleviation of the symptoms of depressive disorder such as major depressive disorder, for example, as measured by the reduction of Montgomery-Asberg Depression Disorder Rating Scale (MADRS) score. In some respects, the term "treatment depressive disorder" refers to the change relative to baseline as measured by MADRS score. In some respects, the term "treatment depressive disorder" refers to relief, as measured by the reduction of MADRS score. In some respects, the term "treatment depressive disorder" refers to 50% or greater improvement as measured by MADRS score. In some respects, treatment depressive disorder, for example, MDD, refers to that MDD severity is reduced by at least 50% on standardized rating scales (as disclosed herein, for example, MADRS). The term depressive disorder especially refers to major depressive disorder, for example, treatment-resistant depression. Although MADRS scale is often used as the scale for measuring depression in this article, term " treatment depressive disorder " can also (or alternatively) refer to the score of improvement in any depression measurement disclosed herein (for example, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, Brief International Neuropsychiatric Interview, Cambridge Automated Neuropsychological Test Battery, Digital Symbol Replacement Task, Emotional Deviation Task etc.).In several embodiments, improvement can be the score of increase, and wherein scale provides higher score for the improvement of depression measurement.Alternatively, in several embodiments, the improvement of score can be the reduction of score, and wherein scale provides higher score for the depressive symptom that strengthens.

[0108] As used herein, the term "treatment refractory" or "treatment resistant depression" or TRD is defined, for example, with reference to the DSM-5 criteria (the entire contents of which are incorporated herein by reference). Treatment resistant depression refers to a type of major depressive disorder in which the patient has not responded (e.g., failed to respond or achieved partial response) to adequate doses of at least one antidepressant, particularly at least two different antidepressants (particularly, two antidepressants, but not more than five during the current depressive episode). In other embodiments, TRD is defined as major depressive disorder in a patient who has not responded to at least two oral antidepressants of adequate dose and duration (e.g., at least 6 weeks in duration) in the current depressive episode. For example, treatment-resistant depression can be a depressive disorder that is resistant or unresponsive to one or more antidepressants, such as the antidepressants described herein, such as selective serotonin reuptake inhibitors (SSRIs), serotonin neuroreceptor reuptake inhibitors (SNRIs), norepinephrine dopamine reuptake inhibitors (NDRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants. The above-listed antidepressant classes are not exhaustive. Treatment-resistant depression can be assessed by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), a self-rating scale for determining treatment resistance in major depressive disorder.

[0109] Those skilled in the art will recognize that failure to respond to an adequate course of treatment for a given antidepressant can be determined retrospectively and / or prospectively. In an embodiment, at least one of the failures to respond to an adequate course of treatment for the antidepressant is determined prospectively. In another embodiment, at least two of the failures to respond to an adequate course of treatment for the antidepressant are determined prospectively. In another embodiment, at least one of the failures to respond to an adequate course of treatment for the antidepressant is determined retrospectively. In another embodiment, at least two of the failures to respond to an adequate course of treatment for the antidepressant are determined retrospectively during the current depressive episode.

[0110] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or agent that causes a biological or pharmaceutical response (including alleviation of one or more symptoms of the disease or disorder being treated) in a subject sought by a doctor or other clinician. In some embodiments of the present disclosure, the therapeutically effective amount of compound (I) is between about 0.1 mg and about 15 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 0.1 mg and about 1 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 0.3 mg and about 1 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 0.5 mg and about 1 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 1 mg and about 5 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 1 mg and about 10 mg. In other embodiments, the therapeutically effective amount of compound (I) is between about 1 mg and about 15 mg. In yet other embodiments, the therapeutically effective amount of compound (I) is about 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. In yet other embodiments, the therapeutically effective amount of compound (I) is 1 mg. In yet other embodiments, the therapeutically effective amount of compound (I) is 4 mg. In yet other embodiments, the therapeutically effective amount of compound (I) is 10 mg.

[0111] As used herein, "females of reproductive potential" refers to all females who are physiologically capable of becoming pregnant, unless they are using a highly effective contraceptive method while taking Compound I and for 1 week after the last treatment. Highly effective contraceptive methods include:

[0112] • Complete abstinence (when this is consistent with the subject's preferences and daily lifestyle). Cyclic abstinence (e.g., calendar, ovulation, temperature, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

[0113] - Female bilateral tubal ligation, female sterilization (with bilateral oophorectomy, with or without hysterectomy), or total hysterectomy at least six weeks prior to re-administration of Compound I. In the case of oophorectomy alone, only if the female's reproductive status has been confirmed by subsequent hormone level assessment.

[0114] Male sterilization (at least 6 months before screening). For female participants in the study, the vasectomized male partner should be the participant's only partner.

[0115] Use of an intrauterine device (IUD) or intrauterine system (IUS). If an IUD or IUS is used, the device or system should have been inserted and well tolerated by the patient for at least 3 months before receiving study treatment.

[0116] The use of oral (estrogen and progestin), injectable, or implantable hormonal contraceptive methods for contraceptive purposes is not permitted.

[0117] Women were considered postmenopausal and without reproductive potential when they had 12 months of natural (spontaneous) amenorrhea and had an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to treatment with Compound I. In the case of oophorectomy alone, a woman was considered without reproductive potential only if her reproductive status had been confirmed by subsequent hormonal level assessment.

[0118] As used herein, the term "subject (eg, patient)" refers to a mammal, preferably a human (male or female). Specifically, the subject is a patient.

[0119] As used herein, a subject (eg, patient) is "in need of" a treatment if the subject (eg, patient) would benefit biologically, medically, or in quality of life from such treatment.

[0120] The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

[0121] Treatments for depression

[0122] The present disclosure provides methods for treating major depressive disorder (MDD). The methods generally involve subcutaneously administering a therapeutically effective amount of Compound I to an individual suffering from MDD. In various embodiments, the treatment is combined with one or more antidepressant therapies (e.g., one or more oral antidepressants).

[0123] In some embodiments, the diagnosis of MDD is confirmed by meeting the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) MDD criteria based on the DSM-5 Formulated Clinical Examination (SCID-5). In some embodiments, the subject is characterized by a Montgomery-Asberg Depression Rating Scale (MADRS) ≥ 20, e.g., ≥ 21, ≥ 22, ≥ 23, ≥ 24, ≥ 25.

[0124] Disclosed herein are methods for treating a depressive disorder (e.g., major depressive disorder) in a patient in need thereof, comprising subcutaneously administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient. The disclosure also relates to methods for treating treatment-resistant depression in a patient in need thereof, comprising subcutaneously administering Compound 1 or a pharmaceutically acceptable salt thereof to the patient.

[0125] The present disclosure particularly relates to methods of treating treatment-resistant depression in adult patients in need thereof, 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.

[0126] The present disclosure provides methods for treating depressive symptoms in subjects (e.g., patients) suffering from depression, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof subcutaneously to the subject (e.g., patient). The present disclosure also provides methods for treating depressive symptoms in subjects (e.g., patients) suffering from major depressive disorder, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof subcutaneously to the subject (e.g., patient). The present disclosure also provides methods for treating depressive symptoms in subjects (e.g., patients) suffering from major depressive disorder with acute suicidal ideation or behavior, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof subcutaneously to the subject (e.g., patient). The present disclosure further provides methods for treating depressive symptoms in subjects (e.g., patients) suffering from treatment-resistant depression, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof subcutaneously to the subject (e.g., patient).

[0127] The present disclosure also provides methods for alleviating at least one depressive symptom in a subject (eg, patient) suffering from a depressive disorder, comprising subcutaneously administering to the subject (eg, patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously to a subject (eg, a patient) to alleviate one or more symptoms associated with major depressive disorder.

[0129] The methods disclosed herein comprise administering to a patient subcutaneously a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition. The pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient. In some embodiments, the methods disclosed herein comprise administering to a patient subcutaneously a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, whether or not in the form of a pharmaceutical composition.

[0130] In some embodiments, the subject (e.g., patient) is characterized as having failed at least one antidepressant treatment according to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) (Gregory M. Chandler, Dan V. Iosifescu, Mark H. Pollack, Steven D. Targum, and Maurizio Fava. Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neuroscience & Therapeutics 16 (2010) 322-325). In some embodiments, the subject (e.g., patient) is characterized as having a suboptimal response to at least one antidepressant treatment. For example, according to the MGH-ATRQ, the subject has a <50% response to at least one antidepressant treatment (≥8 weeks, at an adequate and stable dose for at least 4 weeks). In some embodiments, the subject (e.g., patient) has a single episode of major depressive disorder. In some embodiments, the subject (e.g., patient) has recurrent major depressive disorder. In some embodiments, the subject (e.g., patient) suffers from chronic major depressive disorder. In some embodiments, the subject (e.g., patient) is characterized as suffering from treatment-resistant depression. In some embodiments, the diagnosis of TRD is confirmed by meeting the DSM-5 criteria for MDD and not having enough response to at least two different antidepressants of sufficient dose and duration in the current depressive episode. Typically, the method disclosed herein further comprises administering one or more additional antidepressant treatments, such as oral antidepressants, to the subject (e.g., patient).

[0131] In some embodiments, the disclosure further provides a method for treating a subject (e.g., patient) with recurrent or chronic depression (e.g., recurrent or chronic major depressive disorder), the method comprising administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., patient) in need thereof subcutaneously. In some embodiments, the disclosure further provides a method for treating a subject (e.g., patient) with recurrent major depressive disorder and a current major depressive episode that lasts for at least 8 weeks. In some embodiments, the disclosure further provides a method for treating a subject (e.g., patient) with recurrent major depressive disorder and a current major depressive episode that lasts for at least 8 weeks, wherein the subject (e.g., patient) is treatment-resistant.

[0132] In some embodiments, the present disclosure also provides a method of treating a subject (e.g., a patient) who meets the DSM-5 criteria for MDD based on the Formulated Clinical Examination for DSM-5 (SCID-5), the method comprising subcutaneously administering to the subject (e.g., patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject (e.g., patient) has failed >1 and <8 trials in the current episode according to the MGH ATRQ, and / or has <50% response to current antidepressant therapy (major depressive episode ≥8 weeks) at an adequate or effective and stable dose for at least 4 weeks according to the MGH ATRQ.

[0133] In some embodiments, subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof is used for an outpatient group of depressed subjects (e.g., patients) who are considered to be resistant to treatment. The methods disclosed herein advantageously eliminate the necessity of taking patients to a hospital or clinic for subcutaneous administration. As a result, subjects (e.g., patients) can administer a composition comprising compound (I) or a pharmaceutically acceptable salt thereof at home. In some embodiments, the methods disclosed herein do not require close monitoring of subjects (e.g., patients) in a medically supervised health care environment.

[0134] Dosage and dosing regimen include any combination of those described herein, for example, those described in the administration and dosage sections. For example, in some preferred embodiments, the methods disclosed herein include administering compound (I) or its pharmaceutically acceptable salt subcutaneously to a subject (e.g., patient) in the form of a single subcutaneous injection. Each dose to be administered is within the range of: between about 0.1 mg and about 15 mg, for example, between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or its pharmaceutically acceptable salt. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered at a dosage of about 1 mg. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered at a dosage of about 4 mg. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered at a dosage of about 10 mg.

[0135] 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., patient) in need thereof, the method comprising selecting a subject (e.g., patient) suffering from a depressive disorder.

[0136] 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 (e.g., a patient) has been diagnosed with or is diagnosed with a depressive disorder.

[0137] In various embodiments, there is provided herein a method for treating a depressive disorder in a subject (e.g., a patient) in need thereof, the method comprising administering a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to a subject (e.g., a patient) in need thereof. As disclosed elsewhere herein, in several embodiments, the method comprises administering a dose equal to or less than about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or a compound (I) including and / or spanning the range of the above values. For example, in several embodiments, the method comprises administering a compound (I) in a range of 1 mg to 5 mg, 5 mg to 15 mg, 1 to 12.5 mg, or less than 15 mg. In several embodiments, the subject in need of treatment is a subject suffering from a depressive disorder.

[0138] In various embodiments, provided herein is a method for treating a depressive disorder in a subject (e.g., 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 (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from a depressive disorder.

[0139] In various embodiments, provided herein is a method for treating a depressive disorder in a subject (e.g., 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 (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) has been diagnosed with or is diagnosed with a depressive disorder.

[0140] In certain embodiments, provided herein is a method for treating a depressive disorder in a subject (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from a depressive disorder; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, provided herein is a method for treating a depressive disorder in a subject (e.g., a patient) in need thereof, comprising subcutaneously administering Compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., the patient) has been diagnosed with or is diagnosed with a depressive disorder, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0142] In several embodiments, as disclosed elsewhere herein, the depressive disorder is major depressive disorder. In specific embodiments, there is provided herein a method for treating major depressive disorder in a subject (e.g., patient) in need thereof, the method comprising selecting a subject (e.g., patient) suffering from major depressive disorder; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0143] In several embodiments, as disclosed elsewhere herein, the depressive disorder is major depressive disorder. In a specific embodiment, a method for treating major depressive disorder in a subject (e.g., patient) in need thereof is provided herein, wherein the subject (e.g., patient) has been diagnosed as or is diagnosed as suffering from major depressive disorder, the method comprising subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0144] In several embodiments, as disclosed elsewhere herein, depressive disorder is treatment-resistant depression. In specific embodiments, there is provided herein a method for treating treatment-resistant depression in a subject (e.g., patient) in need thereof, the method comprising selecting a subject (e.g., patient) suffering from treatment-resistant depression; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0145] In several embodiments, as disclosed elsewhere herein, the depressive disorder is treatment-resistant depression. In a specific embodiment, there is provided herein a method for treating treatment-resistant depression in a subject (e.g., patient) in need thereof, wherein the subject (e.g., patient) has been diagnosed with or is diagnosed with treatment-resistant depression, the method comprising subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0146] In several embodiments, as disclosed elsewhere herein, depressive disorder is treatment-resistant depression. In a specific embodiment, there is provided herein a method for treating treatment-resistant depression in a subject (e.g., patient) suffering from major depressive disorder, the method comprising subcutaneously administering a therapeutically effective amount of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0147] In various embodiments, provided herein is a method for long-term treatment of a depressive disorder in a subject (e.g., a patient) in need thereof, comprising administering to the subject (e.g., patient) in need thereof subcutaneously a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof. In embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered for at least six months, e.g., at least one year, up to two years.

[0148] In various embodiments, the present disclosure provides a method of alleviating at least one depressive symptom in a subject (e.g., patient) suffering from a depressive disorder, the method comprising subcutaneously administering to the subject (e.g., patient) a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0149] In various embodiments, the present disclosure provides a method of alleviating at least one depressive symptom in a subject (e.g., a patient) suffering from a depressive disorder, the method comprising subcutaneously administering to the subject (e.g., the patient) a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0150] In various embodiments, the present disclosure provides a method for alleviating at least one depressive symptom in a subject (e.g., patient) suffering from a depressive disorder, the method comprising administering to the subject (e.g., patient) subcutaneously a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, wherein the subject (e.g., patient) has failed to produce an adequate response to two or more antidepressant treatments prior to the administration of compound (I) or a pharmaceutically acceptable salt thereof. In embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0151] In various embodiments, the present disclosure proposes a method for alleviating at least one depressive symptom in a subject (e.g., patient) suffering from a depressive disorder, the method comprising administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to the subject (e.g., patient), wherein the subject (e.g., patient) has been diagnosed with or is diagnosed with a depressive disorder. In an embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0152] In various embodiments, as disclosed elsewhere herein, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality 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 a specific embodiment, the depressive disorder is major depressive disorder. In another specific embodiment, the depressive disorder is treatment-resistant depression. In an embodiment, major depressive disorder comprises a single major depressive episode. In an embodiment, major depressive disorder comprises recurrent major depressive episodes.

[0153] In various embodiments, as disclosed elsewhere herein, the subject (e.g., patient) has a depressive episode, e.g., a major depressive episode, wherein the depressive episode, e.g., a major depressive episode, is unresponsive to treatment with at least one antidepressant, i.e., the subject (e.g., patient) is unresponsive to treatment with at least one antidepressant in a current major depressive episode. In embodiments, at least one antidepressant is an oral antidepressant. One or more antidepressants can be administered to the patient in sufficient dosages, which can be determined by the attending physician and / or can be administered in accordance with the dosage prescribed by its label. Similarly, the antidepressant has been administered for an appropriate duration, e.g., a duration as indicated on its label. In embodiments, the antidepressant has been administered for a duration of at least four weeks, e.g., a duration of at least six weeks.

[0154] In various embodiments, the subject (e.g., patient) has a depressive episode, such as a major depressive episode, wherein the depressive episode, such as a major depressive episode, is unresponsive to treatment with at least two antidepressants, i.e., the subject (e.g., patient) is unresponsive to treatment with at least two antidepressants in a current major depressive episode. In an embodiment, at least one of the at least two antidepressants is an oral antidepressant. One or more antidepressants can be administered to the patient in a sufficient dose, which can be determined by the attending physician and / or can be administered in accordance with the dose prescribed by its label. Similarly, the antidepressant has been administered for an appropriate duration, for example, for a duration as indicated on its label. In an embodiment, the antidepressant has been administered for a duration of at least four weeks, for example, for a duration of at least six weeks.

[0155] In a specific embodiment, the present disclosure provides a method for alleviating at least one depressive symptom in a subject (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from major depressive disorder; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0156] In a specific embodiment, the present disclosure provides a method of alleviating at least one depressive symptom in a subject (e.g., a patient) in need thereof, wherein the subject (e.g., the patient) has been diagnosed with or is diagnosed with major depressive disorder; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0157] In a specific embodiment, the present disclosure provides a method for alleviating at least one depressive symptom in a subject (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from treatment-resistant depression; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0158] In a specific embodiment, the present disclosure provides a method of alleviating at least one depressive symptom in a subject (e.g., a patient) in need thereof, wherein the subject (e.g., the patient) has been diagnosed with or is diagnosed with treatment-resistant depression; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0159] In various embodiments, the present disclosure provides a method for treating major depressive disorder (e.g., treatment-resistant depression), comprising 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 (e.g., a patient) in need of treatment has a major depressive episode, and wherein the subject (e.g., a patient) has not responded to at least one antidepressant in the current major depressive episode.

[0160] In various embodiments, the present disclosure provides a method of treating a depressive disorder (e.g., major depressive disorder, e.g., treatment-resistant depression) in a subject (e.g., a patient) in need thereof, the method comprising the steps of:

[0161] (a) determining or having determined a baseline MADRS score for a subject (e.g., a patient);

[0162] (b) subcutaneously administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to the subject (e.g., patient), wherein the amount of Compound (I) or a pharmaceutically acceptable salt thereof improves (e.g., reduces) the MADRS score by about at least 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%, relative to a measured baseline MADRS score, wherein the baseline is the subject's (e.g., patient's) total MADRS score prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof; and optionally

[0163] (c) periodically reassessing the subject (eg, patient) after step (b) to determine relative effectiveness; wherein reassessing comprises measuring the subject's (eg, patient's) MADRS score.

[0164] In various embodiments, the methods disclosed herein further comprise the steps of: after treatment with Compound (I) or a pharmaceutically acceptable salt thereof, regularly assessing the subject (e.g., patient) for evidence of therapeutic benefit to determine whether continued treatment is necessary. In embodiments, the subject (e.g., patient) is assessed after about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks of treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0165] In various embodiments, the present disclosure provides a method of treating major depressive disorder in a subject (e.g., a patient) in need thereof, wherein the patient has not responded to at least one (e.g., at least two) antidepressants in a current major depressive episode, the method comprising administering a first antidepressant to the subject (e.g., the patient) over a period of at least 4 weeks, e.g., at least 6 weeks, followed by subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof to the patient, and optionally, continuing treatment with the first antidepressant.

[0166] In various embodiments, the present disclosure provides a method of treating treatment-resistant depression in a subject (e.g., a patient) in need thereof, wherein the patient has not responded to at least one (e.g., at least two) antidepressants in a current major depressive episode, the method comprising administering a first antidepressant to the patient over a period of at least 4 weeks, e.g., at least 6 weeks, followed by subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof to the patient, and optionally, continuing treatment with the first antidepressant.

[0167] In various embodiments, the method of treatment further comprises the step of determining or having determined the MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, for example at 24 hours, 7 days, 14 days, 21 days and / or 28 days compared to a baseline assessment, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score of the subject (e.g., patient) before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0168] In various embodiments, the subject (e.g., patient) has a reduced MADRS total score following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, for example, the subject (e.g., patient) has a reduced MADRS total score 24 hours, 7 days, 14 days, 21 days, and / or 28 days following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment.

[0169] In various embodiments, the MADRS total score of the subject (e.g., patient) after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof is improved (e.g., decreased) by more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, in particular more than 50%, compared to the baseline assessment. For example, the MADRS total score of the subject (e.g., patient) 24 hours, 7 days, 14 days, 21 days and / or 28 days after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof is improved by more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, in particular more than 50%, compared to the baseline assessment.

[0170] In various embodiments, the subject (e.g., patient) has a total MADRS score of less than 12, e.g., less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment. For example, the subject (e.g., patient) has a total MADRS score of less than 12, e.g., less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, 24 hours, 7 days, 14 days, 21 days, and / or 28 days following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment.

[0171] In various embodiments, following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, the MADRS total score of the subject (e.g., patient) is reduced by greater than or at least about: 30, 25, 20, 15, 10, 5 points (or a range of values ​​across and / or including the above) as compared to a baseline assessment. In various embodiments, following subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, the MADRS total score of the subject (e.g., patient) is equal to or less than about: 30, 25, 20, 15, 10, 5 points (or a range of values ​​across and / or including the above) as compared to a baseline assessment. In several embodiments, the post-treatment MADRS score is assessed 24 hours, 7 days, 14 days, 21 days, and / or 28 days after the initial subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0172] In various embodiments, after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, the subject (e.g., patient) has an improved score on any depression measure disclosed herein (e.g., Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, Mini-International Neuropsychiatric Interview, Cambridge Automated Neuropsychological Battery, Digit Symbol Substitution Task, Emotional Deviation Task, etc.), compared to a baseline assessment, which improvement (e.g., an increase or decrease, as appropriate) is equal to or at least about: 25%, 30%, 40%, 50%, 60%, 70%, 80%, 100% (or a range across and / or including the above values). In several embodiments, the score after treatment is assessed 24 hours, 7 days, 14 days, 21 days, and / or 28 days after the initial subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0173] In various embodiments, the subject (e.g., patient) has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and does not have major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder.

[0174] In various embodiments, the subject (e.g., patient) aged 18 to 65 years has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0175] In various embodiments, the subject (e.g., patient) has not had an acute depressive episode lasting more than two consecutive years and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0176] In various embodiments, the subject (e.g., patient) does not have an acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-injury in major depressive disorder.

[0177] In various embodiments, the subject (e.g., patient) does not have borderline personality disorder or antisocial personality disorder and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0178] In various embodiments, the subject (e.g., patient) is not clinically diagnosed with autism, dementia, or intellectual disability and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0179] In various embodiments, the subject (e.g., patient) has no history of suicide attempts or suicidal behavior and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0180] In various embodiments, the subject (e.g., patient) is not pregnant or lactating and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

[0181] In various embodiments, the subject (e.g., patient) has no history of active HIV, Covid-19, and hepatitis B or C infection, and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality 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.

[0182] In various embodiments, the subject (e.g., patient) has a resting QTcF of not ≥ 450 msec (male) or not ≥ 460 msec (female) and suffers from a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-injury in major depressive disorder.

[0183] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.1 mg and about 15 mg.

[0184] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.1 mg and about 1 mg.

[0185] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.3 mg and about 1 mg.

[0186] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.5 mg and about 1 mg.

[0187] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 5 mg.

[0188] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 15 mg.

[0189] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 10 mg.

[0190] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 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.

[0191] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0192] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0193] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0194] Advantageously, Compound (I) or a pharmaceutically acceptable salt thereof may be administered once as a single dose.

[0195] In any embodiment of the methods disclosed herein, Compound (I) is administered as the free base.

[0196] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from a depressive disorder; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof. In embodiments, the subject (e.g., patient) has been diagnosed with or is diagnosed with major depressive disorder.

[0197] In various embodiments, present disclosure provides a method of administering compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to a subject (e.g., patient) in need thereof, wherein the subject (e.g., patient) in need thereof is a subject (e.g., patient) who has been diagnosed with or is diagnosed with a depressive disorder; and wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg. In an embodiment, the subject (e.g., patient) has been diagnosed with or is diagnosed with major depressive disorder.

[0198] 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 (e.g., a patient) in need thereof is a subject (e.g., a patient) suffering from a major depressive episode, and wherein the subject (e.g., a patient) has not responded to at least one antidepressant treatment in the current major depressive episode.

[0199] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) in need of treatment is a subject (e.g., a patient) suffering from a depressive disorder and is not suffering from major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder. In an embodiment, the subject (e.g., a patient) has been diagnosed with or is diagnosed with major depressive disorder.

[0200] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) in need of treatment is a subject (e.g., a patient) suffering from a depressive disorder and having not had an acute depressive episode for more than two consecutive years. In an embodiment, the subject (e.g., a patient) has been diagnosed with or is diagnosed with a major depressive disorder.

[0201] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) in need of treatment is a subject (e.g., a patient) suffering from a depressive disorder and having no acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification. In an embodiment, the subject (e.g., a patient) has been diagnosed with or is diagnosed with a major depressive disorder.

[0202] In various embodiments, present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., patient) in need thereof, wherein the subject (e.g., patient) in need of treatment is a subject (e.g., patient) suffering from a depressive disorder and not having borderline personality disorder or antisocial personality disorder. In an embodiment, the subject (e.g., patient) in need of treatment is a subject (e.g., patient) who has been diagnosed with or is diagnosed with a major depressive disorder.

[0203] In various embodiments, present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., patient) in need thereof, wherein the subject (e.g., patient) suffers from a depressive disorder and does not have a clinical diagnosis of autism, dementia, or intellectual disability. In an embodiment, the subject (e.g., patient) in need of treatment is a subject (e.g., patient) who has been diagnosed with or is diagnosed with a major depressive disorder.

[0204] In various embodiments, present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., patient) in need thereof, wherein the subject (e.g., patient) suffers from a depressive disorder and has no history of suicide attempts or suicidal behavior. In an embodiment, the subject (e.g., patient) in need of treatment is a subject (e.g., patient) who has been diagnosed with or is diagnosed with a major depressive disorder.

[0205] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) is suffering from a depressive disorder and is not pregnant or lactating. In an embodiment, the subject (e.g., a patient) in need of treatment is a subject (e.g., a patient) who has been diagnosed with or is diagnosed with a major depressive disorder.

[0206] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., the patient) suffers from a depressive disorder and has no history of active HIV, Covid-19, and hepatitis B or C infection. In embodiments, the subject (e.g., the patient) in need of treatment is a subject (e.g., a patient) who has been diagnosed with or is diagnosed with major depressive disorder.

[0207] In various embodiments, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) suffers from a depressive disorder, wherein the subject (e.g., a patient) suffers from depression and has a resting QTcF of not ≥ 450 msec (male) or not ≥ 460 msec (female). In an embodiment, the subject (e.g., a patient) in need of treatment is a subject (e.g., a patient) who has been diagnosed with or is diagnosed with major depressive disorder.

[0208] In various embodiments, the present disclosure provides a method of subcutaneously administering a compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, wherein the subject (e.g., a patient) has a depressive disorder and an average systolic blood pressure of not >140 mmHg or an average diastolic blood pressure of not >90 mmHg. In several embodiments, after subcutaneous administration of compound (I), the patient's blood pressure does not rise to an average systolic blood pressure of >140 mmHg or a diastolic blood pressure of >90 mmHg.

[0209] In various embodiments, the present disclosure provides methods of subcutaneously administering Compound (I) or a pharmaceutically acceptable salt thereof to a subject (eg, patient) in need thereof, wherein the subject (eg, patient) suffers from a depressive disorder and is not pregnant.

[0210] In various embodiments, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality 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. In specific embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

[0211] In several embodiments as disclosed elsewhere herein, the reduction of depressive symptoms and / or depressive disorders using Compound (I) disclosed elsewhere herein is measured using any one or more of the test conditions provided herein, including those provided in the Examples section below. In several embodiments, the reduction of depressive symptoms and / or depressive disorders is measured by self-report, Montgomery-Asberg Depression Rating Scale (MDRS), or a combination thereof. Depression Rating Scale (MADRS), Mini International Neuropsychiatric Interview (MINI) (e.g., version 7.0.2), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia Suicide Severity Rating Scale (C-SSRS), Clinical Global Impression (CGI) or measured by any single depression measure (e.g., symptom) reported in the above scales. In several embodiments, the reduction of depressive symptoms and / or depressive disorder refers to a reduction of any of the aforementioned scales, measures (e.g., any one or more measures of the MADRS scale) or symptoms by equal to or at least about 50%. In several embodiments, the alleviation of depressive symptoms and / or depressive disorders refers to the alleviation of any of the aforementioned scales, measures or symptoms (relative to baseline), which is equal to or at least about: 10% alleviation, 25% alleviation, 30% alleviation, 40% alleviation, 50% alleviation, 60% alleviation, 70% alleviation, 80% alleviation, 90% alleviation, 100% alleviation or a range including and / or spanning the above values. In several embodiments, the alleviation of depressive symptoms and / or depressive disorders is measured at or at least about 24 hours, 7 days, 14 days, 21 days and / or 28 days after subcutaneous administration of compound (I). In several embodiments, the alleviation of depressive symptoms and / or depressive disorders can be measured as an improvement in the score of a positive outcome (improved mood, etc.).

[0212] In several embodiments, the CADSS, MOAA / S, and AAESI are used to demonstrate the safety of compound (I) administration. The CADSS is a questionnaire that assesses dissociative effects. Each item is scored from 0 to 4 points, and the individual scores are summed to obtain a total score, ranging from a low of 0 to a high of 92 points. Trained staff administering the scale will also record their subjective interpretation of the participant's mental state and overall health, as well as whether any findings may be related to the study drug. The MOAA / S is a scale used to assess participant responsiveness, with scores ranging from 0 (= no response to painful trapezius squeeze) to 5 (= easy response to name spoken in a normal tone [awake]). Memory gaps / forgetfulness are AEs of special interest (AESI). Memory assessments using directed questions are assessed by qualified personnel. In several embodiments, the change in a patient's safety score before and after administration is less than or equal to approximately: 10%, 20%, 30%, 40%, or a range including and / or spanning the above values.

[0213] In some embodiments, the patient population is selected based on the classification of the participant as a CYP2D6 metabolizer phenotype and / or a CYP3A4 metabolizer phenotype. In some embodiments, patients taking CYP2D6 inhibitors or having reduced CYP2D6 activity are excluded from the patient population. In some embodiments, patients taking CYP3A4 inhibitors or having reduced CYP3A4 activity are excluded from the patient population.

[0214] In several embodiments, local tolerance of subcutaneous injection is high (and injection of Compound (I) results in low incidence, low grade lesions or mild symptoms of the aforementioned measures). In several embodiments, subcutaneous injection of Compound (I) provides mild to moderate AEs or no AEs in patients.

[0215] All previous and following examples relating to methods of treatment apply equally to:

[0216] Compound (I) or a pharmaceutically acceptable salt thereof for use in the therapeutic methods according to the present disclosure;

[0217] Use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment methods according to the present disclosure;

[0218] a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment according to the present disclosure; and

[0219] Use of a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof in a method of treatment according to the present disclosure.

[0220] Administration and dosage

[0221] In several embodiments, provided herein are methods for subcutaneously administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof. In the context of this disclosure, the amount administered refers to the free base of Compound (I). In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered to a subject (e.g., a patient) in a fixed dose.

[0222] In various embodiments, there is provided herein a method of administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., patient) in need thereof subcutaneously. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in a fixed dose. In various embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is calculated based on patient weight. In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg of patient weight.

[0223] In various embodiments, the present disclosure provides methods of subcutaneously administering a dose of Compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, e.g., a patient, between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0224] In various embodiments, present disclosure provides a method of administering a compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to a subject (e.g., patient) in need thereof, for example, a dose between about 1 mg and about 15 mg, for example, between about 1 mg and about 10 mg. In several embodiments, the method includes administering a subcutaneous dose equal to or less than about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or a compound (I) including and / or spanning the range of the above values. For example, in several embodiments, the method includes administering a subcutaneous dose range of 1 mg to 5 mg, 1 mg to 10 mg, 5 mg to 15 mg, 1 to 12.5 mg, or less than 15 mg of compound (I). In several embodiments, the subject in need of treatment is a subject suffering from a depressive disorder.

[0225] In various embodiments, as disclosed elsewhere herein, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and 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 between about 1 mg and about 15 mg.

[0226] In various embodiments, as disclosed elsewhere herein, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and 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 between about 1 mg and about 10 mg.

[0227] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection at a dose of about 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.

[0228] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0229] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0230] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0231] In various embodiments, the method comprises subcutaneously administering Compound (I) or a pharmaceutically acceptable salt thereof as a single subcutaneous injection.

[0232] In various embodiments, the method comprises administering Compound (I) or a pharmaceutically acceptable salt thereof subcutaneously in the upper arm or abdominal region.

[0233] In a specific embodiment, the present disclosure provides a method of subcutaneously administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (e.g., a patient) in need thereof, the method comprising selecting a subject (e.g., a patient) suffering from treatment-resistant depression; and subcutaneously administering between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0234] In a specific embodiment, the present disclosure provides a method for treating treatment-resistant depression, comprising administering to a subject (e.g., a patient) in need thereof a dose of compound (I) or a pharmaceutically acceptable salt thereof, between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg, wherein the subject (e.g., the patient) has been diagnosed with or is diagnosed with treatment-resistant depression.

[0235] In various embodiments, Compound (I) is administered as the free base.

[0236] Dosage regimen

[0237] In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered as a single dose without repetition. In several embodiments, compound (I) is administered by a dosing regimen. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered once a week. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered twice a week. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered weekly for an amount equal to or less than about: 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times or a range including and / or spanning the above values. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered once every two weeks. In various embodiments, compound (I) or its pharmaceutically acceptable salt is administered once every three weeks. In yet other embodiments, compound (I) or its pharmaceutically acceptable salt is administered once a month. In yet other embodiments, compound (I) or its pharmaceutically acceptable salt is administered once every six weeks. In various embodiments, the dose of Compound (I) or a pharmaceutically acceptable salt thereof is administered equal to or more than once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks, or a range including and / or spanning the above values.

[0238] In various embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 2 years. In some embodiments, treatment with Compound (I) or a pharmaceutically acceptable salt thereof continues for equal to or at least about: 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, about 2 years, or a range including and / or spanning the above values.

[0239] Packaging or pharmaceutical products

[0240] In further specific embodiments, the disclosure further relates to a package or pharmaceutical product as described herein, wherein Compound (I) is particularly a free base. In further embodiments of the package or pharmaceutical product described herein, the treatment instructions direct the administration of between about 0.1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof, for example, between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof.

[0241] In further embodiments of the packages or pharmaceutical products described herein, the treatment instructions direct the administration of about 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 of Compound (I) or a pharmaceutically acceptable salt thereof.

[0242] In yet further embodiments of the packages or pharmaceutical products described herein, the therapeutic instructions direct that Compound (I) or a pharmaceutically acceptable salt thereof be administered subcutaneously. Additionally, in further specific embodiments of the packages or pharmaceutical products described herein, the therapeutic instructions direct that Compound (I) or a pharmaceutically acceptable salt thereof be administered once every two weeks, once every three weeks, once a month, or once every six weeks.

[0243] Subjects suitable for treatment

[0244] The disclosed method is suitable for treating individuals diagnosed with major depressive disorder. The disclosed method is particularly suitable for treating individuals diagnosed with treatment-resistant or refractory depression. Particularly suitable subjects for treatment with 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 two or more but no more than five previous antidepressant treatments of sufficient dose and duration (e.g., a duration of ≥6 weeks), wherein the two failed treatments are two different antidepressants, 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 who have responded <50% to at least one antidepressant treatment (duration ≥8 weeks, sufficient and stable dose for at least 4 weeks) according to the MGH-ATRQ.

[0245] The disclosed methods are also applicable to subjects with recurrent major depressive disorder (MDD) and a current major depressive episode lasting at least 8 weeks, e.g., as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The diagnosis can also be confirmed by SCID-5 and clinical psychiatric evaluation.

[0246] In various embodiments, the individual is at risk for suicide.

[0247] In various embodiments, the subject is resistant (e.g., has no response or a negative response) to at least one antidepressant drug other than Compound (I) or a pharmaceutically acceptable salt thereof. In yet other embodiments, the subject has a partial response to at least one antidepressant drug other than Compound (I) or a pharmaceutically acceptable salt thereof.

[0248] In various embodiments, the subject (e.g., patient) is characterized as having treatment-resistant or refractory depression. In various embodiments, the subject (e.g., patient) is characterized as having treatment-resistant or refractory depression and is at risk of suicide.

[0249] In various embodiments, the subject (eg, patient) has a MADRS score of at least 20, eg, at least 21, at least 22, at least 23, at least 24 at baseline.

[0250] In various embodiments, the subject (eg, patient) is between 18 and 65 years old.

[0251] In various embodiments, the subject (eg, patient) has no history of treatment failure with esketamine, ketamine, or arketamine.

[0252] In various embodiments, the subject (e.g., patient) suffers from a depressive episode, such as a major depressive episode, wherein the depressive episode (e.g., major depressive episode) is unresponsive to treatment with at least one antidepressant (e.g., conventional antidepressants), i.e., the subject (e.g., patient) is unresponsive to treatment with at least one antidepressant in the current major depressive episode. In an embodiment, at least one antidepressant is an oral antidepressant. One or more antidepressants can be administered to the patient in a sufficient dose, which can be determined by the attending physician and / or can be administered in accordance with the dose prescribed by its label. Similarly, the antidepressant has been administered for an appropriate duration, e.g., for a duration as indicated on its label. In an embodiment, the antidepressant has been administered for a duration of at least four weeks, e.g., for a duration of at least six weeks.

[0253] In various embodiments, the subject (e.g., patient) has a depressive episode, such as a major depressive episode, wherein the depressive episode (e.g., major depressive episode) is unresponsive to treatment with at least two antidepressants (e.g., one or more of which can be conventional antidepressants), i.e., the subject (e.g., patient) is unresponsive to treatment with at least two antidepressants in the current major depressive episode. In an embodiment, at least one of the at least two antidepressants is an oral antidepressant. One or more antidepressants can be administered to the patient in a sufficient dose, which can be determined by the attending physician and / or can be administered in accordance with the dose specified in its label. Similarly, the antidepressant has been administered for an appropriate duration, e.g., a duration as indicated on its label. In an embodiment, the antidepressant has been administered for a duration of at least four weeks, e.g., a duration of at least six weeks.

[0254] In various embodiments, the subject (eg, patient) is male or female.

[0255] In various embodiments, the subject (eg, patient) has not had an acute depressive episode lasting more than two consecutive years.

[0256] In various embodiments, the subject (eg, patient) has not received electroconvulsive therapy during the current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0257] In various embodiments, the subject (eg, patient) has not received transcranial magnetic stimulation during the current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0258] In various embodiments, the subject (eg, patient) has not received vagus nerve stimulation during the current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0259] In various embodiments, the subject (eg, patient) has not received deep brain stimulation during the current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0260] In various embodiments, the subject (eg, patient) has not been previously or currently diagnosed with major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder, eg, as determined by the SCID-5.

[0261] In various embodiments, the subject (eg, patient) does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification.

[0262] In various embodiments, the subject (eg, patient) has not received detoxification therapy within one month prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0263] In various embodiments, the subject (eg, patient) does not have borderline personality disorder or antisocial personality disorder, eg, based on DSM-5 criteria.

[0264] In various embodiments, the subject (eg, patient) does not have a clinical diagnosis of autism, dementia, or intellectual disability.

[0265] In various embodiments, the subject (eg, patient) has no history of suicide attempts or behaviors within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0266] In various embodiments, the subject (eg, patient) does not exhibit suicidal thoughts, eg, as determined by an affirmative response to Q4 or Q5 on the CSSRS at baseline.

[0267] In various embodiments, the subject (e.g., patient) does not exhibit significant signs of renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) < 40 mL / min / 1.73 m at baseline. 2 To indicate.

[0268] In various embodiments, the subject (eg, patient) has no history of hypersensitivity to Compound (I) or a pharmaceutically acceptable salt thereof, or drugs with a similar mechanism of action, ie, drugs that affect NMDA receptors.

[0269] In various embodiments, the subject (e.g., patient) does not have active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

[0270] In various embodiments, the subject (eg, patient) has no history of epilepsy other than childhood febrile seizures.

[0271] In various embodiments, the subject (e.g., patient) does not have a cardiac abnormality or cardiac repolarization abnormality including any of the following:

[0272] a) History of myocardial infarction, angina pectoris or coronary artery bypass surgery within 6 months before treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0273] b) a history of clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, or high-degree atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0274] In various embodiments, the subject (eg, patient) has a resting QTcF of not > 450 msec (male) or not > 460 msec (female) at baseline.

[0275] In various embodiments, the subject (e.g., patient) does not have risk factors for torsades de pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or any of the following:

[0276] a) Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome.

[0277] b) One or more concomitant medications with a “known risk of TdP” that cannot be discontinued or replaced by a safe alternative.

[0278] In various embodiments, the subject (eg, patient) does not have a mean systolic blood pressure >140 mmHg, a diastolic blood pressure >90 mmHg at baseline; or a history of a hypertensive crisis.

[0279] In various embodiments, the subject (eg, patient) has no history of hemorrhagic stroke or known cerebrovascular disorders (eg, aneurysms or arteriovenous malformations) or known aneurysmal vascular disease at other sites (eg, the aorta).

[0280] In some embodiments, the subject (eg, patient) is not a pregnant or lactating (lactating) female.

[0281] In some embodiments, the subject (eg, patient) is not a female of childbearing potential and is not using highly effective contraception.

[0282] In some embodiments, the subject (e.g., patient) is not a sexually active male who is unwilling to use a condom during sexual intercourse while taking Compound 1 or a pharmaceutically acceptable salt thereof and within 1 week after stopping drug treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the subject (e.g., patient) is not taking any of the following drugs as defined in Table 1 during treatment with Compound 1 or a pharmaceutically acceptable salt thereof:

[0284] Table 1

[0285]

[0286]

[0287] Response Metrics

[0288] 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-Asberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity (CGI-S) scale, the Clinical Global Impression-Improvement (CGI-I) scale, the Patient's Global Impression of Change (PGIC), the DSM-5 SCID-5 Formulated Clinical Examination, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Hamilton Depression Rating Scale (HAM-D), and the Mini-International Neuropsychiatric Interview (MINI).

[0289] An improvement in an index or scale known in the art (such as those described below) indicates that Compound (I) is effective for treating MDD. Such improvement can be determined by comparing pre-treatment and post-treatment scores of subjects (e.g., patients) suffering from MDD.

[0290] Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ)

[0291] In various embodiments, the MGH-ATRQ is used to diagnose and / or monitor depression in patients. The MGH-ATRQ uses a stepwise procedure to examine the adequacy of the duration and dosage of previous and current antidepressant treatments (Chandler 2010). When assessing the duration and dosage of antidepressants, the examiner must always inquire about adherence to each treatment. In addition, the MGH-ATRQ assesses the degree of improvement from 0% (no improvement at all) to 100% (complete improvement).

[0292] Montgomery Asberg Depressive Disorder Rating Scale (MADRS)

[0293] In certain embodiments, MADRS is used to diagnose and / or monitor patients. The Montgomery Asberg Depression Rating Scale (MADRS, Sigma (SIGMA) version) is a scale assessed by clinicians, designed to measure depressive disorder severity and detect changes caused by antidepressant treatment: the test consists of 10 items, each scored from 0 (item absent or normal) to 6 (symptoms are severe or persistent), with a possible total score of 60. The higher the score, the more severe the disease. MADRS evaluates obvious sadness, reported sadness, inner tension, sleep, appetite, attention, fatigue, interest level, pessimistic thoughts and suicidal thoughts.

[0294] In one embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of a depressive disorder, eg, as disclosed herein, wherein the treatment of depression is determined by an improvement in the subject's (eg, patient's) total MADRS score.

[0295] Hamilton Depression Rating Scale (HAM-D)

[0296] In some embodiments, the HAM-D is used to diagnose and / or monitor patients. 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 assess the severity of depression in patients and to evaluate the efficacy of antidepressant therapy. HAM-D scores are generally interpreted as follows: very severe, >23; severe, 19-22; moderate, 14-18; mild, 8-13; no depression, 0-7. Response to treatment can be defined as a patient whose HAM-D score decreases by 50% or more. Remission is defined as a HAM-D score of 7 or less.

[0297] Clinical Global Impression-Severity (CGI-S)

[0298] In some embodiments, the CGI-S is used to diagnose and / or monitor patients. The CGI-S (Guy 1976) is a clinician-rated scale that measures the overall severity of a patient's illness and compares it to the severity observed by the physician in other patients. Patients are rated on a scale of 1 to 7, with 1 representing "normal" and 7 representing "the sickest patient." The CGI-S is administered by investigators, subinvestigators, or raters with extensive professional training and experience in assessing psychiatric disorders.

[0299] In one embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of a depressive disorder, eg, as disclosed herein, wherein the treatment of depression is determined by an improvement in the subject's (eg, patient's) CGI-S total score.

[0300] Clinical Global Impression of Improvement (CGI-I)

[0301] In some embodiments, the CGI-I is used to diagnose and / or monitor patients. The Clinical Global Impression of Improvement (CGI-I) scale (Guy 1976) is a clinician-rated scale used to assess overall improvement or worsening of a psychiatric disorder, regardless of whether the researcher believes this is a result of medication. Patients are rated on a scale of 1 to 7, with 1 indicating that the patient has improved significantly and 7 indicating that the patient has worsened significantly.

[0302] In one embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously for the treatment of a depressive disorder, eg, as disclosed herein, wherein the treatment of depression is determined by an improvement in the subject's (eg, patient's) CGI-I total score.

[0303] Patient Global Impression of Change (PGIC)

[0304] In some embodiments, the PGIC is used to diagnose and / or monitor patients. The PGIC scale is designed to quantify disease activity relative to baseline. Participants are asked to calculate the difference between their current and previous health status based on a Likert scale. The PGIC consists of a number of points that show optimal patient preference, discrimination, and test-retest ability, and is adjusted for specific conditions and disease parameters.

[0305] DSM-5 SCID-5 standardized clinical examination

[0306] In various embodiments, the SCID-5 is used to diagnose and / or monitor depression in patients. The SCID-5 is a semi-structured interview guide used to make primary DSM-5 diagnoses (formerly diagnosed on Axis I). This clinician-rated diagnostic assessment is conducted by a researcher, sub-researcher, or assessor who has extensive professional training and experience in diagnosing mental illnesses.

[0307] Pharmaceutical composition

[0308] In several embodiments, pharmaceutical compositions comprising Compound (I) are provided. In several embodiments, the pharmaceutical formulation is suitable for administration to a subject in need of treatment. In several embodiments, pharmaceutical compositions suitable for subcutaneous administration of the present disclosure comprise a combination of Compound (I) and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions before use, which may contain one or more (or all) of antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending agents or thickening agents (e.g., as described in "Remington Essentials of Pharmaceutics, 2013, 1st edition, edited by Linda Felton, Pharmaceutical Press 2012, ISBN 978 0 85711 105 0; in particular in Chapter 30). In several embodiments, pharmaceutical excipients that can be used in combination with Compound (I) include, for example, "Handbook of Pharmaceutical Excipients, 2012, 7th edition, Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, eds., ISBN 978 0 85711 027 5". Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions disclosed herein include one or more of water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate and cyclodextrins). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0309] After the pharmaceutical composition is formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated powder 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 disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to, for example, )), while in other embodiments multiple-use containers (e.g., multiple-use vials) are provided.

[0310] In some embodiments, the pharmaceutical composition is aqueous. In some embodiments, the pharmaceutical composition comprises 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., liquid). In some embodiments, the dry form of Compound (I) is constituted or reconstituted with a carrier prior to use (including at the time of care).

[0311] Specific pharmaceutical compositions for use according to the present disclosure include lyophilized formulations comprising Compound (I) or a pharmaceutically acceptable salt thereof mixed with water. In embodiments, the lyophilized formulation comprises Compound (I) as a free base. In several embodiments, Compound (I) is reconstituted prior to use.

[0312] Concomitant therapy

[0313] In various embodiments, the present disclosure provides a method of treating a depressive disorder in a subject (e.g., a patient) in need thereof, comprising subcutaneously administering to the subject (e.g., the 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 (e.g., an antidepressant treatment).

[0314] In several embodiments, a subject (eg, a patient) may be treated concurrently with an antidepressant and Compound (I) or a pharmaceutically acceptable salt thereof, wherein both are administered according to their prescribed dosing regimens.

[0315] In various embodiments, a "subject (e.g., patient) in need thereof" may be a subject (e.g., patient) who has been prescribed or is currently taking at least one other therapeutic agent ("background therapy") prior to receiving treatment with Compound (I) or a pharmaceutically acceptable salt thereof. Background therapy may be, for example, a standard of care medication prescribed for a mental disorder (e.g., a depressive disorder). Background therapy may be, for example, at least one additional antidepressant disclosed herein. Background therapy may be, for example, a conventional antidepressant. Background therapy may be, for example, at least one additional antidepressant and mood stabilizer, such as lithium, as disclosed herein. Background therapy may be, for example, at least one additional antidepressant and antipsychotic, such as an atypical antipsychotic, as disclosed herein. Background therapy may also include other concomitant medications, such as benzodiazepines. Class drugs, does not prohibit any psychological treatment. In some embodiments, after the subject (e.g., patient) receives compound (I) or a pharmaceutically acceptable salt thereof, the subject (e.g., patient) in need continues background therapy. In other embodiments, the subject (e.g., patient) in need stops receiving background therapy before receiving compound (I) or a pharmaceutically acceptable salt thereof, for example, immediately or gradually stops. In other embodiments, the subject (e.g., patient) receives background therapy for at least 4 weeks, for example, at least 6 weeks, before treatment with compound (I) or a pharmaceutically acceptable salt thereof. In other embodiments, the subject (e.g., patient) receives background therapy for at least 4 weeks, for example, at least 6 weeks, before treatment with compound (I) or a pharmaceutically acceptable salt thereof, and continues background therapy after the subject (e.g., patient) receives compound (I) or a pharmaceutically acceptable salt thereof.

[0316] Treatment with Compound (I) or a pharmaceutically acceptable salt thereof and the background therapies described herein can be used as an augmentation strategy for the treatment of depressive disorders as described herein.A augmentation strategy is particularly useful for the treatment of treatment-resistant depression.

[0317] In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered in addition to one or more other antidepressants currently administered to a subject (e.g., a patient) (including current antidepressants to which the subject (e.g., a patient) has had an inadequate response). In other embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered in addition to an antidepressant not previously administered to a subject (e.g., a patient). In other embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered in a regimen with one or more antidepressants previously administered to a subject (e.g., a patient).

[0318] 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 yet other embodiments, the other antidepressant therapy includes three antidepressants.

[0319] Thus, in one aspect of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in combination with at least one other therapeutic agent to treat a depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously. The depressive disorder may be any of the ones disclosed herein. In embodiments, the depressive disorder is MDD. In particular, the depressive disorder is TRD. In embodiments, the at least one other therapeutic agent is at least one antidepressant, such as an oral antidepressant.

[0320] In several embodiments, Compound (I) and at least one other therapeutic agent, for example, one or more antidepressants (including one or more conventional and herbal antidepressants), one or more antipsychotics, mood stabilizers, one or more benzodiazepines The drugs of the same class may be administered by the same or different routes of administration. Examples of suitable methods of administering the antidepressant include, but are not limited to, oral, intravenous, intranasal, intramuscular, subcutaneous, transdermal, oral, or rectal. In certain embodiments, the at least one additional therapeutic agent is at least one other antidepressant administered orally.

[0321] Thus, compound (I) or a pharmaceutically acceptable salt thereof can be administered as a combination therapy, for example, as an adjunct or additional therapy to one or more other treatments or therapies for a mental disorder (e.g., a depressive disorder). Compound (I) or a pharmaceutically acceptable salt thereof can be administered with one or more additional therapeutic agents, for example, in combination with one to three additional therapeutic agents, for example, in combination with one to two additional therapeutic agents, for example, in combination with one additional therapeutic agent. In a specific embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one other therapeutic agent currently administered to a subject (e.g., a patient). In an embodiment, one or more additional therapeutic agents are selected from one or more antidepressants, one or more antipsychotics, one or more mood stabilizers, one or more benzodiazepines, In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, e.g., an oral antidepressant, to which the subject, e.g., patient, has an inadequate response.

[0322] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered as a combination therapy with one or more additional antidepressants; wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as an acute treatment. In another embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered as a combination therapy with one or more additional antidepressants; wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as an acute treatment and wherein the one or more antidepressants are administered as a long-term treatment.

[0323] In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to a subject (e.g., a patient) who is receiving background therapy as described above for a period of time (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 longer).

[0324] In various embodiments, compound (I) or a pharmaceutically acceptable salt thereof is provided for use in treating a depressive disorder in a patient, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered as an add-on therapy to a patient receiving background therapy as described above for a period of time (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 longer). In some embodiments, treatment with compound (I) or a pharmaceutically acceptable salt thereof while the patient is receiving background therapy as described above is continued for a period equal to or greater than about: 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, about 2 years, or a period of time including and / or spanning the range of the above values.

[0325] One of ordinary skill in the art can readily determine the one or more additional therapeutic agents (e.g., one or more antidepressants, one or more antipsychotics, one or more mood stabilizers, one or more benzodiazepines, as defined herein) Therapeutically effective amounts / dosage levels and dosage regimens of the drug (e.g., a class of drugs) are determined and administered according to their prescribed dosage regimen (e.g., the dosage regimen prescribed by the attending physician and / or as indicated on their labeling). For example, therapeutic dosages and regimens for approved marketed agents are publicly available, for example, as listed on package labels, in standard dosage guides, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / www.pdrel.com), or other sources.

[0326] Examples of antidepressants that can be used in combination or background therapy according to the present disclosure are antidepressants approved by the FDA for major depressive disorder.

[0327] As disclosed elsewhere herein, examples of antidepressants that can be used in combination or background therapy according to the present disclosure include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants, e.g., as described herein.

[0328] In an embodiment, the depressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, desvenlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, pirpindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofiazine, noxetine, vilazodone, vortioxetine, and bupropion.

[0329] In certain embodiments, the antidepressant is selected from the group consisting of serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), or a combination thereof.

[0330] In certain embodiments, 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.

[0331] In various embodiments, at least one antidepressant treatment, such as one of the above-described antidepressants, is being used or is being prescribed to treat a current major depressive episode in a subject (e.g., patient) with major depressive disorder (e.g., treatment-resistant depression).

[0332] As disclosed herein, Compound (I) or a pharmaceutically acceptable salt thereof can be administered in combination with another antidepressant (as 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.

[0333] In various embodiments, as disclosed elsewhere herein, no other antidepressant drug is administered to a subject (eg, patient) during administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0334] In various embodiments, Compound (I) is administered as the free base, as disclosed elsewhere herein.

[0335] In various embodiments, as disclosed elsewhere herein, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality 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. In specific embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

[0336] As disclosed elsewhere herein, all of the above embodiments and the following embodiments relating to the concomitant therapies of the present disclosure also apply:

[0337] Compound (I) or a pharmaceutically acceptable salt thereof for use in concomitant therapy according to the present disclosure;

[0338] Use of compound (I) or a pharmaceutically acceptable salt thereof in concomitant therapy according to the present disclosure;

[0339] a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof for use in concomitant therapy according to the present disclosure; and

[0340] Use of a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof in concomitant therapy according to the present disclosure.

[0341] Further embodiments of the present disclosure

[0342] In another aspect, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0343] In another aspect, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in alleviating at least one depressive symptom in a subject (e.g., a patient) suffering from a depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0344] In another aspect, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0345] In an embodiment, the depressive disorder is selected from major depressive disorder, in particular treatment-resistant depression, suicidality 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. In a specific embodiment, the depressive disorder is major depressive disorder. In another embodiment, the major depressive disorder is treatment-resistant depression.

[0346] On the other hand, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms, wherein compound (I) or its pharmaceutically acceptable salt is administered subcutaneously. The present disclosure relates to a compound or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms in major depressive disorder, wherein compound (I) or its pharmaceutically acceptable salt is administered subcutaneously. The present disclosure further relates to a compound or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms in major depressive disorder with acute suicidal ideation or behavior, wherein compound (I) or its pharmaceutically acceptable salt is administered subcutaneously. The present disclosure further relates to a compound or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression, wherein compound (I) or its pharmaceutically acceptable salt is administered subcutaneously.

[0347] In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in treating major depressive disorder, wherein the major depressive disorder is unresponsive to at least two antidepressant therapies (at least one of which is used to treat the current major depressive episode), wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously. In an embodiment, the at least two antidepressants are two different antidepressants.

[0348] In an embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, for example, by subcutaneous injection, at a dose of between about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg or 0.32 mg / kg of patient body weight.

[0349] In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered subcutaneously at a dosage between about 0.1 mg and about 15 mg, for example, by subcutaneous injection. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 0.1 mg and about 1 mg. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 0.3 mg and about 1 mg. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 0.5 mg and about 1 mg. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 1 mg and about 5 mg. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 1 mg and about 10 mg. In an embodiment, compound (I) or its pharmaceutically acceptable salt is administered at a dosage between about 1 mg and about 15 mg. In further 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.

[0350] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 4 mg, or about 10 mg.

[0351] In a specific embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder (e.g., treatment-resistant depression), wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0352] In a specific embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder, wherein the major depressive disorder is unresponsive to at least one antidepressant therapy for a current major depressive episode, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0353] In a specific embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder, wherein the major depressive disorder is refractory to at least two antidepressant therapies for a current major depressive episode, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg.

[0354] In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in treating major depressive disorder, wherein the major depressive disorder is unresponsive to at least two antidepressant therapies (at least one of which is used to treat a current major depressive episode), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg. In embodiments, the at least two antidepressants are two different antidepressants.

[0355] In a specific embodiment, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating recurrent major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0356] In a specific embodiment, the disclosure further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating recurrent major depressive disorder in a subject (e.g., a patient) and a current major depressive episode that lasts for at least 8 weeks, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg. In a specific embodiment, the major depressive episode lasts for at least 8 weeks but no more than 24 months.

[0357] In an embodiment, the depressive disorder is characterized by treatment-resistant depression. In an embodiment, the diagnosis of TRD is confirmed by meeting the DSM-5 criteria for MDD and having an inadequate response to at least two different antidepressants of adequate dose and duration in the current depressive episode. In a specific embodiment, the subject (e.g., patient) has not responded to two or more but no more than five previous antidepressant treatments of adequate dose and duration (e.g., ≥6 weeks duration) according to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), wherein the two failed treatments are two different antidepressants.

[0358] In an embodiment, the subject (e.g., patient) is characterized by having a <50% response to at least one antidepressant treatment, e.g., according to the MGH-ATRQ, the subject currently has a major depressive episode lasting ≥8 weeks and has been receiving antidepressant therapy for at least 4 weeks at an adequate and stable dose (i.e., an effective dose). In an embodiment, the subject (e.g., patient) has a single episode of major depressive disorder. In an embodiment, the subject (e.g., patient) has recurrent major depressive disorder.

[0359] In certain embodiments, the subject is a human patient.

[0360] In certain embodiments, the subject is an adult patient.

[0361] In another embodiment, compound (I) or its pharmaceutically acceptable salt is administered as a single dose without repetition. In another embodiment, compound (I) is administered by a dosing regimen. In another embodiment, compound (I) or its pharmaceutically acceptable salt is administered once a week. In another embodiment, compound (I) or its pharmaceutically acceptable salt is administered twice a week. In another embodiment, compound (I) or its pharmaceutically acceptable salt is administered once every two weeks. In another embodiment, compound (I) or its pharmaceutically acceptable salt is administered once every three weeks. In yet further embodiments, compound (I) or its pharmaceutically acceptable salt is administered once a month. In yet further embodiments, compound (I) or its pharmaceutically acceptable salt is administered once every six weeks.

[0362] In certain embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks or less frequently.

[0363] In other embodiments, the treatment further comprises administering one or more additional therapeutic agents, for example, one or more standard of care drugs for treating mental disorders (e.g., depressive disorders). In embodiments, the treatment further comprises administering one or more additional therapeutic agents prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof for a period of about at least 4 weeks, for example, about at least 6 weeks. In embodiments, after treatment with Compound (I) or a pharmaceutically acceptable salt thereof, treatment with one or more additional therapeutic agents is continued. In embodiments, the one or more additional therapeutic agents are selected from one or more antidepressants, one or more antipsychotics, one or more mood stabilizers, one or more benzodiazepines, In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, for example, an oral antidepressant.

[0364] In embodiments, the one or more additional therapeutic agents are selected from antidepressants, antipsychotics, mood stabilizers, benzodiazepines, In certain embodiments, the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, and combinations thereof.

[0365] In another embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered in addition to one or more other antidepressants currently administered to the subject (e.g., patient), including current antidepressants to which the subject (e.g., patient) has had an inadequate response. In another embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered in addition to an antidepressant not previously administered to the subject (e.g., patient). In another embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is administered in a regimen with one or more antidepressants previously administered to the subject (e.g., patient).

[0366] In a specific embodiment, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a subject (e.g., patient), wherein the subject (e.g., patient) has not responded to at least one antidepressant therapy in a current major depressive episode, wherein the treatment comprises administering a first antidepressant to the subject (e.g., patient) over a period of at least 4 weeks (e.g., at least 6 weeks), followed by subcutaneous administration of a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof to the subject (e.g., patient), and optionally, continuing treatment with the first antidepressant.

[0367] In a specific embodiment, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a subject (e.g., patient), wherein the subject (e.g., patient) has not responded to at least two antidepressant therapies in a current major depressive episode, wherein the treatment comprises administering a first antidepressant to the subject (e.g., patient) over a period of at least 4 weeks (e.g., at least 6 weeks), followed by subcutaneous administration of a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg of Compound (I) or a pharmaceutically acceptable salt thereof to the subject (e.g., patient), and optionally, continuing treatment with the first antidepressant.

[0368] In further embodiments, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, and wherein the treatment further comprises administration of one or more additional therapeutic agents, e.g., an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine drugs or a combination thereof.

[0369] As described herein, compound (I) can be used as an adjunctive therapy, or in other words, used as an adjunct to one or more therapeutic agents (e.g., one or more antidepressants), or used in combination with one or more therapeutic agents (e.g., one or more antidepressants), for example, a patient may have already been administered or is also administered one or more antidepressants. Thus, in further specific embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof, for use as described herein, including subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, as an adjunctive therapy with an effective amount of one or more therapeutic agents (e.g., one or more antidepressants). In further specific embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof, for use as described herein, including subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents (e.g., one or more antidepressants). In further specific embodiments, the present disclosure relates to compound (I) or a pharmaceutically acceptable salt thereof, for use as described herein, including subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents (e.g., one or more antidepressants).

[0370] In further specific embodiments, the disclosure further relates to packaging or pharmaceutical products as described herein, wherein the treatment instructions guide the subcutaneous administration of an effective amount of compound (I) or a pharmaceutically acceptable salt thereof, as an adjunctive therapy for an effective amount of one or more therapeutic agents (e.g., one or more antidepressants). In further specific embodiments, the disclosure further relates to packaging or pharmaceutical products as described herein, wherein the treatment instructions guide the 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 (e.g., one or more antidepressants). In further specific embodiments, the disclosure further relates to packaging or medicines as described herein, wherein the treatment instructions guide the 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 (e.g., one or more antidepressants). The one or more antidepressants may be selected from any antidepressant disclosed herein.

[0371] In further embodiments, provided is 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.

[0372] In further embodiments, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents to treat major depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0373] In further embodiments, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in combination with one or more additional therapeutic agents to treat treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0374] In a specific embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in combination with one or more oral antidepressants to treat major depressive disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0375] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in combination with one or more oral antidepressants to treat treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0376] In a specific embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in combination with one or more oral antidepressants to treat treatment-resistant depression, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, or between about 1 mg and about 15 mg.

[0377] In a specific embodiment, the disclosure further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression in a patient, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, and wherein the treatment further comprises administering one or more oral antidepressants. In an embodiment, the patient is an adult.

[0378] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.1 mg.

[0379] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.2 mg.

[0380] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.3 mg.

[0381] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.4 mg.

[0382] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 mg.

[0383] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.6 mg.

[0384] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.7 mg.

[0385] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.8 mg.

[0386] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.9 mg.

[0387] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg.

[0388] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg.

[0389] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 3 mg.

[0390] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg.

[0391] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 mg.

[0392] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 6 mg.

[0393] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 7 mg.

[0394] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 8 mg.

[0395] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 9 mg.

[0396] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg.

[0397] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 11 mg.

[0398] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 mg.

[0399] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 13 mg.

[0400] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 14 mg.

[0401] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 15 mg.

[0402] In further embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg, about 4 mg, or about 10 mg.

[0403] In an embodiment, 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, a norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor (MAOI) including a reversible inhibitor of monoamine oxidase (RIMA), or a multimodal antidepressant.

[0404] In an embodiment, the depressant is selected from the group consisting of fluoxetine, duloxetine, venlafaxine, desvenlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine, tranylcypromine, selegiline, moclobemide, pirpindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofiazine, noxetine, vilazodone, vortioxetine, and bupropion.

[0405] In certain embodiments, the antidepressant therapy is selected from the group consisting of serotonin reuptake inhibitors (SSRIs), selective serotonin, norepinephrine reuptake inhibitors (SNRIs), and combinations thereof.

[0406] In certain embodiments, the antidepressant therapy is selected from the group consisting of SSRIs, SNRIs, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof.

[0407] In certain embodiments, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline, and combinations thereof.

[0408] In certain embodiments, the antidepressant is an oral antidepressant.

[0409] Further embodiments of the present disclosure are summarized as follows:

[0410] Example a

[0411] Embodiment 1a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0412] Example 2a. A pharmaceutical composition for use in treating a depressive disorder, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is administered subcutaneously.

[0413] Example 3a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a depressive disorder, wherein the treatment comprises the following steps:

[0414] (a) determining or having determined a baseline MADRS score for a subject, such as a patient; and

[0415] (b) administering compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to the subject, e.g., patient, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof improves the MADRS score by about 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%, relative to a measured baseline MADRS score, wherein the baseline is the subject's, e.g., patient's, MADRS total score prior to subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0416] Embodiment 4a. A compound for use as described in embodiment 3a or a pharmaceutically acceptable salt thereof, wherein the subject, eg, patient, is periodically evaluated after step (b) to determine relative effectiveness, wherein the evaluation comprises measuring the subject, eg, patient's MADRS score.

[0417] Embodiment 5a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder is selected from major depressive disorder, in particular treatment-resistant depression, suicidality 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.

[0418] Embodiment 6a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder is major depressive disorder, such as acute MDD.

[0419] Embodiment 7a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder is treatment-resistant depression.

[0420] Embodiment 8a. A compound for use as described in embodiment 7a, or a pharmaceutically acceptable salt thereof, wherein the treatment-resistant depression comprises partial resistance.

[0421] Example 9a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0422] Example 10a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms in major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0423] Embodiment 11a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms in major depressive disorder with acute suicidal ideation or behavior, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0424] Example 12a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating depressive symptoms in treatment-resistant depression, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0425] Embodiment 13a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of alleviating at least one depressive symptom in a subject, eg, a patient, having a depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0426] Embodiment 14a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0427] Embodiment 15a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in preventing a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0428] Embodiment 16a. The compound for use according to any one of embodiments 14a and 15a, or a pharmaceutically acceptable salt thereof, wherein the major depressive episode lasts for at least 4 weeks, eg, for at least 6 weeks, at least 8 weeks.

[0429] Example 17a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, particularly acute MDD, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0430] Example 18a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a single episode of major depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0431] Embodiment 19a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating recurrent major depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0432] Embodiment 20a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating recurrent major depressive disorder and a current major depressive episode lasting at least 4 weeks, e.g., at least 6 weeks, e.g., at least 8 weeks, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0433] Embodiment 21a. A compound for use according to any one of embodiments 14a to 20a, or a pharmaceutically acceptable salt thereof, wherein the major depressive episode lasts for at least 6 weeks, eg, for at least 8 weeks but less than 24 months.

[0434] Embodiment 22a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode, eg, the current depressive episode, is inadequately responsive to at least one antidepressant treatment.

[0435] Embodiment 23a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode is partially responsive to at least one antidepressant treatment, such as in the current depressive episode.

[0436] Embodiment 24a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode, eg, the current depressive episode, has not been adequately responsive to at least two antidepressant treatments.

[0437] Embodiment 25a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode is partially responsive to at least two antidepressant treatments, such as in the current depressive episode.

[0438] Embodiment 26a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode, eg, the current depressive episode, has not been adequately responsive to at least two but not more than five antidepressant treatments.

[0439] Embodiment 27a. The compound for use as described in any one of Embodiments 24a to 26a, or a pharmaceutically acceptable salt thereof, wherein the at least two antidepressant treatments are two different antidepressants.

[0440] Embodiment 28a. A compound for use as described in any one of embodiments 22a to 27a, or a pharmaceutically acceptable salt thereof, wherein the one or more antidepressant treatments have been administered for at least 4 weeks, eg, for at least 6 weeks.

[0441] Embodiment 29a. A compound for use as described in any one of embodiments 22a to 28a, or a pharmaceutically acceptable salt thereof, wherein 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)), or a multimodal antidepressant.

[0442] Embodiment 30a. A compound for use as described in any one of embodiments 22a to 29a, or a pharmaceutically acceptable salt thereof, wherein 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.

[0443] Embodiment 31a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0444] Embodiment 32a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating major depressive disorder in a subject, e.g., a patient, wherein the subject, e.g., patient meets the DSM-5 criteria for MDD based on the Structured Clinical Examination for DSM-5 (SCID-5), and wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0445] Embodiment 33a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the treatment further comprises the following steps: after treatment with Compound (I) or a pharmaceutically acceptable salt thereof, periodically assessing the subject, e.g., the patient, for evidence of therapeutic benefit to determine whether continued treatment is necessary.

[0446] Embodiment 34a. A compound or a pharmaceutically acceptable salt thereof for use as described in Embodiment 33a, wherein the subject, e.g., patient, is evaluated after about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks of treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0447] Embodiment 35a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg or 0.32 mg / kg of patient body weight.

[0448] Embodiment 36a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of between about 0.1 mg and about 15 mg.

[0449] Embodiment 37a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of between about 0.1 mg and about 1 mg.

[0450] Embodiment 38a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of between about 0.3 mg and about 1 mg.

[0451] Embodiment 39a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.5 mg and about 1 mg.

[0452] Embodiment 40a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of between about 1 mg and about 5 mg.

[0453] Embodiment 41a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of between about 1 mg and about 10 mg.

[0454] Embodiment 42a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 15 mg.

[0455] Embodiment 43a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, 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.

[0456] Embodiment 44a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, 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.

[0457] Embodiment 45a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, 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.

[0458] Embodiment 46a. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once without repetition.

[0459] Embodiment 47a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks or less frequently.

[0460] Embodiment 48a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every three weeks or less frequently.

[0461] Embodiment 49a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once a month or less frequently.

[0462] Embodiment 50a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every six weeks or less frequently.

[0463] Embodiment 51a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein treatment with Compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 2 years.

[0464] Embodiment 52a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein after treatment with Compound (I) or a pharmaceutically acceptable salt thereof, the score is improved in one of a plurality of depression assessment tools selected from the group consisting of: Montgomery-Asberg Depression Rating Scale (MADRS), Mini-International Neuropsychiatric Interview (MINI e.g., version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia-Suicidality Severity Rating Scale (C-SSRS), and Clinical Global Impression (CGI).

[0465] Embodiment 53a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has recurrent major depressive disorder and a current major depressive episode lasting at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks.

[0466] Embodiment 54a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, that is resistant to treatment.

[0467] Embodiment 55a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a partially resistant subject, such as a patient.

[0468] Embodiment 56a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has had an inadequate response or no response to other antidepressant therapies prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, e.g., in a current major depressive episode.

[0469] Embodiment 57a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has had an inadequate response or no response to at least one antidepressant drug, e.g., in a current major depressive episode.

[0470] Embodiment 58a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has had an inadequate response or no response to at least two antidepressants, e.g., in a current major depressive episode.

[0471] Embodiment 59a. A compound for use as described in any one of embodiments 56a to 58a, or a pharmaceutically acceptable salt thereof, wherein the inadequate response or no response comprises a partial response.

[0472] Embodiment 60a. A compound for use as described in any one of Embodiments 56a to 59a, or a pharmaceutically acceptable salt thereof, wherein the current major depressive episode lasts for about at least about 4 weeks, e.g., at least about 6 weeks, at least about 8 weeks, in particular for about at least 8 weeks but not more than 24 months.

[0473] Embodiment 61a. A compound for use as described in any one of embodiments 56a to 60a, or a pharmaceutically acceptable salt thereof, wherein the antidepressant is according to any one of embodiments 29a and 30a.

[0474] Embodiment 62a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, having a MADRS score of at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25 at baseline.

[0475] Embodiment 63a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the treatment further comprises the step of determining or having determined the MADRS total score after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, e.g., 24 hours, 7, 14, 21 and / or 28 days after subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score of the subject, e.g., the patient, before subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0476] Embodiment 64a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the subject, e.g., patient, has a reduced MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has a reduced MADRS total score 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0477] Embodiment 65a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the subject, e.g., patient, has an improvement in MADRS total score of more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has an improvement in MADRS total score of more than 30%, e.g., 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0478] Embodiment 66a. A compound or pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the subject, e.g., patient, has a MADRS total score of less than 12 after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has a MADRS total score of less than 12 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0479] 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 a psychotic disorder, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0480] Embodiment 68a. The use according to embodiment 67a, wherein the compound or a pharmaceutically acceptable salt thereof is used as described in any one of embodiments 1a to 66a.

[0481] Embodiment 69a. The use of any one of embodiments 1a to 66a, wherein the treatment further comprises administering one or more additional therapeutic agents.

[0482] Embodiment 70a. The use as described in Embodiment 69a, wherein the treatment is carried out in addition to one or more standard of care medications for the treatment of the psychotic disorder, and Compound (I) or a pharmaceutically acceptable salt thereof.

[0483] Embodiment 71a. The use of any one of embodiments 67a to 70a, wherein the psychiatric disorder is a depressive disorder.

[0484] Embodiment 72a. The use according to embodiment 71a, wherein the depressive disorder is major depressive disorder.

[0485] Embodiment 73a. The use of embodiment 72a, wherein the major depressive disorder is treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, or seasonal affective disorder.

[0486] Embodiment 74a. A compound for use as described in any one of Embodiments 67a to 73a, or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering the one or more additional therapeutic agents for a period of about at least 4 weeks, such as about at least 6 weeks, prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 75a. A compound for use as described in any one of Embodiments 67a to 74a, or a pharmaceutically acceptable salt thereof, wherein treatment with the one or more additional therapeutic agents is continued after treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0488] Embodiment 76a. A compound for use as described in any one of embodiments 67a to 75a, or a pharmaceutically acceptable salt thereof, wherein the one or more additional therapeutic agents are selected from antidepressants, antipsychotics, mood stabilizers, benzodiazepines, A group of drugs and their combinations.

[0489] Embodiment 77a. A compound for use as described in any one of Embodiments 67a to 76a, or a pharmaceutically acceptable salt thereof, wherein at least one of the one or more additional therapeutic agents is an antidepressant, eg, an oral antidepressant.

[0490] Embodiment 78a. A compound for use as described in any one of Embodiments 67a to 77a, or a pharmaceutically acceptable salt thereof, wherein the one or more additional therapeutic agents are one or more antidepressants.

[0491] Embodiment 79a. A compound for use as described in any one of embodiments 76a to 78a, or a pharmaceutically acceptable salt thereof, wherein the disorder, e.g., during a current major depressive episode, is inadequately responsive or unresponsive to at least one, e.g., at least two, of one or more additional therapeutic agents or standard of care medications.

[0492] Embodiment 80a. A compound for use as described in any one of Embodiments 76a to 79a, or a pharmaceutically acceptable salt thereof, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) including reversible inhibitors of monoamine oxidase (RIMAs), multimodal antidepressants, and combinations thereof.

[0493] Embodiment 81a. A compound for use as described in Embodiment 80a, or a pharmaceutically acceptable salt thereof, wherein 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.

[0494] Embodiment 82a. A compound for use as described in any one of Embodiments 76a to 81a, or a pharmaceutically acceptable salt thereof, wherein 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.

[0495] Embodiment 83a. A compound for use as described in any one of embodiments 76a to 82a, or a pharmaceutically acceptable salt thereof, 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.

[0496] Embodiment 84a. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously in the upper arm or abdominal area.

[0497] Embodiment 85a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as a single subcutaneous injection.

[0498] Embodiment 86a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition optionally comprising at least one pharmaceutically acceptable excipient.

[0499] Embodiment 87a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) is administered as the free base.

[0500] Embodiment 88a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) is formulated for delivery from a subcutaneous injection device.

[0501] Embodiment 89a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) is formulated for delivery as a single subcutaneous injection from a subcutaneous injection device.

[0502] Embodiment 90a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has failed to respond to two or more, but no more than five, prior antidepressant treatments at adequate doses and durations (e.g., for at least 6 weeks), as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), wherein the two failed treatments are two different antidepressants.

[0503] Embodiment 91a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, at an effective and stable dose for at least 4 weeks, and the subject, e.g., the patient has a <50% response to at least one antidepressant treatment, e.g., according to the MGH-ATRQ, e.g., during a major depressive episode lasting ≥8 weeks.

[0504] Embodiment 92a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, diagnosed with recurrent major depressive disorder (MDD) and a current major depressive episode lasting at least 8 weeks, e.g., as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.

[0505] Embodiment 93a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, characterized by treatment-resistant or refractory depression.

[0506] Embodiment 94a. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding embodiments, wherein the compound or pharmaceutically acceptable salt thereof is administered to a human patient.

[0507] Embodiment 95a. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to an adult patient.

[0508] Embodiment 96a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of treatment failure with esketamine, ketamine, or allketamine.

[0509] Embodiment 97a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having a depressive episode (e.g., a major depressive episode), wherein the subject, e.g., the patient, has not responded to treatment with at least one antidepressant drug in the current depressive episode.

[0510] Embodiment 98a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having a depressive episode (e.g., a major depressive episode), wherein the subject, e.g., the patient, has not responded to treatment with at least two antidepressant drugs in the current depressive episode.

[0511] Embodiment 99a. A compound for use as described in any one of Embodiments 97a and 98a, or a pharmaceutically acceptable salt thereof, wherein at least one antidepressant is an oral antidepressant.

[0512] Embodiment 100a. A compound for use as described in any one of embodiments 97a to 99a, wherein the antidepressant has been administered for at least four weeks, eg, for at least six weeks.

[0513] Embodiment 101a. A compound or a pharmaceutically acceptable salt thereof for use as described in any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a male or female subject, such as a patient.

[0514] Embodiment 102a. The compound or pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the compound or pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not had an acute depressive episode lasting more than two consecutive years.

[0515] Embodiment 103a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not received electroconvulsive therapy in a current episode of depression or within the year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0516] Embodiment 104a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is currently experiencing a depressive episode or has not received transcranial magnetic stimulation within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0517] Embodiment 105a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not received vagus nerve stimulation during a current episode of depression or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0518] Embodiment 106a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not received deep brain stimulation in a current episode of depression or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0519] Embodiment 107a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not been previously or currently diagnosed with major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder, e.g., as determined by SCID-5.

[0520] Embodiment 108a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification.

[0521] Embodiment 109a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not undergone detoxification treatment within one month prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0522] Embodiment 110a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, 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, such as based on DSM-5 criteria.

[0523] Embodiment 111a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not been clinically diagnosed with autism, dementia, or intellectual disability.

[0524] Embodiment 112a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has no history of suicide attempts or suicidal behavior within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0525] Embodiment 113a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not exhibit suicidal ideation and intent, e.g., as determined by a "yes" response to Q4 or Q5 at baseline on the CSSRS.

[0526] Embodiment 114a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient who does not exhibit an estimated glomerular filtration rate (eGFR) < 40 mL / min / 1.73 m at baseline. 2 Subjects, such as patients, who demonstrate evidence of significant renal insufficiency.

[0527] Embodiment 115a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of allergy to Compound (I) or a pharmaceutically acceptable salt thereof, or a drug with a similar mechanism of action (i.e., a drug that affects NMDA receptors).

[0528] Embodiment 116a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not have active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

[0529] Embodiment 117a. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of epilepsy other than childhood febrile seizures.

[0530] Embodiment 118a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not have a cardiac abnormality or cardiac repolarization abnormality including any of the following:

[0531] a) History of myocardial infarction, angina pectoris or coronary artery bypass surgery within 6 months before treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0532] b) a history of clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, or high-degree atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0533] Embodiment 119a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, whose resting QTcF at baseline is not ≥450 msec (male) or ≥460 msec (female).

[0534] Embodiment 120a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not have risk factors for torsades de pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or any of the following:

[0535] a) Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome.

[0536] b) One or more concomitant medications with a “known risk of TdP” that cannot be discontinued or replaced by a safe alternative.

[0537] Embodiment 121a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, whose mean systolic blood pressure at baseline is not >140 mmHg or diastolic blood pressure is not >90 mmHg; or a previous history of hypertensive crisis.

[0538] Embodiment 122a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysms or arteriovenous malformations) or known aneurysmal vascular disease at other sites (e.g., the aorta).

[0539] Embodiment 123a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is not a pregnant or nursing (lactating) female.

[0540] Embodiment 124a. A compound or a pharmaceutically acceptable salt thereof for use as described in any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is not a female of childbearing potential and not using highly effective contraception.

[0541] Embodiment 125a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is not a sexually active male who is unwilling to use a condom during sexual intercourse while taking Compound 1 or a pharmaceutically acceptable salt thereof and within 1 week after stopping drug treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0542] Embodiment 126a. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is not taking any of the following medications as defined in Table 1 during treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0543] Example 127a. A therapeutic agent for use in treating a psychiatric disorder, e.g., a depressive disorder, e.g., major depressive disorder, e.g., treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-injury in major depressive disorder, and seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0544] Embodiment 128a. A therapeutic agent for use as described in embodiment 127a, wherein the therapeutic agent is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines A group of drugs and their combinations.

[0545] Embodiment 129a. The therapeutic agent for use as described in any one of Embodiments 127a and 128a, wherein the therapeutic agent is an antidepressant, eg, an oral antidepressant.

[0546] Embodiment 130a. The therapeutic agent for use as described in any one of Embodiments 127a to 129a, wherein the therapeutic agent is administered prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof for a period of about at least 4 weeks, e.g., about at least 6 weeks.

[0547] Embodiment 131a. The therapeutic agent for use as described in any one of Embodiments 127a to 130a, wherein treatment with the therapeutic agent is continued after treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0548] Embodiment 132a. The therapeutic agent for use as described in any one of Embodiments 128a to 131a, wherein 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), or a multimodal antidepressant.

[0549] Embodiment 133a. The therapeutic agent for use as described in any one of Embodiments 128a to 132a, wherein 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.

[0550] Embodiment 134a. The therapeutic agent for use as described in any one of embodiments 128a to 133a, wherein the antipsychotic or mood stabilizer is selected from the group consisting of a lithium member (e.g., lithium carbonate), valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

[0551] Embodiment 135a. The therapeutic agent for use as described in any one of Embodiments 127a to 134a, wherein the treatment with Compound (I) or a pharmaceutically acceptable salt thereof is according to any one of Embodiments 1a to 66a and 84a to 126a.

[0552] Embodiment 136a. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating treatment-resistant depression in an adult patient, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, wherein the treatment is combined with at least one oral antidepressant.

[0553] Embodiment 137a. A compound or a pharmaceutically acceptable salt thereof as described in Embodiment 136a for use as described in any one of Embodiments 33a to 66a, 80a to 82a, and 84a to 126a.

[0554] Certain features described in this disclosure in the context of separate embodiments may also be implemented in combination in a single embodiment. Conversely, different features described in the context of a single implementation may also be implemented in multiple embodiments separately or in any suitable subcombination. Furthermore, although features may be described above as functioning in certain combinations, one or more features from a claimed combination may in some cases be deleted from that combination, and the combination may be claimed as a subcombination or a variation of a subcombination.

[0555] Example b:

[0556] Example 1b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a depressive disorder, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0557] Example 2b. 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 treating a depressive disorder, wherein the pharmaceutical composition is administered subcutaneously.

[0558] Example 3b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a depressive disorder, wherein the treatment comprises the following steps:

[0559] (a) determining or having determined a baseline MADRS score for a subject, such as a patient; and

[0560] (b) administering compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to the subject, e.g., patient, wherein the amount of compound (I) or a pharmaceutically acceptable salt thereof improves the MADRS score by about 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%, relative to a measured baseline MADRS score, wherein the baseline is the subject's, e.g., patient's, MADRS total score prior to subcutaneous administration of compound (I) or a pharmaceutically acceptable salt thereof.

[0561] Embodiment 4b. The use according to embodiment 3b, wherein the subject, eg, patient, is regularly assessed after step (b) to determine relative effectiveness, wherein the assessment comprises measuring the subject, eg, patient's MADRS score.

[0562] Embodiment 5b. The use according to any of the preceding embodiments, wherein the depressive disorder is selected from major depressive disorder, in particular treatment-resistant depression, suicidality 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.

[0563] Embodiment 6b. The use according to any one of the preceding embodiments, wherein the depressive disorder is major depressive disorder, such as acute MDD.

[0564] Embodiment 7b. The use according to any one of the preceding embodiments, wherein the depressive disorder is treatment-resistant depression.

[0565] Embodiment 8b. The use as described in embodiment 7b, wherein the treatment-resistant depression comprises partial resistance.

[0566] Example 9b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating depressive symptoms, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0567] Example 10b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating depressive symptoms in major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0568] Example 11b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating depressive symptoms in major depressive disorder with acute suicidal ideation or behavior, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0569] Example 12b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating depressive symptoms in treatment-resistant depression, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0570] Example 13b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0571] Example 14b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0572] Example 15b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing a major depressive episode, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0573] Embodiment 16b. The use of any one of embodiments 14b and 15b, wherein the major depressive episode lasts for at least 4 weeks, eg, at least 6 weeks, at least 8 weeks, eg, about 8 weeks.

[0574] Example 17b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of major depressive disorder, particularly acute MDD, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0575] Example 18b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating single-episode major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0576] Example 19b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating recurrent major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0577] Example 20b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating recurrent major depressive disorder and a current major depressive episode lasting at least 6 weeks, such as at least 8 weeks, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0578] Embodiment 21b. The use of any one of embodiments 14b to 20b, wherein the major depressive episode lasts for at least 6 weeks, eg, lasts for at least 8 weeks, but less than 24 months.

[0579] Embodiment 22b. The use of any one of the preceding embodiments, wherein the depressive disorder or depressive episode, eg, the current depressive episode, is inadequately responsive to at least one antidepressant treatment.

[0580] Embodiment 23b. The use according to any one of the preceding embodiments, wherein the depressive disorder or depressive episode is partially responsive to at least one antidepressant treatment, such as in the current depressive episode.

[0581] Embodiment 24b. The use of any one of the preceding embodiments, wherein the depressive disorder or depressive episode, eg, the current depressive episode, has not been adequately responsive to at least two antidepressant treatments.

[0582] Embodiment 25b. The use of any one of the preceding embodiments, wherein the depressive disorder or depressive episode is partially responsive to at least two antidepressant treatments, such as in the current depressive episode.

[0583] Embodiment 26b. The use of any of the preceding embodiments, wherein the depressive disorder or depressive episode, eg, the current depressive episode, has not been adequately responsive to at least two but no more than five antidepressant treatments.

[0584] Embodiment 27b. The use of any one of embodiments 24b to 26b, wherein the at least two antidepressant treatments are two different antidepressants.

[0585] Embodiment 28b. The use of any one of embodiments 22b to 27b, wherein the one or more antidepressant treatments have been administered for at least 4 weeks, eg, for at least 6 weeks.

[0586] Embodiment 29b. The use of any one of embodiments 22b to 28b, wherein 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), or a multimodal antidepressant.

[0587] Embodiment 30b. The use of any one of embodiments 22b to 29b, wherein 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.

[0588] Example 31b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating treatment-resistant depression, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0589] Example 32b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating major depressive disorder in a subject, e.g., a patient, wherein the subject, e.g., the patient meets the DSM-5 criteria for MDD based on the Standardized Clinical Examination for DSM-5 (SCID-5), and wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0590] Embodiment 33b. The use of any of the preceding embodiments, wherein the treatment further comprises the step of periodically assessing the subject, e.g., the patient, for evidence of therapeutic benefit following treatment with Compound (I) or a pharmaceutically acceptable salt thereof to determine whether continued treatment is warranted.

[0591] Embodiment 34b. The use of embodiment 33b, wherein the subject, eg, patient, is evaluated after about 2 weeks, about 4 weeks, about 6 weeks, or more than about 6 weeks of treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0592] Embodiment 35b. A compound for use as described in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg or 0.32 mg / kg of patient body weight.

[0593] Embodiment 36b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.1 mg and about 15 mg.

[0594] Embodiment 37b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.1 mg and about 1 mg.

[0595] Embodiment 38b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.3 mg and about 1 mg.

[0596] Embodiment 39b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 0.5 mg and about 1 mg.

[0597] Embodiment 40b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 5 mg.

[0598] Embodiment 41b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 10 mg.

[0599] Embodiment 42b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between about 1 mg and about 15 mg.

[0600] Embodiment 43b. The use of any of the preceding embodiments, 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.

[0601] Embodiment 44b. The use according to any one of the preceding embodiments, 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.

[0602] Embodiment 45b. The use according to any one of the preceding embodiments, 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.

[0603] Embodiment 46b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once without repetition.

[0604] Embodiment 47b. A compound for use as described in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks or less frequently.

[0605] Embodiment 48b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every three weeks or less frequently.

[0606] Embodiment 49b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once a month or less frequently.

[0607] Embodiment 50b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered once every six weeks or less frequently.

[0608] Embodiment 51b. The use of any of the preceding embodiments, wherein treatment with Compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 2 years.

[0609] Embodiment 52b. The use of any of the preceding embodiments, wherein after treatment with Compound (I) or a pharmaceutically acceptable salt thereof, the score is improved in one of a plurality of depression assessment tools selected from the group consisting of: Montgomery-Asberg Depression Rating Scale (MADRS), Mini-International Neuropsychiatric Interview (MINI), e.g., version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia-Suicidality Severity Rating Scale (C-SSRS), and Clinical Global Impression (CGI).

[0610] Embodiment 53b. The use according to any one of the preceding embodiments, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, suffering from recurrent major depressive disorder and a current major depressive episode lasting at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks.

[0611] Embodiment 54b. The use according to any one of the preceding embodiments, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, that is resistant to treatment.

[0612] Embodiment 55b. The use according to any one of the preceding embodiments, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a partially resistant subject, such as a patient.

[0613] Embodiment 56b. The use of any of the preceding embodiments, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has had an inadequate response or no response to other antidepressant therapies prior to treatment with compound (I) or a pharmaceutically acceptable salt thereof, e.g., in a current major depressive episode.

[0614] Embodiment 57b. The use of any of the preceding embodiments, 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 inadequate response or no response to at least one antidepressant, such as in a current major depressive episode.

[0615] Embodiment 58b. The use of any of the preceding embodiments, 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 inadequate response or no response to at least two antidepressants, such as in a current major depressive episode.

[0616] Embodiment 59b. The use of any one of embodiments 56b to 58b, wherein the inadequate response comprises a partial response.

[0617] Embodiment 60b. The use of any one of embodiments 56b to 59b, wherein the current major depressive episode lasts for about at least about 4 weeks, e.g., at least about 6 weeks, at least about 8 weeks, in particular for about at least 8 weeks but not more than 24 months.

[0618] Embodiment 61b. The use of any one of embodiments 56b to 60b, wherein the antidepressant is according to any one of embodiments 29b and 30b.

[0619] Embodiment 62b. The use of any one of the preceding embodiments, wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having a MADRS score of at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25 at baseline.

[0620] Embodiment 63b. The use as described in any of the preceding embodiments, wherein the treatment further comprises the step of determining or having determined the MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, e.g., 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 a baseline assessment, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score of the subject, e.g., the patient, before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0621] Embodiment 64b. The use of any one of the preceding embodiments, wherein the subject, e.g., patient, has a reduced MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has a reduced MADRS total score 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0622] Embodiment 65b. The use of any one of the preceding embodiments, wherein the subject, e.g., patient, has an improvement in MADRS total score of more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has an improvement in MADRS total score of more than 30%, e.g., 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0623] Embodiment 66b. The use of any one of the preceding embodiments, wherein the subject, e.g., patient, has a MADRS total score of less than 12 after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, e.g., the subject, e.g., patient, has a MADRS total score of less than 12 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 a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0624] Example 67b. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a psychotic disorder depressive disorder in combination with one or more additional therapeutic agents, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0625] Embodiment 68b. The use according to embodiment 67b, wherein the compound or a pharmaceutically acceptable salt thereof is used as described in any one of embodiments 1b to 66b.

[0626] Embodiment 69b. The use of any one of embodiments 1b to 66b, wherein the treatment further comprises administering one or more additional therapeutic agents.

[0627] Embodiment 70b. The use as described in embodiment 69b, wherein the treatment is carried out in addition to one or more standard of care medications for the treatment of the psychotic disorder, and Compound (I) or a pharmaceutically acceptable salt thereof.

[0628] Embodiment 71b. The use of any one of embodiments 67b to 70b, wherein the psychiatric disorder is a depressive disorder.

[0629] Embodiment 72b. The use according to embodiment 71b, wherein the depressive disorder is major depressive disorder.

[0630] Embodiment 73b. The use as described in embodiment 72b, wherein the major depressive disorder is treatment-resistant depression, suicidality 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, or seasonal affective disorder.

[0631] Embodiment 74b. The use of any one of embodiments 67b to 74b, wherein the treatment comprises administering the one or more additional therapeutic agents for about at least 4 weeks, such as about at least 6 weeks, prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0632] Embodiment 75b. The use of any one of embodiments 67b to 75b, wherein the treatment with the one or more additional therapeutic agents is continued after treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0633] Embodiment 76b. The use of any one of embodiments 67b to 76b, wherein the one or more additional therapeutic agents are selected from antidepressants, antipsychotics, mood stabilizers, benzodiazepines, A group of drugs and their combinations.

[0634] Embodiment 77b. The use of any one of embodiments 67b to 77b, wherein at least one of the one or more additional therapeutic agents is an antidepressant, eg, an oral antidepressant.

[0635] Embodiment 78b. The use of any one of embodiments 67b to 78b, wherein the one or more additional therapeutic agents are one or more antidepressants.

[0636] Embodiment 79b. The use of any one of embodiments 76b to 78b, wherein the disorder is inadequately responsive or unresponsive to at least one, e.g., at least two, of one or more additional therapeutic agents or standard of care medications, e.g., during a current major depressive episode.

[0637] Embodiment 80b. The use of any one of embodiments 76b to 79b, wherein 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), a multimodal antidepressant, and combinations thereof.

[0638] Embodiment 81b. The use as described in embodiment 80b, wherein 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.

[0639] Embodiment 82b. The use of any one of embodiments 76b to 81b, wherein 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.

[0640] Embodiment 83b. The use of any one of embodiments 76b to 82b, 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.

[0641] Embodiment 84b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously in the upper arm or abdominal area.

[0642] Embodiment 85b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as a single subcutaneous injection.

[0643] Embodiment 86b. The use according to any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, optionally comprising at least one pharmaceutically acceptable excipient.

[0644] Embodiment 87b. The use according to any one of the preceding embodiments, wherein compound (I) is administered as the free base.

[0645] Embodiment 88b. The use according to any of the preceding embodiments, wherein Compound (I) is formulated for delivery from a subcutaneous injection device.

[0646] Embodiment 89b. The use according to any of the preceding embodiments, wherein Compound (I) is formulated for delivery as a single subcutaneous injection from a subcutaneous injection device.

[0647] Embodiment 90b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has failed to respond to two or more, but no more than five, prior antidepressant treatments at adequate doses and durations (e.g., for at least 6 weeks), as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), wherein the two failed treatments are two different antidepressants.

[0648] Embodiment 91b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, at an effective and stable dose for at least 4 weeks, the subject, e.g., a patient having a <50% response to at least one antidepressant treatment, e.g., according to the MGH-ATRQ, e.g., during a major depressive episode lasting ≥8 weeks.

[0649] Embodiment 92b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, diagnosed with recurrent major depressive disorder (MDD) and a current major depressive episode lasting at least 8 weeks, e.g., as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.

[0650] Embodiment 93b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, characterized by treatment-resistant or refractory depression.

[0651] Embodiment 94b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human patient.

[0652] Embodiment 95b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to an adult patient.

[0653] Embodiment 96b. The use of any one of the preceding embodiments, 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 allketamine.

[0654] Embodiment 97b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having a depressive episode (e.g., a major depressive episode), wherein the subject, e.g., the patient, has not responded to treatment with at least one antidepressant drug in the current depressive episode.

[0655] Embodiment 98b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, having a depressive episode (e.g., a major depressive episode), wherein the subject, e.g., the patient, has not responded to treatment with at least two antidepressant drugs in the current depressive episode.

[0656] Embodiment 99b. The use of any one of embodiments 97b and 98b, wherein at least one antidepressant is an oral antidepressant.

[0657] Embodiment 100b. The use of any one of embodiments 97b to 99b, wherein the antidepressant has been administered for at least four weeks, eg, for at least six weeks.

[0658] Embodiment 101b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a male or female subject, such as a patient.

[0659] Embodiment 102b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not had an acute depressive episode lasting more than two consecutive years.

[0660] Embodiment 103b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not received electroconvulsive therapy in a current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0661] Embodiment 104b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not received transcranial magnetic stimulation in a current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0662] Embodiment 105b. The use of any one of the preceding embodiments, 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 during a current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0663] Embodiment 106b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not received deep brain stimulation in a current depressive episode or within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0664] Embodiment 107b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has not been previously or currently diagnosed with major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder, e.g., as determined by SCID-5.

[0665] Embodiment 108b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification.

[0666] Embodiment 109b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not undergone detoxification treatment within one month prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0667] Embodiment 110b. The use of any one of the preceding embodiments, 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, such as based on DSM-5 criteria.

[0668] Embodiment 111b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has not been clinically diagnosed with autism, dementia, or intellectual disability.

[0669] Embodiment 112b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of suicide attempts or suicidal behavior within one year prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0670] Embodiment 113b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not exhibit suicidal ideation and intent, e.g., as determined by a "yes" response to Q4 or Q5 at baseline on the CSSRS.

[0671] Embodiment 114b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient who does not exhibit an estimated glomerular filtration rate (eGFR) < 40 mL / min / 1.73 m at baseline. 2 Subjects, such as patients, who demonstrate evidence of significant renal insufficiency.

[0672] Embodiment 115b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of allergy to compound (I) or a pharmaceutically acceptable salt thereof or a drug with a similar mechanism of action (i.e., a drug that affects NMDA receptors).

[0673] Embodiment 116b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not have active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

[0674] Embodiment 117b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who has no history of epilepsy other than childhood febrile seizures.

[0675] Embodiment 118b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who does not have a cardiac abnormality or cardiac repolarization abnormality including any of the following:

[0676] a) History of myocardial infarction, angina pectoris or coronary artery bypass surgery within 6 months before treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0677] b) a history of clinically significant arrhythmia (e.g., ventricular tachycardia), complete left bundle branch block, or high-degree atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0678] Embodiment 119b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose resting QTcF at baseline is not ≥450 msec (male) or ≥460 msec (female).

[0679] Embodiment 120b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who does not have risk factors for torsade de pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, a history of heart failure, or a history of clinically significant / symptomatic bradycardia, or any of the following:

[0680] a) Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome.

[0681] b) One or more concomitant medications with a “known risk of TdP” that cannot be discontinued or replaced by a safe alternative.

[0682] Embodiment 121b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, whose mean systolic blood pressure at baseline is not >140 mmHg or diastolic blood pressure is not >90 mmHg; or a previous history of hypertensive crisis.

[0683] Embodiment 122b. The use of any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who has no history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysms or arteriovenous malformations) or known aneurysmal vascular disease at other sites (e.g., the aorta).

[0684] Embodiment 123b. The use according to any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is not a pregnant or lactating (lactating) female.

[0685] Embodiment 124b. The use according to any of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, such as a patient, who is not a female of childbearing potential and who is not using highly effective contraception.

[0686] Embodiment 125b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is not a sexually active male who is unwilling to use a condom during sexual intercourse while taking Compound 1 or a pharmaceutically acceptable salt thereof and within 1 week after stopping treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0687] Embodiment 126b. The use of any one of the preceding embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a subject, e.g., a patient, who is not taking any of the following drugs as defined in Table 1 during treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0688] Example 127b. Use of a therapeutic agent in the manufacture of a medicament for treating a psychiatric disorder, e.g., a depressive disorder, e.g., major depressive disorder, e.g., treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, self-injury in major depressive disorder, and seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0689] Embodiment 128b. A therapeutic agent for use as described in embodiment 127b, wherein the therapeutic agent is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines A group of drugs and their combinations.

[0690] Embodiment 129b. The therapeutic agent for use as described in any one of Embodiments 127b and 128b, wherein the therapeutic agent is an antidepressant, eg, an oral antidepressant.

[0691] Embodiment 130b. The therapeutic agent for use as described in any one of Embodiments 127b to 129b, wherein the therapeutic agent is administered prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof for a period of about at least 4 weeks, e.g., about at least 6 weeks.

[0692] Embodiment 131b. The therapeutic agent for use as described in any one of Embodiments 127b to 130b, wherein treatment with the therapeutic agent is continued after treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

[0693] Embodiment 132b. The therapeutic agent for use as described in any one of Embodiments 128b to 131b, wherein 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), or a multimodal antidepressant.

[0694] Embodiment 133b. The therapeutic agent for use as described in any one of embodiments 128b to 132b, wherein 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.

[0695] Embodiment 134b. The therapeutic agent for use as described in any one of embodiments 128b to 133b, wherein the antipsychotic or mood stabilizer is selected from the group consisting of a lithium member (e.g., lithium carbonate), valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

[0696] Embodiment 135b. The therapeutic agent for use as described in any one of Embodiments 127b to 134b, wherein the treatment with Compound (I) or a pharmaceutically acceptable salt thereof is according to any one of Embodiments 1b to 66b and 84b to 126b.

[0697] Embodiment 136b. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating treatment-resistant depression in adult patients, wherein the compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously, wherein the treatment is combined with at least one oral antidepressant.

[0698] Embodiment 137b. The use of embodiment 136a, wherein the use is as described in any one of embodiments 33a to 66a, 80a to 82a, and 84a to 126a.

[0699] Example c

[0700] Example 1c. A method of treating a depressive disorder in a subject, such as a patient, in need thereof, comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0701] Example 2c. A method for treating a depressive disorder in a subject in need thereof, such as a patient, comprising subcutaneously administering 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.

[0702] Example 3c. A method of alleviating at least one depressive symptom in a subject, such as a patient, suffering from a depressive disorder, comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0703] Example 4c. A method for long-term treatment of a depressive disorder in a subject in need thereof, such as a patient, comprising subcutaneously administering Compound (I) or a pharmaceutically acceptable salt thereof to the subject in need thereof, such as a patient.

[0704] Example 5c. A method of treating treatment-resistant depression in a subject, such as a patient, suffering from major depressive disorder, comprising subcutaneously administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof.

[0705] Example 6c. A method of subcutaneously administering Compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such as a patient, comprising subcutaneously administering Compound (I) under the skin of the subject.

[0706] Example 7c. A method for treating a depressive disorder in a subject, such as a patient, in need thereof, comprising the steps of:

[0707] a. determining or having determined a baseline MADRS score for a subject, such as a patient; and

[0708] b. administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to the subject, e.g., patient, wherein the amount of Compound (I) or a pharmaceutically acceptable salt thereof improves the MADRS score by about 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%, relative to a measured baseline MADRS score, wherein the baseline is the subject's, e.g., patient's, MADRS total score prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0709] Embodiment 8c. The method of embodiment 7c, wherein the subject, eg, patient, is evaluated periodically after step (b) to determine relative effectiveness, wherein the evaluation comprises measuring the subject, eg, patient's MADRS score.

[0710] Embodiment 9c. The method of any one of the preceding embodiments, wherein the subject, eg, patient, has been diagnosed with or is diagnosed with a depressive disorder.

[0711] Embodiment 10c. The method of any one of the preceding embodiments, wherein the subject, eg, patient, has been diagnosed with or is diagnosed with major depressive disorder.

[0712] Embodiment 11c. The method of any one of the preceding embodiments, wherein the subject, eg, patient, has been diagnosed with or is diagnosed with treatment-resistant depression (TRD).

[0713] Embodiment 12c. The method of any of the preceding embodiments, wherein the score is improved in one of a plurality of depression assessment tools selected from the group consisting of: Montgomery-Asberg Depression Rating Scale (MADRS), Mini-International Neuropsychiatric Interview (MINI), 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).

[0714] Embodiment 13c. The method of any of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 1 mg and about 15 mg, wherein the amount administered refers to the free base of Compound (I).

[0715] Embodiment 14c. The method of any of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously at a dose of between about 1 mg and about 10 mg, wherein the administered amount refers to the free base of Compound (I).

[0716] Embodiment 15c. The method of any of the preceding embodiments, wherein 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 amount administered refers to the free base of Compound (I).

[0717] Embodiment 16c. The method of any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, eg, patient, once a week.

[0718] Embodiment 17c. The method of any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, eg, patient, twice a week.

[0719] Embodiment 18c. The method of any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, eg, patient, once every two weeks.

[0720] Embodiment 19c. The method of any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, eg, patient, once every three weeks.

[0721] Embodiment 20c. The method of any one of the preceding embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, eg, patient, a) once a month; or b) once every six weeks.

[0722] Embodiment 21c. The method of any of the preceding embodiments, wherein treatment with Compound (I) or a pharmaceutically acceptable salt thereof continues for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 2 years.

[0723] Embodiment 22c. The method of any of the preceding embodiments, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and attempt, major depressive disorder with suicidal behavior, and self-harm in major depressive disorder.

[0724] Embodiment 23c. The method of any preceding embodiment, wherein the depressive disorder is major depressive disorder.

[0725] Embodiment 24c. The method of any preceding embodiment, wherein the depressive disorder is treatment-resistant depression.

[0726] Embodiment 25c. The method of any one of the preceding embodiments, wherein the subject, eg, patient, has failed to adequately respond to two or more antidepressant treatments prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

[0727] Embodiment 26c. The method of embodiment 25c, wherein the antidepressant treatment 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)), or a multimodal antidepressant.

[0728] Embodiment 27c. The method of embodiment 26c, wherein the antidepressant treatment 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.

[0729] Embodiment 28c. The method of any one of the preceding embodiments, wherein the subject, eg, patient, is experiencing a major depressive episode.

[0730] Embodiment 29c. The method of any one of embodiments 25c to 28c, wherein at least one of the two or more antidepressants is used to treat a current major depressive episode.

[0731] Embodiment 30c. The method of embodiment 29c, wherein the subject, eg, patient, is unresponsive to the at least one antidepressant in the current major depressive episode.

[0732] Embodiment 31c. The method of embodiment 30c, wherein the at least one antidepressant is an oral antidepressant.

[0733] Embodiment 32c. The method of embodiment 29c, wherein the subject, eg, patient, has not responded to at least two antidepressant drugs in the current major depressive episode.

[0734] Embodiment 33c. The method of embodiment 32c, wherein the at least two antidepressants are different.

[0735] Embodiment 34c. The method of any one of embodiments 32c and 33c, wherein at least one of the at least two antidepressants is an oral antidepressant.

[0736] Embodiment 35c. The method of any one of emb...

Claims

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

2. A method for treating a depressive disorder in a subject in need thereof, such as a patient, comprising subcutaneously administering to the subject, such as a 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.

3. A method for alleviating 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 the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

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

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

6. A method for treating major depressive disorder in a subject, such as a patient, in need thereof, wherein the subject, such as a patient, meets the DSM-5 criteria for MDD based on the DSM-5 Formulated Clinical Examination (SCID-5), the method comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

7. A method for treating treatment-resistant depression in a subject, such as a patient, in need thereof, comprising subcutaneously administering to the subject, such as a patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

8. A method for treating depressive symptoms of major depressive disorder in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

9. A method for treating a major depressive episode in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

10. A method for preventing a major depressive episode in a subject, such as a patient, in need thereof, the method comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

11. A method for treating recurrent major depressive disorder and current major depressive episode in a subject, such as a 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.

12. The method of any one of claims 9 to 11, wherein the major depressive episode lasts for at least 4 weeks, e.g., at least 6 weeks, e.g., at least 8 weeks.

13. The method of any one of claims 9 to 12, wherein the major depressive episode lasts at least 8 weeks but no longer than 24 months.

14. A method for treating a major depressive disorder in a subject, such as a patient, in need thereof, wherein the subject, such as the patient, has not responded to at least two antidepressant treatments, wherein at least one antidepressant treatment is used to treat a current major depressive episode, the method comprising subcutaneously administering to the subject, such as the patient, a therapeutically effective amount of compound (I), or a pharmaceutically acceptable salt thereof.

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

16. The method of any one of the preceding claims, wherein the treatment further comprises administering to the subject, eg, patient, one or more additional therapeutic agents.

17. The method of any of the preceding claims, wherein the treatment further comprises administering one or more pharmacological standard of care treatments to the subject, e.g., patient.

18. The method of any one of the preceding claims, wherein the subject, e.g., patient, is treatment resistant.

19. The method of any one of the preceding claims, wherein the subject, e.g., patient, is partially resistant.

20. The method of any of the preceding claims, wherein the subject, e.g., patient, has failed to adequately respond to at least one antidepressant treatment.

21. The method of any of the preceding claims, wherein the subject, e.g., patient, has failed to adequately respond to at least two antidepressant treatments.

22. The method of any one of the preceding claims, wherein the subject, e.g., patient, is at risk of suicide.

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

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

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

26. The method of 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 an adult patient in need thereof, the method comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof in combination with at least one oral antidepressant.

28. The method of any one of claims 14 to 27, wherein 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)), or a multimodal antidepressant.

29. The method of claim 28, wherein 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.

30. The method of any one of claims 16 to 29, wherein the subject, e.g., patient, continues to be treated with the one or more additional therapeutic agents or standard of care treatment following treatment with Compound (I) or a pharmaceutically acceptable salt thereof.

31. A method as claimed in any one of the preceding claims, comprising the steps of: (a) determining or having determined a baseline MADRS score for the subject, e.g., patient; as well as (b) administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof subcutaneously to the subject, e.g., the patient, wherein the amount of Compound (I) or a pharmaceutically acceptable salt thereof improves the MADRS score by about 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%, relative to a measured baseline MADRS score, 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.

32. The method of claim 31 , wherein the subject, e.g., patient, is periodically assessed after step (b) to determine relative effectiveness, wherein the assessment comprises measuring the subject, e.g., patient's MADRS score.

33. The method according to any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 0.1 mg and 15 mg, wherein the amount administered refers to the free base of Compound (I).

34. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 0.1 mg and 1 mg, wherein the amount administered refers to the free base of Compound (I).

35. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 0.3 mg and 1 mg, wherein the amount administered refers to the free base of Compound (I).

36. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 0.5 mg and 1 mg, wherein the administered amount refers to the free base of Compound (I).

37. The method according to any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 1 mg and 5 mg, wherein the amount administered refers to the free base of Compound (I).

38. The method according to any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 1 mg and 10 mg, wherein the amount administered refers to the free base of Compound (I).

39. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered at a dose of between 1 mg and 15 mg, wherein the amount administered refers to the free base of Compound (I).

40. The method of any of the preceding claims, wherein 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 amount administered refers to the free base of Compound (I).

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

42. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, such as a patient, once a week.

43. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, such as a patient, twice a week.

44. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, such as a patient, once every two weeks.

45. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, such as a patient, once every three weeks.

46. ​​The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered to the subject, e.g., patient, a) once a month; or b) once every six weeks.

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

48. The method of any of the preceding claims, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality 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 of claim 48, wherein the depressive disorder is major depressive disorder.

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

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

52. The method of claim 51, wherein the treatment-resistant depression comprises partial resistance.

53. The method of any of the preceding claims, wherein the score is improved compared to baseline in one of a plurality of depression assessment tools selected from the group consisting of the Montgomery-Asberg Depression Rating Scale (MADRS), the Mini-International Neuropsychiatric Interview (MINI), e.g., version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia-Suicidality Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI).

54. The method of any of the preceding claims, wherein the subject, e.g., 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 25 prior to administration of Compound (I) or a pharmaceutically acceptable salt thereof.

55. The method of any one of the preceding claims, further comprising the steps of: The efficacy of the treatment is assessed by determining or having determined the MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, for example at 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, compared to a baseline assessment, wherein the baseline is the MADRS total score of the subject, e.g., the patient, before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

56. The method of any one of the preceding claims, wherein the subject, e.g., patient, has a reduced MADRS total score after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, for example, the subject, e.g., patient has a reduced MADRS total score at 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, compared to a baseline assessment, wherein the baseline is the MADRS total score of the subject, e.g., patient, before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

57. The method of any of the preceding claims, wherein the subject, e.g., patient, has an improvement in MADRS total score of more than about 30%, e.g., more than about 35%, more than about 40%, more than about 45%, more than about 50%, after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, for example, the subject, e.g., patient, has an improvement in MADRS total score of more than about 30%, e.g., more than about 35%, more than about 40%, more than about 45%, more than about 50%, 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, compared to a baseline assessment, wherein the baseline is the subject, e.g., patient's MADRS total score before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

58. The method of any one of the preceding claims, wherein the subject, e.g., patient, has a MADRS total score of less than 12 after subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, for example, the subject, e.g., patient, has a MADRS total score of less than 12 at 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, compared to a baseline assessment, wherein baseline is the MADRS total score of the subject, e.g., patient, before subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

59. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered subcutaneously in the upper arm or abdominal area.

60. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as a subcutaneous injection.

61. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as a single subcutaneous injection.

62. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is administered as a free base.

63. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is formulated for delivery from a subcutaneous injection device.

64. The method of any one of the preceding claims, wherein Compound (I) or a pharmaceutically acceptable salt thereof is formulated for delivery as a single subcutaneous injection from a subcutaneous injection device.

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