KR20250019704A - Subcutaneous administration and dosing method of onpasprodil for use in the treatment of depressive disorders - Google Patents

Abstract

The present invention relates to subcutaneous dosages of compound I, or a pharmaceutically acceptable salt thereof, for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of NR2B-containing NMDA receptors, including but not limited to 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, suicidality, and seasonal affective disorder. The present invention also relates to the use of compound I, or a pharmaceutically acceptable salt thereof, in the treatment of treatment-resistant depression in a patient having major depressive disorder.
[Chemical Formula I]

Description

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

claim of priority

This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/365749, filed June 2, 2022, the disclosure of which is incorporated herein by reference in its entirety.

Technical field

The present invention relates to the treatment of major depressive disorder (MDD), including treatment-resistant depression. The present invention further relates to subcutaneous dosages and/or regimens of compound I, or a pharmaceutically acceptable salt thereof, for the treatment of 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 suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder and/or a combination of any of the foregoing). Some embodiments relate to subcutaneous dosages of Compound I, or a pharmaceutically acceptable salt thereof, for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of NR2B-containing NMDA receptors, including but not limited to depressive disorders (e.g., major depressive disorder, treatment-resistant depression, 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/or combinations of any of the foregoing). Some embodiments relate to the use of Compound I, or a pharmaceutically acceptable salt thereof, for the treatment of treatment-resistant depression in a patient having major depressive disorder.

Depression is a serious and life-threatening condition with high morbidity and chronic disease course. It is a common disease that affects more than 264 million people worldwide (WHO (2020) World Health Organization: Depression (Depression. Key facts) (Internet) Available from https://crediblemeds.org/). When depression is moderate or severe and lasts for a long time, it causes significant distress to the person, impairing their ability to work, care for themselves, and maintain relationships.

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 the majority 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). These chronic symptoms often render patients treatment-resistant.

Treatment-resistant depression (TRD) is defined as the absence of clinically meaningful improvement following treatment with at least two different antidepressant medications at appropriate doses for adequate durations.

Patients with TRD are at high risk for suicidal ideation and experience a disproportionate burden of disease that results in 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).

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

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 psychotogenic side effects. Additionally, ketamine is rapid-acting and has been shown to reduce suicidality. Ketamine’s efficacy provides a rationale for targeting N-methyl-D-aspartate (NMDA) receptor inhibition as a rapid-onset antidepressant mechanism.

SPRAVATO® (esketamine), a non-competitive NMDA receptor antagonist, is approved for the treatment of TRD and is also approved by the U.S. Food and Drug Administration (FDA) for MDD with acute suicidal ideation or behavior and by the European Medicines Agency (EMA) for moderate to severe episodes of MDD as an acute short-term treatment together with an oral antidepressant for the rapid reduction of symptoms that constitute a psychiatric emergency, in clinical judgment. Although both ketamine and SPRAVATO® have demonstrated some level of efficacy and have a rapid onset of action, their safety profiles are not without significant adverse effects for both patients and clinicians.

Targeting specific subsets of NMDA receptors is one approach that potentially mitigates the detrimental effects of NMDA receptor inhibition while retaining antidepressant efficacy. Infusion of traxoprodil, a selective negative allosteric modulator of the NR2B subtype of NMDA receptors, also known as CP-101,606, is effective in patients with TRD with a magnitude and duration of response comparable to ketamine, with a low potential to produce dissociative effects in patients. MK-0657 (rislenemdaz, a selective NR2B antagonist, also known as MK-0657 or CERC-30) does not induce dissociative effects in patients with TRD and was generally safe.

Conventional pharmacologic treatments for major depressive disorder (MDD) include antidepressants belonging to different classes. These include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), serotonin neuroepinephrine 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 treatment, fail, and then try another of these treatments, which may also fail again, and are thus termed "treatment resistant."

The rationale for proposing new dosing regimens for a given drug is that the development of such dosing regimens requires balancing patient compliance, therapeutic efficacy, and the side effects of the drug; this is a goal that is not easily achieved and requires considerable skill.

Therefore, there is a significant unmet medical need for more effective or better tolerated short-acting antidepressants, treatments that can effectively interrupt depressive episodes and prevent future depressive episodes.

In some embodiments, novel methods for treating a depressive disorder are provided herein. In some embodiments, the depressive disorder is major depressive disorder. In some embodiments, the depressive disorder is treatment-resistant depression. In some embodiments, the depressive disorder is one in which a rapid-acting antidepressant effect could potentially be beneficial (including, but not limited to, major depressive disorder, treatment-resistant depression, or other depressive disorders disclosed herein). In some embodiments, the rapid response is meaningful in individuals suffering from treatment-resistant depression, including populations that have failed to respond to conventional antidepressants used for an appropriate duration and at an appropriate dose. Depressive disorders often result in suicidal thoughts or behaviors that put patients at risk. Additionally, even when conventional antidepressants are eventually effective, conventional antidepressant treatment can take several weeks to achieve therapeutic benefit. Thus, there is a need for rapid-acting and safe antidepressant treatments. Some embodiments disclosed herein address these and other problems disclosed herein. Compound I, or the compound of formula I, as used herein, is 6-((1 S )-2-((3a R ,5 R ,6a S )-5-(2-fluorophenoxy) hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)-1-hydroxyethyl)pyridin-3-ol of the following formula:

[Chemical Formula I]

The INN name is Onpasprodil. Onpasprodil is an NR2B-NMDA receptor non-allosteric modulator (NAM) which may be prepared as described in WO2016/049165, the entire contents of which are herein incorporated by reference.

Compound I, or a pharmaceutically acceptable salt thereof, is a highly potent, selective, and reversible low molecular weight NR2B-containing NMDA receptor NAM. The treatment(s) disclosed herein are intended to enable patients to achieve a rapid and significant antidepressant effect, particularly in patients with treatment-resistant depression.

Some embodiments disclosed herein provide methods for treating depressive disorders, particularly major depressive disorder, particularly treatment-resistant depression, using compound I and/or novel formulations comprising compound I. In some embodiments, advantageously, compound I is provided in a rapid-acting form and has a rapid onset of activity in a patient. In some embodiments, the methods for treating depressive disorders (e.g., major depressive disorder, treatment-resistant depression, etc.) have increased efficacy when compound I is provided as a super rapid-acting formulation (e.g., a subcutaneous formulation). A rapid response (e.g., achieved using compound I as disclosed herein) is significant in the treatment of resistant depression, even in populations that have failed to respond to conventional antidepressants used for an appropriate duration and at an appropriate dose. In some embodiments, compositions of compound I as disclosed herein are effective in treating depressive disorders (e.g., major depressive disorder, treatment-resistant depression, etc.) in populations that have failed to respond to conventional antidepressants used for an appropriate duration and at an appropriate dose. In some embodiments, an appropriate duration is the period of time over which a conventional antidepressant would be expected to achieve sufficient efficacy in the patient.

Therefore, there remains a need to achieve rapid antidepressant effects, as patients with major depression are at risk for suicide or self-harm, while conventional antidepressant medications can take several weeks to take effect.

Additionally, patients with major depressive disorder with suicidality often require hospitalization of 4-5 days. Compound I, which has a rapid onset of effect, may reduce the number of days a patient is hospitalized (or may prevent hospitalization altogether), thus providing an advantage over other antidepressants that require at least 4 weeks for a patient to respond to treatment. In some embodiments, treatment with Compound I as disclosed herein reduces the length of hospitalization by at least about 1 day, 2 days, 3 days, 4 days, 5 days, or a range including and/or spanning the aforementioned values. For example, in some embodiments, treatment with Compound I as disclosed herein reduces the length of hospitalization 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.

In some embodiments, treatment with compound I enables patients to rapidly achieve significant improvements in depressive symptoms and suicidality.

The present invention also aims to alleviate one or more depressive symptoms in a patient with major depressive disorder, particularly treatment-resistant depression. The present invention is based in part on the treatment of major depressive disorder in a patient in need of adjunctive treatment for major depressive disorder, particularly treatment-resistant depression.

The present invention also aims to alleviate one or more depressive symptoms in patients with major depressive disorder with suicidality, 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 some embodiments, the present invention overcomes these shortcomings by providing subcutaneous doses of compound I.

In a first aspect, a method of 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 therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In a second aspect, a method of treating a depressive disorder in a subject, e.g., a patient, in need thereof is provided, 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.

In a third aspect, a method is provided for reducing 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 therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In a fourth aspect, a method of treating major depressive disorder in a subject, e.g., a patient, in need thereof is provided, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

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

In a further aspect, a method of treating treatment-resistant depression in a subject, e.g., a patient, in need thereof is provided, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In a further aspect, a method of treating a major depressive episode in a subject, e.g., a patient, in need thereof is provided, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In a further aspect, a method of preventing a major depressive episode in a subject, e.g., a patient, in need thereof is provided, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In a further aspect, a method is provided for treating recurrent major depressive disorder and a current major depressive episode 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.

In another aspect of the invention, the method comprises adjuvant 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 can include, for example, at least one member of the group consisting of lithium, conventional antidepressants, herbal antidepressants, mood stabilizers, antipsychotics, and benzodiazepines.

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.

In another aspect, a method of treating major depressive disorder in a subject, e.g., a patient, in need thereof is provided, wherein the subject, e.g., the patient, has failed to respond to at least two prior antidepressant treatments, at least one of which is used to treat a 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.

In a further aspect, a method of treating treatment-resistant depression in an adult patient in need thereof is provided, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, together with at least one oral antidepressant.

Figure 1 illustrates the duration of the study protocol described in Example 3.
Figure 2 shows the reversal activity of compound I in haloperidol-induced catalepsy in rats treated by subcutaneous injection with vehicle (negative control), compound I (1, 3, 10, and 30 mg/kg), or ketamine (1, 3, 10, and 30 mg/kg, positive control). Data are presented as mean ± SEM (N=10). Data were analyzed by one-way ANOVA. *p<0.05 compared to haloperidol (hal) + vehicle.
Figure 3 shows locomotor activity in rats following treatment by subcutaneous injection with vehicle (negative control), compound I (1, 3, 10, and 30 mg/kg), or ketamine (1, 3, 10, and 30 mg/kg, positive control).
Figure 4 shows the effects of ketamine and compound I on locomotor activity in rats using quantitative electroencephalography (qEEG). 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 presented as mean ± SEM (N=10). Data were analyzed by one-way ANOVA.

Some embodiments disclosed herein relate to a subcutaneous dosage of Compound I, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder mediated by negative allosteric modulation or inhibition of an NR2B-NMDA receptor. In some embodiments, the disease or disorder mediated by negative allosteric modulation or inhibition of an NR2B-NMDA receptor is a depressive disorder. In some embodiments, the invention relates to a subcutaneous dosage of Compound I, or a pharmaceutically acceptable salt thereof, for the treatment of major depressive disorder (including but not limited to treatment-resistant depression). Additional diseases or disorders mediated by negative allosteric modulation or inhibition of an NR2B-NMDA receptor for which the subcutaneous dosage of the invention may also be useful include suicidality of 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 of major depressive disorder, seasonal affective disorder. Some embodiments disclosed herein are directed to methods of treating a depressive disorder in a subject, e.g., a patient, in need thereof. In some embodiments, the methods comprise subcutaneously administering to a subject, e.g., a patient, a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the depressive disorder is major depressive disorder. In some embodiments, the major depressive disorder is treatment-resistant depression. Some embodiments are directed to the use of Compound I, or a pharmaceutically acceptable salt thereof, in the treatment of treatment-resistant depression in a patient having major depressive disorder.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) of the American Psychiatric Association provides a diagnostic tool for identifying the disorders described herein. Those skilled in the art will recognize that alternative nomenclature, nosology, and classification systems for the psychiatric disorders described herein exist and that these evolve as medical and scientific advances occur.

definition

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. A feature described under one heading (e.g., compositions) may be used in combination with a feature described under a different heading (e.g., methods of treatment). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It should be noted that the use of a particular term when describing a particular feature or aspect of the invention should not be taken to imply that that term is being redefined herein to include any specific feature or aspect of the invention to which that term relates.

Terms and phrases used in this application, and particularly their variations in the appended claims, unless expressly stated otherwise, are to be construed as open-ended rather than restrictive. By way of example only, the term "including" should be read to mean "including without limitation," "including but not limited to," etc.; the term "comprising," as used herein, is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least; the term "include" should be interpreted as "including but not limited to;" the term "examples" is used to provide illustrative instances of the items under discussion and is not an exhaustive or limited list; The use of terms such as "preferably," "preferably," "desirable," or "desiring," and words of similar import should not be construed to imply that any particular feature is critical, essential, or even important to the structure or function of the invention, but instead should be understood only as intended to highlight alternative or additional features that may or may not be utilized in particular embodiments of the invention. Furthermore, the term "comprising" should be construed as synonymous with the phrases "having at least" or "comprising at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may also include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components. Similarly, a group of items joined by the conjunction 'and' should not be read to require that each and every one of those items be present in the group, but rather should be read as 'and/or' unless explicitly stated otherwise. Similarly, a group of items joined by the conjunction 'or' should not be read to require mutual exclusivity among the items in the group, but rather should be read as 'and/or' unless explicitly stated otherwise.

Additionally, the phrase "consisting essentially of" will be understood to include the specifically mentioned elements and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any element not specified.

With respect to the use of substantially any plural and/or singular terms herein, those skilled in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. Various singular/plural permutations may be expressly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measurements are recited in different dependent claims does not indicate that a combination of such measurements cannot be advantageously used. Any reference signs in the claims should not be construed as limiting the scope.

Reference throughout this specification to "an 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 an 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.

When referring to a variety of characteristics, the term "or a range including and/or spanning the aforementioned values" may be used. This term (and variations thereof) means including any range including or spanning any of the aforementioned values. For example, with respect to a % improvement in mood, the % could be expressed as "greater than or equal to about 1%, 5%, 10%, 20%, or a range including and/or spanning the aforementioned values." This language includes a particular % provided and ranges exceeding that value (e.g., greater than or equal to about 1%, greater than or equal to about 5%, greater than or equal to about 10%, and greater than or equal to about 20%), as well as % ranges spanning those values (e.g., from 1% to 20%, from 1% to 10%, from 1% to 5%, from 5% to 20%, from 5% to 10%, and from 10% to 20%). Similarly, with respect to % improvement in mood, the % can be expressed as "about 1%, 5%, 10%, 20% or less, or a range including and/or spanning the aforementioned values." This language includes ranges of % across those values (e.g., about 1% or less, about 5% or less, about 10% or less, and about 20% or less) as well as ranges of % across those values (e.g., from 1% to 20%, from 1% to 10%, from 1% to 5%, from 5% to 20%, from 5% to 10%, and from 10% to 20%).

Compound I used in the present invention, a compound of 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 of the following formula:

[Chemical Formula I]

The INN name is onfasprodil. Onfasprodil is a highly potent, selective, and reversible, small molecule 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 low frequency of dissociative adverse events. The relative contribution of each individual subtype of NMDAR to the detrimental effects of pan-NMDAR inhibition is not well understood due to the lack of selective inhibitors for the various subtypes, but together, these results suggest that it is feasible to achieve safe yet rapid-onset antidepressant efficacy with compounds that selectively inhibit NR2B-containing NMDA receptors.

The terms "salt", "salts" or "salt form" as used herein refer to an acid addition salt or a base addition salt of the respective compound, e.g., a compound as defined herein (e.g., Compound I or, e.g., a further pharmaceutically active ingredient as defined herein). "Salt" particularly includes a "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound and is typically not biologically or otherwise undesirable. The compounds as defined herein (e.g., Compound I or, e.g., a further pharmaceutically active ingredient as defined herein) are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The compounds of the present invention are capable of forming acid addition salts, and thus, as used herein, the term pharmaceutically acceptable salt of Compound I means a pharmaceutically acceptable acid addition salt of Compound I.

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

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

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.

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

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

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, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

Pharmaceutically acceptable salts can be synthesized from basic or acid moieties by conventional chemical methods. Typically, such salts are prepared by reacting the free acid form of the compound with a stoichiometric amount of a suitable base (e.g., a Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting the free base form of the compound with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent, or in mixtures of the two. Generally, it is preferred to use a non-aqueous medium, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, whenever possible. Additional lists of suitable salts are found in, for example, "Remington's Pharmaceutical Sciences", 22 ^nd edition, Mack Publishing Company (2013); and can be found in ["Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2 ^nd edition)].

Some quantitative expressions given herein are not limited to the term "about." Whether or not the term "about" is explicitly used, all quantities given herein are understood to refer to actual given values, and also to approximations to such given values that would reasonably be inferred based on ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given values. In an embodiment, the term "about" refers to a range of ±10% of the stated value.

The term "adjunct therapy" as used herein, also known as adjunctive therapy, additional therapy, add-on therapy, or augmentation therapy, is a therapy given in addition to a primary or initial therapy. In embodiments, the primary or initial therapy in the context of the present invention is, for example, an antidepressant therapy as disclosed herein. Non-pharmacological treatments, such as psychotherapy and transcranial magnetic stimulation, are also available and are options for adjunctive therapy.

Unless otherwise stated, the terms "antidepressant," "antidepressant treatment," "conventional antidepressant," and the like, as used herein, shall mean any pharmaceutical agent that can be used to treat depression. Antidepressant, antidepressant treatment, or conventional antidepressant also include those listed under the list of antidepressant medications in the MGH Antidepressant Treatment Response Questionnaire (ATRQ), the entire contents of which are incorporated herein by reference. In certain cases, antidepressant treatment may 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 (RIMA)), and 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 that target 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., Prozac®), duloxetine (e.g., Cymbalta®), desvenlafaxine (e.g., Pristiq®), venlafaxine (e.g., Effexor®), milnacipran (e.g., Savella®), citalopram (e.g., Celexa®), escitalopram (e.g., Lexapro®), fluvoxamine (e.g., Luvox®), paroxetine (e.g., Paxil®, Pexeva®), sertraline (e.g., Zoloft®). Examples of monoamine oxidase inhibitors include isocarboxazidide (e.g., Marplan®), phenelzine (e.g., Nardil®), tranylcypromine (e.g., Parnate®), and selegiline (e.g., Eldepryl®, Emsam®). Examples of reversible inhibitors of monoamine oxidase include moclobemide (e.g. Aurorix®), perindol (e.g. Pirazidol®). Norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tricyclic antidepressants include amitriptyline (e.g. Elavil®, Endep®), clomipramine (e.g. Anafranil®), doxepin (e.g. Adapin®, Sinequan®, Quitaxon®, Aponal®), imipramine (e.g. Tofranil®), trimipramine (e.g. Surmontil®), amoxapine (e.g. Asendin®), desipramine (e.g. Norpramin®), maprotiline (e.g. Ludiomil®), nortriptyline (e.g. Pamelor®), protriptyline (e.g. Vivactil®), pipopezine (e.g. Azafen®), noxiptrine (e.g. Agedal®, Elronon®). Suitable examples of multimodal antidepressants include vilazodone (e.g. Viibryd®), vortioxetine (e.g. Trintellix®, Brintellix®). Suitable norepinephrine dopamine reuptake inhibitors include bupropion (e.g., Wellbutrin®). In embodiments, “antidepressants,” “antidepressant therapy,” and “conventional antidepressants” are FDA approved for the treatment of MDD.

The term "antipsychotic" includes, but is not limited to:

(a) typical or conventional antipsychotics, such as phenothiazines (e.g. chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazine), thioxanthenes (e.g. thiothixene, flupentixo), butyrophenones (e.g. hyoperidol), dibenzoxazepines (e.g. loxapine), dihydroindolones (e.g. molindone), substituted benzamides (e.g. sulpride, amisulpride), and the like; and

(b) atypical antipsychotics, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, and the like; and others, such as sonepiprazole, aripiprazole, nemonapride, 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.

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 pharmaceutical agents disclosed herein) can be readily determined by those of skill in the art. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for marketing are publicly available, e.g., as listed on the package label, in standard dosage guidelines, in standard dosage reference books, such as the Physician's Desk Reference (available from Medical Economics Company or online at http:///www.pdrel.com), or from other sources.

The term "AUClast" as used herein refers to the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration. In a general context, "time zero" refers to the time of subcutaneous injection of the intended dose.

Except as otherwise indicated herein, the terms “baseline” or “baseline assessment” herein mean the time immediately preceding the initiation of treatment with Compound I, or a pharmaceutically acceptable salt thereof.

The terms "combination therapy", "combination", and "combination administration" shall mean treating a patient in need thereof by administering Compound I, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, for example as adjunctive therapy, wherein the additional therapeutic agents are administered by any suitable means. The agents may be administered simultaneously or sequentially in any order for all or part of the treatment period. The terms "combination therapy", "combination", and "combination administration" also encompass adjunctive therapy as defined herein. The terms "combination therapy", "combination", and "combination administration" also encompass treatment with Compound I, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents, such as, for example, a standard of care medication prescribed for a psychiatric disorder, for example, a depressive disorder, as defined herein. In an embodiment, compound I is administered as a regimen with 1 to 5 additional therapeutic agents (e.g., 1, 2, 3, 4, or 5 additional therapeutic agents). In another embodiment, compound I is administered as a regimen with 1, 2, 3, 4, or 5 additional therapeutic agents. In another embodiment, compound I is administered as a regimen with 1 or 2 additional therapeutic agents. In another embodiment, compound I is administered as a regimen with one other therapeutic agent. In a further embodiment, compound I is administered as a regimen with an additional therapeutic agent (s) currently being administered to the patient, including a current antidepressant(s) to which the patient has an inadequate response. In yet a further embodiment, compound I is administered as a regimen with one or more additional therapeutic agents not previously administered to the patient. In yet another embodiment, compound I is administered as a regimen with one or more additional therapeutic agents previously administered to the patient. When Compound I and the additional therapeutic agent(s) are administered in separate dosage forms, the number of daily doses administered for each compound can be the same or different, and more typically can be different. The additional therapeutic agent(s) can be administered as prescribed by the treating physician and/or as per its label, and Compound I is administered as described herein. Typically, the patient is on concurrent treatment with both the antidepressant and Compound I, wherein both are administered according to the prescribed dosage regimen. Compound I and the antidepressant(s) can be administered concurrently, in divided or single forms, at the same or different times during the course of therapy, according to simultaneous or alternating regimens. In embodiments, the additional therapeutic agent(s) is selected from one or more antidepressants, antipsychotics, e.g., atypical antipsychotics, mood stabilizers, e.g., lithium, benzodiazepines, and combinations thereof. In certain embodiments, the one or more additional therapeutic agents are one or more antidepressants.

The terms “depressive episode” or “major depressive episode” as used herein refer to the features of major depressive disorder as defined herein.

A "major depressive episode" may be defined as a depressed mood or loss of interest for at least 2 weeks that may be accompanied by other symptoms of depression, particularly symptoms of major depressive disorder sufficient to meet criteria for major depression as specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition: DSM-5. The symptoms must be present most of the day (i.e., at least two-thirds of the patient's waking hours) and nearly every day for at least 2 consecutive weeks (i.e., at least 10 out of 14 days). A "depressed mood" is often described as the patient feeling sad, hopeless, helpless, or worthless. The patient may also appear sad to an observer, for example, through facial expression, posture, voice, and tearfulness. In children and adolescents, the mood may be irritable. A "loss of interest" is often described as the patient feeling less interested in hobbies or taking no pleasure in activities that the patient previously found enjoyable.

A major depressive episode may be accompanied by other symptoms of depression, including significant weight loss or gain when not dieting (e.g., more than a 5% weight change in a month), 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; difficulty thinking or concentrating; or indecisiveness; and recurrent thoughts of death, recurrent suicidal ideation with or without a specific plan, or suicide attempts.

The term "Cmax" as used herein shall refer to the maximum measured plasma concentration following any administration, e.g., single or repeated administrations. In some embodiments, the methods disclosed herein further comprise the step of measuring plasma levels in the patient.

The term "depressive disorder" as used herein means a clinical disorder that includes a markedly sad or depressed mood and is accompanied by psychological and/or physical symptoms. The depressive disorder can be a mild depressive disorder, a moderate depressive disorder, a severe depressive disorder, a clinical depressive disorder, or a postpartum depressive disorder. Exemplary depressive disorders include, but are not limited to, major depressive disorder including suicidality of 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 major depressive disorder with self-harm, persistent depressive disorder, seasonal affective disorder, perinatal depression, e.g., postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, geriatric depression, depression due to a recognized stressor, treatment-resistant depression, partially resistant depression, and combinations thereof, each of which is contemplated to be treated using the methods and compositions described herein. Many methods and techniques are well known to those of skill in the art for diagnosing a depressive disorder, assessing the status or severity of such condition or symptoms thereof over time, and monitoring changes in the status or severity of such condition or symptoms thereof over time, including response to treatment or therapy. In an embodiment, the depressive disorder is major depressive disorder. In a further embodiment, the depressive disorder is treatment-resistant depression. In another embodiment, the depressive disorder is seasonal affective disorder.

The term "depressive symptoms" as used herein refers to one or more symptoms associated with a depressive disorder, particularly major depressive disorder, including persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, guilt, and/or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleeping or insomnia, overeating or loss of appetite, difficulty thinking, concentrating, or making decisions, suicidal ideation, and suicide attempts. The presence, number, severity, frequency, and duration of such symptoms can vary from individual to individual and from time to time for a given individual. Depressive symptoms can occur in a depressive disorder, for example, major depressive disorder.

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

The term "failed to respond" as used herein refers to an inadequate response to a previous or current antidepressant treatment due to inadequate efficacy, for example, where the patient demonstrates little or no improvement in current symptoms. The previous or current antidepressant treatment has been used for an appropriate duration and at an appropriate dose, for example, a therapeutically effective dose. For example, the previous or current antidepressant treatment has been used for a duration of at least 4 weeks, for example, at least 6 weeks. In some embodiments, a patient who has failed to respond to a medication is a patient who has been treated with the medication for a duration of at least about 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or a range including and/or spanning the aforementioned values. An inadequate response can be assessed by a clinician skilled in the treatment of the condition.

As used herein, "inadequate response" refers to a patient experiencing a decrease in depressive symptom severity of less than about 50% from the start of treatment. Typically, an inadequate response occurs during an active/present episode of depression. In some embodiments, an inadequate response refers to a patient experiencing a decrease in depressive symptom severity of less than about 26 to about 50% from the start of treatment. In other embodiments, an inadequate response refers to a patient experiencing a decrease in depressive 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% from the start of treatment initiation. In some embodiments, an inadequate response refers to the patient experiencing a decrease in depressive symptom severity of less than or equal to 25% from baseline in treatment, a decrease in depressive symptom severity of less than or equal to 10% from baseline in treatment, a decrease in depressive symptom severity of less than or equal to 5% from baseline in treatment, or a decrease in depressive symptom severity of 0% from baseline in treatment. Patient 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.

The term "major depressive disorder", or MDD, as used herein, is defined, for example, by 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 psychiatric disorder that meets five or more of the following symptoms that have occurred during the same 2-week period and that represent a change from previous functioning; at least one of the symptoms is (i) depressed mood or (ii) loss of interest or pleasure:

i) depressed/sad mood; ii) loss of interest or pleasure; iii) significant weight loss or gain when not dieting or decreased or increased appetite; iv) insomnia or hypersomnia; v) psychomotor agitation or retardation; vi) fatigue or loss of energy; vii) feelings of worthlessness or excessive or inappropriate guilt; viii) impaired thinking or concentration, or indecisiveness; ix) recurrent thoughts of death or suicidal ideation, plans, or attempts; 2) the 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 attributable to the physiological effects of a substance or another medical condition; and 5) there have been no manic or hypomanic episodes (Diagnostic and Statistical Manual of Mental Disorders, 5th ed., American Psychiatric Association, 2013). The table below further defines criteria for major depressive episode/disorder:

In principle, the term major depressive disorder as used in accordance with the present invention 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.

The term "drugs with a known risk of torsade de pointes" refers to any drug that can prolong the QT interval and cause torsade de pointes. Examples of drugs known to cause torsade de pointes are listed at www.qtdrugs.org.

The term "non-responder" or "non-responsive" as used herein means that a patient does not experience clinically meaningful improvement following treatment (e.g., less than a 50% change from baseline on a given depression assessment test, less than a 25% change from baseline on a given depression assessment test, less than a 10% change from baseline on a given depression assessment test, less than a 5% change from baseline on a given depression assessment test, less than a 0% change from baseline on a given depression assessment test (or a range including and/or spanning the aforementioned values)), or the improvement is not statistically significant. In some embodiments, the depression assessment test is the MADRS. In some embodiments, the depression assessment test is the MGH-ATRQ. In some embodiments, the depression assessment test is the Hamilton Depression Scale (HAM-D). In some embodiments, the depression assessment test is the Clinical Global Impression-Survey (CGI-S). To the extent that a patient is said to have a partial response to treatment, this refers to some mild to moderate symptomatic improvement since initiation of treatment, but some of the initial symptoms still present and bother the patient and these persistent symptoms still affect behavior and functioning. For example, the patient's motivation, productivity, and interest in daily activities may still be impaired. In one embodiment, the patient is doing better than at baseline, but symptoms persist and require additional antidepressant treatment. In another embodiment, the patient experiences a <50% but ≥25% decrease from baseline depression scale scores, including but not limited to, for example, MADRS, MGH-ATRQ, HAM-D, CGI-S.

The term "patient" as used herein refers to a subject suffering from a disorder that would benefit from treatment. In an embodiment, the subject, e.g., the patient, has a major depressive disorder. Mild depressive disorder, moderate depressive disorder, and severe or major depressive disorder can be characterized by a total score of the Montgomery-Osberg Depression Disorder Rating Scale (MADRS) for the severity of depressive symptoms. For example, the patient has a MADRS score of 24 or greater prior to treatment with Compound I, or a pharmaceutically acceptable salt thereof. In a particular embodiment, the patient has a diagnosis of recurrent major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by both the SCID-5 and an appropriate clinical psychiatric evaluation, and a current major depressive episode of at least 4 weeks, such as at least 6 weeks, such as at least 8 weeks. In a particular embodiment of the invention, the patient is in need of adjunctive treatment for treatment-resistant depression. In a particular embodiment, the patient is an adult. The term “adult” as used herein refers to a human being who is 18 years of age or older.

The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one active ingredient or therapeutic agent that is administered to a subject, e.g., a patient, to treat a particular condition (i.e., a disease, disorder or condition or at least one of the clinical symptoms thereof) affecting the subject, e.g., the patient.

The term "pharmaceutically acceptable excipient" as used herein includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, absorption delaying agent, salt, preservative, drug stabilizer, binder, excipient, disintegrant, glidant, sweetener, flavoring agent, dye, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 22 ^nd Ed. Mack Printing Company, 2013, pp. 1049-1070). Any conventional carrier is contemplated for use in the therapeutic or pharmaceutical compositions, provided that it is not incompatible with the active ingredient.

The term “pregnancy” as used herein is defined as the state of a woman after fertilization and until the end of gestation as confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

The term "preparatory behavior" as used herein means an act or preparation for attempting suicide, but before the potential for harm begins. This may include anything beyond utterance or thought, such as gathering a method (e.g., buying a gun, collecting pills) or preparing for death by suicide (e.g., writing a suicide note, giving away items).

The term "psychotherapy" as used herein refers to the informed and intentional application of clinical methods and interpersonal stances derived from established psychological principles for the purpose of helping people modify their behavior, cognitions, emotions, and/or other personal characteristics in directions deemed desirable by the participant.

The term “self-harm” as used herein means intentionally perpetrating a painful, destructive, or harmful act without the intent to kill.

The term “standard of care treatment” as used herein refers to physician-prescribed treatment for patients suffering from a psychiatric disorder, such as major depressive disorder, including but not limited to patients with suicidal tendencies and/or suicidal ideation assessed as being at imminent risk for suicide.

Typically, standard care treatment is given as prescribed by the treating physician or other health care professional and is administered in conjunction with compound I treatment, e.g., the standard care treatment is given for the same treatment duration as the compound I treatment. The standard care treatment may also precede treatment with compound I and may continue after treatment with compound I is discontinued. With respect to the antidepressant used in the standard care treatment, the compound I and the antidepressant(s) may be administered via the same or different routes of administration.

"Subject" or "individual" are used interchangeably and refer to a human or non-human animal. The terms include mammals, such as humans. In some embodiments, the subject is a mammal. The subject also refers to, for example, a primate (e.g., 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 subject suffering from, at risk for, or potentially suffering from a disorder described herein. In some embodiments, the subject is a human suffering from, at risk for, or potentially suffering from a disorder described herein. In some embodiments, the subject is a patient, i.e., a subject suffering from or at risk for a disorder described herein or a subject in need of treatment for a disorder 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.

The term "suicide" as used herein means death caused by a self-directed harmful act with the arbitrary intent to die as a result of the act.

The term "suicidal tendencies" as used herein refers to suicide (suicidal ideation) and suicidal thoughts, suicide attempts, and preparatory acts (suicidal behavior).

The term "suicide attempt" as used herein means a non-fatal, self-directed, potentially harmful act with the intention of dying as a result of the act. A suicide attempt may or may not result in injury.

The term “suicidal behavior” as used herein includes suicide, suicide attempts, and acts preparatory to suicide.

The term "suicidal ideation" as used herein refers to either passive thoughts of wanting to die or active thoughts of suicide, without preparatory behavior. Suicidal ideation refers to thinking about or planning suicide. The ideation can range from making a detailed plan to briefly considering it, but does not include the final act of suicide. Passive suicidal ideation is when a person has thoughts of suicide or self-harm, but does not plan to carry them out. Active suicidal ideation is when a person has thoughts of suicide or self-harm, but plans to carry them out.

The terms "suicidal ideation with intent" or "suicidal ideation with suicidal intent" as used herein refer to passive thoughts of wanting to die or active thoughts of suicide with the hope, goal, purpose, or aim of committing self-destructive acts that culminate in death. Suicidal ideation with intent or suicidal ideation with suicidal intent can be assessed by a suicidal ideation rating scale, which refers to any of a number of standardized questionnaires, clinical instruments, or symptom inventories that are used to measure the severity of suicidal ideation. Such suicidal ideation symptom rating scales include, but are not limited to, the Suicidal Ideation Inventory (SSI), the Suicidal State Form (SSF), the Timed Suicide Tracking Scale (S-STS), or the Columbia Suicide Severity Rating Scale (C-SSRS).

The term "nonintentional suicidal ideation" as used herein refers to either passive thoughts of wanting to die or active thoughts of suicide but without the intent to do so.

The term "stable dose" as used herein refers to no change in the dose or type of agent.

The terms "treat," "treating," "treatment," or "therapy," as used herein, mean obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results may include, but are not limited to, alleviation of one or more symptoms in a patient with major depressive disorder or treatment-resistant depression as defined herein. One aspect of treatment is, for example, that the treatment should have minimal adverse effects on the patient, and for example, that the agent used should have a high level of safety, for example, without producing the side effects of previously known treatments. For example, the term "alleviation," as used herein with respect to symptoms of a condition, refers to reducing at least one of the frequency and severity of symptoms of the condition in the patient.

The term "treating a depressive disorder" as used herein may refer to a decrease in symptoms of a depressive disorder, such as major depressive disorder, as measured, for example, by a decrease in the Montgomery-Osberg Depression Disorder Rating Scale (MADRS) score. In some embodiments, the term "treating a depressive disorder" refers to a change from baseline as measured by the MADRS score. In some embodiments, the term "treating a depressive disorder" refers to remission as measured by a decrease in the MADRS score. In some embodiments, the term "treating a depressive disorder" refers to an improvement of at least 50% as measured, for example, by the MADRS score. In some embodiments, treating a depressive disorder, such as MDD, refers to a decrease in MDD severity by at least 50% on a standardized rating scale, such as those disclosed herein, for example, the MADRS. The term depressive disorder refers specifically to major depressive disorder, such as treatment-resistant depression. Although the MADRS scale is often used herein as a measure of depression, the term "treating a depressive disorder" can also (or alternatively) refer to improved scores on any of the depression measures disclosed herein (e.g., the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, the Mini-International Neuropsychiatric Interview, the Cambridge Automated Neuropsychological Test Battery, the Digit Symbol Substitution Task, the Emotion Bias Task, etc.). In some embodiments, the improvement can be an increased score, in which case the scale provides a higher score for improvement on the depression measure. Alternatively, in some embodiments, the improvement in a score can be a decreased score, in which case the scale provides a higher score for heightened depression symptoms.

The term "treatment refractory" or "treatment resistant depression" or TRD as used herein is defined, for example, with reference to 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 a partial response) to at least one antidepressant at an adequate dose and duration for the current depressive episode, particularly to at least two different antidepressants, particularly to two antidepressants, but not more than five antidepressants. In another embodiment, TRD is defined as major depressive disorder in a patient who has not responded to at least two oral antidepressants at an adequate dose and duration, for example, for a duration of at least 6 weeks, for 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, for example, selective serotonin reuptake inhibitors (SSRIs), serotonin neuroepinephrine 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, as described herein. The above-listed classes of antidepressants are not exhaustive. Treatment-resistant depression can be assessed by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), a self-rating scale used to determine treatment resistance in major depressive disorder.

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

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

As used herein, “female of childbearing potential” refers to any female who is physiologically capable of becoming pregnant, unless she is using a highly effective method of contraception while taking Compound I and for 1 week after the last treatment. Highly effective methods of contraception include:

· Complete abstinence (if preferred by the subject and consistent with daily life style). Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation) and withdrawal are not acceptable methods of contraception.

· Bilateral tubal ligation, female sterilization (surgical bilateral oophorectomy with or without hysterectomy), or total hysterectomy at least 6 weeks prior to taking Compound I. In the case of oophorectomy alone, only if the woman's reproductive status has been confirmed by follow-up hormone level assessment.

· Male sterilization (at least 6 months prior to screening). For female participants in the study, the male partner who had a vasectomy must be the participant’s only partner.

· Use of an intrauterine device (IUD) or intrauterine system (IUS). If an IUD or IUS is used, the device or system must have been in place for at least 3 months prior to study treatment and must be well tolerated by the patient.

Oral (estrogen and progesterone), injectable or implantable hormonal contraceptives, and other forms of hormonal contraception are not approved for contraception.

Women were considered postmenopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to treatment with Compound I. If they had undergone oophorectomy alone, women were considered not of childbearing potential only if their reproductive status was confirmed by follow-up hormone level assessments.

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

A subject, e.g., a patient, as used herein is "in need of" such treatment if such subject, e.g., a patient, would benefit biologically, medically, or quality of life-wise from such treatment.

The use of any examples or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose any limitation on the scope of the invention otherwise claimed.

How to treat depression

The present invention provides methods for treating major depressive disorder (MDD). The methods generally involve subcutaneously administering to a subject having MDD a therapeutically effective amount of compound I. In various embodiments, the treatment is administered in combination with one or more antidepressant therapies, for example, one or more oral antidepressants.

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

Disclosed herein is a method of treating a depressive disorder, e.g., major depressive disorder, in a patient in need thereof, said method comprising subcutaneously administering to the patient Compound I, or a pharmaceutically acceptable salt thereof. The invention also relates to a method of treating treatment-resistant depression in a patient in need thereof, said method comprising subcutaneously administering to the patient Compound I, or a pharmaceutically acceptable salt thereof.

The present invention relates particularly to a method for treating treatment-resistant depression in an adult patient in need thereof, said method comprising administering subcutaneously to the patient a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, together with at least one oral antidepressant.

The present invention provides a method of treating depressive symptoms in a subject, e.g., a patient, having depression, the method comprising administering to the subject, e.g., compound I, or a pharmaceutically acceptable salt thereof, The present invention also provides a method of treating depressive symptoms in a subject, e.g., a patient, having major depressive disorder, comprising administering to the subject, e.g., compound I, or a pharmaceutically acceptable salt thereof, The present invention also provides a method for treating depressive symptoms in a subject, e.g., a patient, having major depressive disorder with acute suicidal ideation or behavior, comprising administering to the subject, e.g., compound I, or a pharmaceutically acceptable salt thereof, The present invention further provides a method of treating depressive symptoms in a subject, e.g., a patient, having treatment-resistant depression, the method comprising administering to the subject, e.g., compound I, or a pharmaceutically acceptable salt thereof, Includes a step of administering subcutaneously to a patient.

The present invention also provides a method of reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, said 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 some embodiments, a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to a subject, e.g., a patient, to alleviate one or more symptoms associated with major depressive disorder.

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

In some embodiments, the subject, e.g., the patient, is characterized as having failed at least one antidepressant treatment based on the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) (Gregory M. Chandler, Dan V. Iosifescu, Mark H. Pollack, Steven D. Targum & Maurizio Fava. Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neuroscience & Therapeutics 16 (2010) 322-325). In some embodiments, the subject, e.g., the patient, is characterized as having a suboptimal response to at least one antidepressant treatment. For example, the subject has a <50% response (at least ≥8 weeks at an adequate and stable dose for at least 4 weeks) to at least one antidepressant treatment according to the MGH-ATRQ. In some embodiments, the subject, e.g., the patient, has a single episode major depressive disorder. In some embodiments, the subject, e.g., the patient, has recurrent major depressive disorder. In some embodiments, the subject, e.g., the patient, has chronic major depressive disorder. In some embodiments, the subject, e.g., the patient, is characterized as having treatment-resistant depression. In some embodiments, a diagnosis of TRD is confirmed by meeting DSM-5 criteria for MDD and failing to adequately respond to at least two different antidepressant medications at appropriate doses and durations for the current depressive episode. Typically, the methods disclosed herein further comprise administering to the subject, e.g., the patient, one or more additional antidepressant treatments, e.g., an oral antidepressant.

In some embodiments, the present invention also provides a method of treating a subject, e.g., a patient, having recurrent or chronic depression, such as recurrent or chronic major depressive disorder, the method comprising subcutaneously administering to a subject, e.g., a patient, in need thereof a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention also provides a method of treating a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode of at least 8 weeks duration. In some embodiments, the present invention further provides a method of treating a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode of at least 8 weeks duration, wherein the subject, e.g., the patient, is treatment resistant.

In some embodiments, the present invention also provides a method of treating a subject, e.g., a patient, meeting DSM-5 criteria for MDD based on the Structured Clinical Interview 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. In some embodiments, the subject, e.g., the patient, has failed >1 and <8 trials in the current episode according to the MGH ATRQ and/or has <50% response (≥8 weeks of major depressive episodes at an adequate or effective and stable dose for at least 4 weeks) to current antidepressant treatment according to the MGH ATRQ.

In some embodiments, subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, is used for outpatient populations of depressed subjects, e.g., patients, who are considered treatment resistant. The methods disclosed herein advantageously eliminate the need to present the patient to a hospital or clinic for subcutaneous administration. As a result, the subject, e.g., the patient, can receive administration of the 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 the subject, e.g., the patient, in a medically supervised medical setting.

Dosage amounts and dosing regimens include any of those described herein, e.g., those described in the Administration and Dosage sections, in any combination. For example, in some preferred embodiments, the methods disclosed herein comprise administering Compound I, or a pharmaceutically acceptable salt thereof, subcutaneously to a subject, e.g., a patient, as a single subcutaneous injection. Each dose to be administered is in the range of about 0.1 mg to about 15 mg, e.g., about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg of Compound I, or a pharmaceutically acceptable salt thereof. In various embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg. In various embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 4 mg. In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 10 mg.

In various embodiments, the present invention provides a method of subcutaneously administering a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, to a subject, e.g., a patient, in need thereof, the method comprising the step of selecting a subject, e.g., a patient, suffering from a depressive disorder.

In various embodiments, the present invention provides a method of administering subcutaneously 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., the patient, has been diagnosed with or has been diagnosed with a depressive disorder.

In various embodiments, provided herein are methods of treating a depressive disorder in a subject, e.g., a patient, in need thereof, the methods comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof. As disclosed elsewhere herein, in some embodiments, the methods comprise administering a dose of Compound I that is less than or equal to about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or a range including and/or spanning any of the aforementioned values. For example, in some embodiments, the methods comprise administering a dose of Compound I in the range of from 1 mg to 5 mg, from 5 mg to 15 mg, from 1 to 12.5 mg, or less than 15 mg. In some embodiments, the subject in need thereof is a subject having a depressive disorder.

In various embodiments, provided herein are methods of treating a depressive disorder in a subject, e.g., a patient, in need thereof, the methods comprising: subcutaneously administering a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., the patient, wherein the methods comprise selecting a subject, e.g., the patient, suffering from a depressive disorder.

In various embodiments, provided herein are methods of treating a depressive disorder in a subject, e.g., a patient, in need thereof, 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., the patient, has been diagnosed with or has been diagnosed with a depressive disorder.

In certain embodiments, provided herein is a method of 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 from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

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

In some embodiments, as disclosed elsewhere herein, the depressive disorder is major depressive disorder. In certain embodiments, provided herein is a method of treating major depressive disorder 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 from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In some embodiments, as disclosed elsewhere herein, the depressive disorder is major depressive disorder. In certain embodiments, provided herein is a method of treating major depressive disorder in a subject, e.g., a patient, in need thereof, wherein the subject, e.g., the patient, has been diagnosed with or has been diagnosed with major depressive disorder, the method comprising subcutaneously administering from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of Compound I, or a pharmaceutically acceptable salt thereof.

In some embodiments, as disclosed elsewhere herein, the depressive disorder is treatment-resistant depression. In certain embodiments, provided herein is a method of treating treatment-resistant depression 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 from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of Compound I, or a pharmaceutically acceptable salt thereof.

In some embodiments, as disclosed elsewhere herein, the depressive disorder is treatment-resistant depression. In certain embodiments, provided herein is a method of treating treatment-resistant depression in a subject, e.g., a patient, in need thereof, wherein the subject, e.g., the patient, has been diagnosed with or has been diagnosed with treatment-resistant depression, the method comprising subcutaneously administering from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of Compound I, or a pharmaceutically acceptable salt thereof.

In some embodiments, as disclosed elsewhere herein, the depressive disorder is treatment-resistant depression. In certain embodiments, provided herein is a method of treating treatment-resistant depression in a subject, e.g., a patient, in need thereof, comprising subcutaneously administering a therapeutically effective amount, e.g., from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of Compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, provided herein are methods for the chronic treatment of a depressive disorder in a subject, e.g., a patient, in need thereof, comprising subcutaneously administering to a subject, e.g., a patient, a dose of Compound I, or a pharmaceutically acceptable salt thereof, from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg. In embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered as a regimen for at least 6 months, for example, for at least 1 year, and up to 2 years.

In various embodiments, the present invention provides a method of reducing 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 therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the present invention provides a method of reducing 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 compound I, or a pharmaceutically acceptable salt thereof, from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In various embodiments, the present invention provides a method of reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, the method comprising subcutaneously administering a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., the patient, wherein the subject, e.g., the patient, has failed to adequately respond to two or more antidepressant treatments prior to administration of Compound I, or pharmaceutically acceptable salt thereof. In embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, or from about 1 mg to about 15 mg.

In various embodiments, the present invention provides a method of reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, the method comprising subcutaneously administering a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., the patient, wherein the subject, e.g., the patient, has been diagnosed with or has been diagnosed with a depressive disorder. In embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In various embodiments, as disclosed elsewhere herein, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder, seasonal affective disorder, or a combination of any of the foregoing. In certain embodiments, the depressive disorder is major depressive disorder. In another certain embodiment, the depressive disorder is treatment-resistant depression. In embodiments, the major depressive disorder comprises a single major depressive episode. In embodiments, the major depressive disorder comprises recurrent major depressive episodes.

In various embodiments, as disclosed elsewhere herein, the subject, e.g., the patient, is suffering from an episode of depression, e.g., a major depressive episode, wherein the episode of depression, e.g., a major depressive episode, has not responded to treatment with at least one antidepressant, i.e., the subject, e.g., the patient, has not responded to treatment with at least one antidepressant for the current major depressive episode. In embodiments, the at least one antidepressant is an oral antidepressant. The antidepressant(s) may be administered to the patient at an appropriate dosage as may be determined by the treating physician and/or may be dosed as prescribed by the label. Similarly, the antidepressant is administered for an appropriate duration of time, e.g., as prescribed by the label. In embodiments, the antidepressant is administered for a duration of at least 4 weeks, e.g., for a duration of at least 6 weeks.

In various embodiments, the subject, e.g., the patient, is suffering from an episode of depression, e.g., a major depressive episode, wherein the depression, e.g., a major depressive episode, has not responded to treatment with at least two antidepressants, i.e., the subject, e.g., the patient, has not responded to treatment with at least two antidepressants for the current major depressive episode. In embodiments, at least one of the at least two antidepressants is an oral antidepressant. The antidepressant(s) may be administered to the patient at an appropriate dosage as may be determined by the treating physician and/or may be dosed as prescribed by the label. Similarly, the antidepressant is administered for an appropriate duration, e.g., as prescribed by the label. In embodiments, the antidepressant is administered for a duration of at least 4 weeks, e.g., for a duration of at least 6 weeks.

In certain embodiments, the invention provides a method of reducing 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 to the subject from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of reducing 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 has been diagnosed with major depressive disorder; the method comprising subcutaneously administering from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of reducing 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 to the subject from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of reducing 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 has been diagnosed with treatment-resistant depression; the method comprising subcutaneously administering from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the present invention provides a method of treating major depressive disorder, e.g., treatment-resistant depression, comprising subcutaneously administering to a subject, e.g., a patient, in need thereof a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof; wherein the subject, e.g., the patient, in need thereof has had a major depressive episode, and the subject, e.g., the patient, has not responded to at least one antidepressant in the current major depressive episode.

In various embodiments, the present invention 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:

(a) determining or having determined the baseline MADRS score of a subject, e.g., a patient;

(b) subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, wherein the amount of compound I, or a pharmaceutically acceptable salt thereof, improves (e.g., decreases) the MADRS score by at least about 30%, for example, 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 MADRS total score for the subject, e.g., the patient, prior to the subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof; and optionally

(c) a step of re-evaluating the subject, e.g., the patient, at regular intervals after step (b) to determine relative effectiveness; wherein the re-evaluation comprises measuring the MADRS score of the subject, e.g., the patient.

In various embodiments, the methods disclosed herein further comprise the step of evaluating the subject, e.g., the patient, at regular intervals after treatment with compound I, or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine whether continued treatment is necessary. In embodiments, the subject, e.g., the patient, Patients are 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.

In various embodiments, the present invention provides a method of treating major depressive disorder in a subject, e.g., a patient, in need thereof, wherein the patient has failed to respond to at least one, e.g., at least two, antidepressant medications 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 subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to the patient, and optionally, continuing treatment with the first antidepressant.

In various embodiments, the present invention provides a method of treating treatment-resistant depression in a subject, e.g., a patient, in need thereof, wherein the patient has failed to respond to at least one, e.g., at least two, antidepressant medications 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 subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to the patient, and optionally, continuing treatment with the first antidepressant.

In various embodiments, the treatment method further comprises a step of determining or having determined a MADRS total score at, for example, 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, to assess the efficacy of the treatment as compared to a baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, 24 hours, 7, 14, 21 and/or 28 days later.

In various embodiments, the subject, e.g., the patient, has an improvement (e.g., decrease) in MADRS total score of greater than 30%, for example greater than 35%, greater than 40%, greater than 45%, greater than 50%, in particular greater than 50%, following subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, for example, the subject, e.g., the patient, has an improvement of greater than 30%, for example greater than 35%, greater than 40%, greater than 45%, greater than 50%, in particular greater than 50%, following 24 hours, 7, 14, 21 and/or 28 days following administration of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, has a MADRS total 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, compared to a baseline assessment, following subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, for example, the subject, e.g., the patient, has a MADRS total 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, 14, 21 and/or 28 days after subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, the subject (e.g., the patient) has a MADRS total score that is reduced by greater than or equal to about 30, 25, 20, 15, 10, 5 points (or a range spanning and/or including the aforementioned values) compared to a baseline assessment. In various embodiments, following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, the subject (e.g., the patient) has a MADRS total score that is less than or equal to about 30, 25, 20, 15, 10, 5 points (or a range spanning and/or including the aforementioned values) compared to a baseline assessment. In some embodiments, the post-treatment MADRS score is assessed 24 hours, 7 days, 14 days, 21 days, and/or 28 days following the initial subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, the subject (e.g., the patient) has an improvement (e.g., an increase or decrease, as the case may be) in scores on any measure of depression disclosed herein (e.g., the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, the Mini-International Neuropsychiatric Interview, the Cambridge Automated Neuropsychological Test Battery, the Digit Symbol Substitution Task, the Affect Bias Task, etc.) of at least about 25%, 30%, 40%, 50%, 60%, 70%, 80%, 100% (or a range spanning and/or including any of the aforementioned values) as compared to a baseline assessment. In some embodiments, the post-treatment scores are assessed 24 hours, 7 days, 14 days, 21 days, and/or 28 days following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

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

In various embodiments, the subject, e.g., the patient, is 18 to 65 years of age 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 suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with self-harm.

In various embodiments, the subject, e.g., the patient, does not have an acute depressive episode lasting more than 2 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 suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

In various embodiments, the subject, e.g., the patient, does not have an acute alcohol or substance use disorder or withdrawal symptoms requiring addiction treatment, and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder.

In various embodiments, the subject, e.g., the 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 with 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 with major depressive disorder.

In various embodiments, the subject, e.g., the patient, does not have a clinical diagnosis of autism, dementia, or intellectual disability, and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality with major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with self-harm.

In various embodiments, the subject, e.g., the patient, does not have a history of suicide attempts or suicidal behavior, and has a depressive disorder, e.g., major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder.

In various embodiments, the subject, e.g., the 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 suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with self-harm.

In various embodiments, the subject, e.g., the patient, does not have a 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 suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder.

In various embodiments, the subject, e.g., the patient, does not have a resting QTcF ≥450 msec (male) or ≥460 msec (female); Depressive disorders, such as 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, and major depressive disorder with self-harm.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 15 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 1 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.3 mg to about 1 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 1 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 5 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 15 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 10 mg.

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.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 4 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 10 mg.

Advantageously, compound I, or a pharmaceutically acceptable salt thereof, may be administered once as a single dose.

In any embodiment of the methods disclosed herein, compound I is administered as a free base.

In various embodiments, the present invention 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 from about 0.1 mg to about 15 mg, e.g., from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof. In embodiments, the subject, e.g., the patient, has been diagnosed with or has been diagnosed with major depressive disorder.

In various embodiments, the present invention provides a method of subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, e.g., a patient, wherein the subject in need thereof, e.g., the patient, is diagnosed or has been diagnosed with a depressive disorder; and compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, e.g., from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg. In embodiments, the subject, e.g., the patient, is diagnosed or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention provides a method of administering subcutaneously 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., the patient, is suffering from a major depressive episode, and wherein the subject, e.g., the patient, has not responded to at least one antidepressant treatment for the current major depressive episode.

In various embodiments, the present invention 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 does not have major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder. In embodiments, the subject, e.g., the patient, has been diagnosed with or has been diagnosed with major depressive disorder.

In various embodiments, the present invention 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 not had an acute depressive episode lasting more than 2 years. In embodiments, the subject, e.g., the patient, has been diagnosed with or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention provides a method of administering subcutaneously 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 does not have withdrawal symptoms that would require treatment for an acute alcohol or substance use disorder or addiction. In one embodiment, the subject, e.g., the patient, has been diagnosed with or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention provides a method of subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, e.g., a patient, wherein the subject in need thereof, e.g., the patient, suffers from a depressive disorder and does not have borderline personality disorder or antisocial personality disorder. In embodiments, the subject in need thereof, e.g., the patient, has been diagnosed with or has been diagnosed with major depressive disorder.

In various embodiments, the present invention 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 does not have a clinical diagnosis of autism, dementia, or intellectual disability. In embodiments, the subject, e.g., the patient, in need thereof is or has been diagnosed with major depressive disorder.

In various embodiments, the present invention 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 does not have a history of suicide attempts or suicidal behavior. In embodiments, the subject, e.g., the patient, in need thereof is or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention 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 is not pregnant or lactating. In embodiments, the subject, e.g., the patient, in need thereof is or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention 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 does not have a history of active HIV, Covid-19, and hepatitis B or C infection. In embodiments, the subject, e.g., the patient, in need thereof is or has been diagnosed with major depressive disorder.

In various embodiments, the present invention 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 does not have a resting QTcF ≥450 msec (male) or ≥460 msec (female). In embodiments, the subject, e.g., the patient, in need thereof is or has been diagnosed with a major depressive disorder.

In various embodiments, the present invention 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 does not have a mean systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg. In some embodiments, after subcutaneously administering Compound I, the blood pressure of the patient does not increase to a mean systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg.

In various embodiments, the present invention 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 is not pregnant.

In various embodiments, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder, seasonal affective disorder, and/or a combination of any of the foregoing. In certain embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

In some embodiments, as disclosed elsewhere herein, the reduction in depressive symptoms and/or depressive disorder using Compound I is measured using any one or more of the test conditions provided herein (including those provided in the Examples section below) as disclosed elsewhere herein. In some embodiments, the reduction in depressive symptoms and/or depressive disorder is measured via self-report, the Montgomery-Osberg Depression Rating Scale (MADRS), the Mini International Neuropsychiatric Interview (M.I.N.I.), e.g., version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicidality Rating Scale (C-SSRS), the Clinical Global Impression (CGI), or via any single measure of depression (e.g., symptoms) reported on any of the above scales. In some embodiments, the reduction in depressive symptoms and/or depressive disorder is a reduction in any of the aforementioned scales, measures (e.g., any one or more measures of the MADRS scale), or symptoms by greater than or equal to about 50%. In some embodiments, the reduction in depressive symptoms and/or depressive disorder is a reduction (from baseline) in any of the aforementioned scales, measurements, or symptoms of greater than or equal to about a 10% reduction, a 25% reduction, a 30% reduction, a 40% reduction, a 50% reduction, a 60% reduction, a 70% reduction, an 80% reduction, a 90% reduction, a 100% reduction, or a range including and/or spanning any of the aforementioned values. In some embodiments, the reduction in depressive symptoms and/or depressive disorder is measured about 24 hours, 7, 14, 21 and/or 28 days after subcutaneously administering Compound I. In some embodiments, the reduction in depressive symptoms and/or depressive disorder can be measured as an improvement in a score for a positive outcome (e.g., improved mood).

In some embodiments, CADSS, MOAA/S, and AAESI are used to demonstrate the safety of Compound I administration. CADSS is a questionnaire that assesses dissociative effects. Each item is scored from 0 to 4, and individual scores are summed to obtain a total score of 0 to 92. Trained staff administering the scale will also record the participant's subjective interpretation of mental status and overall well-being, and whether any outcomes could be related to the study drug. MOAA/S is a scale used to assess participant responsiveness on a scale from 0 (= unresponsive to painful trapezius muscle compression) to 5 (= readily responsive to name spoken in a normal tone [awake]). Memory gaps/amnesia are special interest AEs (AESI). Memory assessment using orientation questions is assessed by qualified staff. In some embodiments, the safety score for the patient before and after dosing changes by less than or equal to about 10%, 20%, 30%, 40%, or a range including and/or spanning the aforementioned values.

In some embodiments, the patient population is selected based on the classification of the participants into a CYP2D6 metabolizer phenotype and/or a CYP3A4 metabolizer phenotype. In some embodiments, patients taking a CYP2D6 inhibitor or having reduced CYP2D6 activity are excluded from the patient population. In some embodiments, patients taking a CYP3A4 inhibitor or having reduced CYP3A4 activity are excluded from the patient population.

In some embodiments, the local tolerability of the subcutaneous injection is high (and injection of compound I results in a low incidence of the aforementioned measures, low grade lesions, or mild symptoms). In some embodiments, subcutaneous injection of compound I results in mild to moderate AEs or no AEs at all in patients.

All the above-mentioned embodiments and the following embodiments relating to the treatment method are equally applicable to:

Compound I, or a pharmaceutically acceptable salt thereof, for use in a method of treatment according to the present invention;

Use of compound I, or a pharmaceutically acceptable salt thereof, in a method of treatment according to the present invention;

A pharmaceutical composition comprising compound I, or a pharmaceutically acceptable salt thereof, for use in a method of treatment according to the present invention; and

Use of a pharmaceutical composition comprising compound I, or a pharmaceutically acceptable salt thereof, in a method of treatment according to the present invention.

Dosage and Administration

In some embodiments, methods are provided herein for subcutaneously administering a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof. In the context of the present invention, the dosage refers to the free base of Compound I. In various embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, as a fixed dose.

In various embodiments, provided herein are methods 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. In various embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered as a fixed dose. In various embodiments, the amount of Compound I, or a pharmaceutically acceptable salt thereof, is calculated based on the patient's body 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 the patient's body weight.

In various embodiments, the present invention provides a method of subcutaneously administering to a subject, e.g., a patient, in need thereof an amount of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, or from about 1 mg to about 15 mg.

In various embodiments, the present invention provides a method of administering subcutaneously to a subject, e.g., a patient, in need thereof, a dose of from about 1 mg to about 15 mg, for example, from about 1 mg to about 10 mg, of compound I, or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a subcutaneous dose of compound I that is less than or equal to about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or a range including and/or spanning any of the aforementioned values. For example, in some embodiments, the method comprises administering a subcutaneous dose of compound I in the range of from 1 mg to 5 mg, from 1 mg to 10 mg, from 5 mg to 15 mg, from 1 to 12.5 mg, or less than 15 mg. In some embodiments, the subject in need thereof is a subject having a depressive disorder.

In various embodiments, as disclosed elsewhere herein, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of from about 1 mg to about 15 mg. In various embodiments, as disclosed elsewhere herein, compound I, or a pharmaceutically acceptable salt thereof, is administered by subcutaneous injection in a dose of from about 1 mg to about 15 mg.

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

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.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered at a dose of about 4 mg.

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 10 mg.

In various embodiments, the method comprises subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, as a single subcutaneous injection.

In various embodiments, the method comprises subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, to the upper arm or abdominal region.

In certain embodiments, the invention 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 to the subject from about 0.1 mg to about 15 mg, e.g., from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention provides a method of treating treatment-resistant depression, comprising administering to a subject in need thereof, e.g., a patient, (wherein the subject, e.g., the patient, has been diagnosed or has been diagnosed with treatment-resistant depression) a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, compound I is administered as a free base.

Dosage Schedule

In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered as a single dose without repetition. In some embodiments, compound I is administered according to a dosing schedule. In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once a week. In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered twice a week. In various embodiments, each week, compound I, or a pharmaceutically acceptable salt thereof, is administered no more than about 1, 2, 3, 4, 5, 6, 7 times, or a range including and/or spanning the aforementioned values. In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once every two weeks. In various embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once every three weeks. In still other embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once a month. In yet another embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered once every six weeks. In various embodiments, the dose of compound I, or a pharmaceutically acceptable salt thereof, is administered once every week, every two weeks, every three weeks, every four weeks, every six weeks, every eight weeks, or a range including and/or spanning the aforementioned values.

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 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, at least about 2 years, or a range including and/or spanning any of the aforementioned values.

Package or pharmaceutical product

In a further specific embodiment, the present invention further relates to a package or pharmaceutical product as described herein, wherein compound I is particularly a free base. In a further embodiment of the package or pharmaceutical product as described herein, the instructions for treatment direct 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, between about 1 mg and about 15 mg of compound I, or a pharmaceutically acceptable salt thereof.

In additional embodiments of the package or pharmaceutical product as described herein, the instructions for treatment direct 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.

In still further embodiments of the package or pharmaceutical product as described herein, the instructions for treatment direct compound I, or a pharmaceutically acceptable salt thereof, for s.c. administration. In still further specific embodiments of the package or pharmaceutical product as described herein, the instructions for treatment direct compound I, or a pharmaceutically acceptable salt thereof, for once every two weeks, once every three weeks, once a month, or once every six weeks.

Subjects suitable for treatment

The disclosed methods are suitable for the treatment of individuals diagnosed with major depressive disorder. The disclosed methods are particularly suitable for the treatment of individuals diagnosed with treatment-resistant or treatment-refractory depression. Subjects particularly amenable to treatment with the methods according to the invention are those who have failed to respond to at least two conventional antidepressant medications. Subjects who have failed to respond to two or more but no more than five prior antidepressant treatments are also amenable to treatment, wherein the two failed treatments are two different antidepressants at appropriate doses and durations, for example, ≥6 weeks duration, as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). Subjects who have a partial response to at least one antidepressant medication are also amenable to treatment. Subjects who have a <50% response (≥8 weeks duration at an appropriate and stable dose for at least 4 weeks) to at least one antidepressant treatment according to the MGH-ATRQ are also amenable to treatment.

The disclosed method is also suitable for subjects with recurrent major depressive disorder (MDD) as defined by, for example, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and a current major depressive episode of at least 8 weeks duration. The diagnosis can be additionally confirmed by both the SCID-5 and a clinical psychiatric assessment.

In various embodiments, the subject is at risk for suicide.

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 further other embodiments, the subject has a partial response to at least one antidepressant drug other than Compound I, or a pharmaceutically acceptable salt thereof.

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

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

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

In various embodiments, the subject, e.g., the patient, does not have a history of treatment failure with esketamine, ketamine, or arketamine.

In various embodiments, the subject, e.g., the patient, is suffering from an episode of depression, e.g., a major depressive episode, wherein the episode of depression, e.g., a major depressive episode, has not responded to treatment with at least one antidepressant (e.g., a conventional antidepressant), i.e., the subject, e.g., the patient, has not responded to treatment with at least one antidepressant for the current major depressive episode. In embodiments, the at least one antidepressant is an oral antidepressant. The antidepressant(s) may be administered to the patient at an appropriate dosage as may be determined by the treating physician and/or may be dosed as prescribed by the label. Similarly, the antidepressant is administered for an appropriate duration, e.g., as prescribed by the label. In embodiments, the antidepressant is administered for a duration of at least 4 weeks, e.g., for a duration of at least 6 weeks.

In various embodiments, the subject, e.g., the patient, is suffering from an episode of depression, e.g., a major depressive episode, wherein the episode of depression, e.g., a major depressive episode, has not responded to treatment with at least two antidepressants (e.g., one or more of which may be conventional antidepressants), i.e., the subject, e.g., the patient, has not responded to treatment with at least two antidepressants for the current major depressive episode. In embodiments, at least one of the at least two antidepressants is an oral antidepressant. The antidepressant(s) may be administered to the patient at an appropriate dosage as may be determined by the treating physician and/or may be dosed as prescribed by the label. Similarly, the antidepressant is administered for an appropriate duration, e.g., as prescribed by the label. In embodiments, the antidepressant is administered for a duration of at least 4 weeks, e.g., for a duration of at least 6 weeks.

In various embodiments, the subject, e.g., the patient, is male or female.

In various embodiments, the subject, e.g., the patient, does not have an acute depressive episode that has persisted for more than 2 years.

In various embodiments, the subject, e.g., the patient, is not receiving electroconvulsive therapy for a current depressive episode or within 1 year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, is not receiving transcranial magnetic stimulation for a current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, is not receiving vagus nerve stimulation for a current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, is not receiving deep brain stimulation for a current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, does not have a previous or current diagnosis of major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features, e.g., as determined by the SCID-5.

In various embodiments, the subject, e.g., the patient, does not have an acute alcohol or substance use disorder or withdrawal symptoms requiring addiction treatment.

In various embodiments, the subject, e.g., the patient, has not had any anti-addiction treatment within 1 month prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, does not have borderline personality disorder or antisocial personality disorder, for example, based on DSM-5 criteria.

In various embodiments, the subject, e.g., the patient, does not have a clinical diagnosis of autism, dementia, or intellectual disability.

In various embodiments, the subject, e.g., the patient, does not have a history of suicide attempt or suicidal behavior within 1 year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g., the patient, does not exhibit suicidal ideation with intent as determined by, for example, yes responses to Q4 or Q5 on the CSSRS at baseline.

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

In various embodiments, the subject, e.g., the patient, does not have a history of hypersensitivity to compound I, or a pharmaceutically acceptable salt thereof, or to drugs of similar mechanism of action, i.e., drugs that affect NMDA receptors.

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

In various embodiments, the subject, e.g., the patient, has no history of seizures other than childhood febrile seizures.

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

a) Within 6 months prior to treatment with compound I or a pharmaceutically acceptable salt thereof;

History of myocardial infarction, angina, or coronary artery bypass grafting.

b) History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g., double-fiber bundle block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound I or its pharmaceutically acceptable salt.

In various embodiments, the subject, e.g., the patient, does not have a resting QTcF ≥450 msec (male) or ≥460 msec (female) at baseline.

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

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

b) Concomitant medication(s) with a “known risk of TdP” that cannot be discontinued or replaced by a safer alternative medication.

In various embodiments, the subject, e.g., the patient, has a baseline mean systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg; or no prior history of hypertensive crisis.

In various embodiments, the subject, e.g., the patient, does not have a history of hemorrhagic stroke or a known cerebrovascular disorder (e.g., an aneurysm or arteriovenous malformation) or a known aneurysmal vascular disease of another location (e.g., the aorta).

In some embodiments, the subject, e.g., the patient, is not a pregnant or breast-feeding woman.

In some embodiments, the subject, e.g., the patient, is not a woman of childbearing potential who is not using highly effective contraception.

In some embodiments, the subject, e.g., the patient, is not a sexually active male who does not intend to use a condom during sexual intercourse while taking Compound I, or a pharmaceutically acceptable salt thereof, and for one week after discontinuing treatment with Compound I, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject, e.g., the patient, is not taking any of the following medications as defined by Table 1 during treatment with Compound I, or a pharmaceutically acceptable salt thereof:

[Table 1]

Reaction measurement value

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-Osberg Depression Rating Scale (MADRS), the Clinical Global Impression-Severity Impression (CGI-S) scale, the Clinical Global Impression-Improvement (CGI-I) scale, the Patient Global Impression of Change (PGIC), the Structured Clinical Interview for DSM-5-SCID-5, the Columbia Suicidality Severity Rating Scale (C-SSRS), the Hamilton Depression Rating Scale (HAM-D), and the Mini-International Neuropsychiatric Interview (M.I.N.I.).

An improvement in any of the indices or measures known in the art, such as those described below, indicates that Compound I is effective in the treatment of MDD. Such improvement can be determined by comparing the pre-treatment score to the post-treatment score of a subject, e.g., a patient, with MDD.

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

In various embodiments, the MGH-ATRQ is used to diagnose and/or monitor depression in patients. The MGH-ATRQ examines the adequacy of the duration and dose of previous and current antidepressant treatment in a stepwise manner (Chandler 2010). When assessing the duration and dose of antidepressants, the investigator should always inquire about the level of compliance with each treatment. In addition, the MGH-ATRQ assesses the degree of improvement on the scale from 0% (no improvement at all) to 100% (completely improved).

Montgomery-Osberg Depressive Disorder Rating Scale (MADRS)

In some embodiments, the MADRS is used to diagnose and/or monitor patients. The Montgomery-Osberg Depressive Disorder Rating Scale (MADRS, SIGMA version) is a clinician-rated scale designed to measure the severity of depressive disorder and to detect changes due to antidepressant treatment: the test consists of 10 items, each of which is scored from 0 (absent or normal) to 6 (severe or persistent symptoms), for a total possible score of 60. Higher scores indicate more severe conditions. The MADRS assesses overt sadness, reported sadness, internal tension, sleep, appetite, concentration, listlessness, interest levels, pessimistic thoughts, and suicidal ideation.

In one embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously for the treatment of a depressive disorder, e.g., as disclosed herein, wherein treatment of the depression is determined by an improvement in the MADRS total score of the subject, e.g., Hanja.

Hamilton Depression Rating Scale (HAM-D)

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

Clinical Global Impression of Severity (CGI-S)

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 relative to the severity of other patients seen by physicians. Patients are rated on a scale of 1 to 7, with 1 representing a "normal state" and 7 representing a "most severely ill patient." The CGI-S is administered by investigators, sub-investigators, or raters who have extensive professional training and experience in assessing mental illness.

In one embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously for the treatment of a depressive disorder, e.g., as disclosed herein, wherein treatment of the depression is determined by an improvement in the CGI-S score of the subject, e.g., the patient.

Clinical Global Impression of Improvement (CGI-I)

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 psychiatric disorders, regardless of whether the investigator considers it to be a result of medication treatment. Patients are rated on a scale of 1 to 7, with 1 indicating that the patient has improved very much and 7 indicating that the patient has worsened very much.

In one embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously for the treatment of a depressive disorder, e.g., as disclosed herein, wherein treatment of the depression is determined by an improvement in the CGI-I score of the subject, e.g., the patient.

Patient Global Impression of Change (PGIC)

In some embodiments, PGIC is used to diagnose and/or monitor patients. The PGIC scale aims 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. PGIC includes a number of scores that demonstrate optimal patient preference, discrimination ability, and test-retest ability, tailored to specific conditions and disease parameters.

Structured Clinical Interview for DSM-5 SCID-5

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 for making major DSM-5 diagnoses (previously diagnosed under Axis I). This clinician-rated diagnostic assessment is administered by investigators, sub-investigators, or raters who have extensive professional training and experience in the diagnosis of mental disorders.

Pharmaceutical composition

In some embodiments, a pharmaceutical composition comprising compound I is provided. In some embodiments, the pharmaceutical formulation is suitable for administration to a subject in need of treatment. In some embodiments, a pharmaceutical composition of the present invention suitable for subcutaneous administration comprises compound I in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders capable of being reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain one or more (or all) of an antioxidant, a buffer, a bacteriostat, a solute that renders the formulation isotonic with the blood of the intended recipient, or a suspending agent or a thickening agent (see, e.g., "Remington Essentials of Pharmaceutics, 2013, 1 ^st Edition, edited by Linda Felton, published by Pharmaceutical Press, 2012, ISBN 978 0 85711 105 0; especially Chapter 30). In some embodiments, pharmaceutical excipients that may be used in combination with compound I are described, e.g., in "Handbook of Pharmaceutical Excipients, 2012, 7 ^th 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 which may be employed in the pharmaceutical compositions disclosed herein include one or more of water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. Proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

After the pharmaceutical composition is formulated, it may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. The formulation may be stored in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or any other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an autoinjector (e.g., similar to an EpiPen®)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

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., a powder, a solid, etc.). In some embodiments, the dry form of Compound I is comprised of or reconstituted with a carrier (e.g., a liquid). In some embodiments, the dry form of Compound I is comprised of or reconstituted with a carrier prior to use, including at the time of treatment.

Certain pharmaceutical compositions for use according to the present invention comprise a lyophilized formulation 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 some embodiments, compound I is reconstituted prior to use.

combination therapy

In various embodiments, the present invention 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.

In some embodiments, the subject, e.g., the patient, may be under co-treatment with both an antidepressant and compound I, or a pharmaceutically acceptable salt thereof, wherein both are administered according to a prescribed dosage regimen.

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

Treatment with compound I, or a pharmaceutically acceptable salt thereof, and background therapy as described herein may be useful as an augmentation strategy for the treatment of a depressive disorder as described herein. Augmentation strategies are particularly useful for the treatment of treatment-resistant depression.

In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered adjunctively with other antidepressant(s) currently being administered to the subject, e.g., the patient, including current antidepressant(s) to which the subject has had an inadequate response. In other embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered adjunctively with antidepressant(s) not previously administered to the subject, e.g., the patient. In still other embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in therapy with antidepressant(s) previously administered to the subject, e.g., the patient.

In some embodiments, the other antidepressant treatment comprises one antidepressant medication. In other embodiments, the other antidepressant treatment comprises two or more antidepressant medications. In further embodiments, the other antidepressant treatment comprises two antidepressant medications. In still further embodiments, the other antidepressant treatment comprises three antidepressant medications.

Accordingly, in an aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with at least one other therapeutic agent for treating a depressive disorder, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously. The depressive disorder can be any of those disclosed herein. In 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.

In some embodiments, compound I and at least one other therapeutic agent, e.g., antidepressant(s) (including conventional and herbal antidepressant(s)), antipsychotic(s), mood stabilizer(s), benzodiazepine(s), can be administered via the same or different routes of administration. Examples of suitable routes of administration of the antidepressant include, but are not limited to, oral, intravenous, intranasal, intramuscular, subcutaneous, transdermal, buccal, or rectally. In certain embodiments, the at least one other therapeutic agent is at least one other antidepressant that is administered orally.

Accordingly, compound I, or a pharmaceutically acceptable salt thereof, can be administered as a combination therapy, for example, as an adjunct or add-on therapy to one or more other treatments or therapies for a psychiatric disorder, for example, a depressive disorder. Compound I, or a pharmaceutically acceptable salt thereof, can be administered in combination with one or more additional therapeutic agents, for example, in combination with 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 certain embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a regimen with at least one other therapeutic agent currently being administered to the subject, e.g., the patient. In embodiments, the one or more additional therapeutic agents are selected from the group consisting of an antidepressant(s), an antipsychotic(s), a mood stabilizer(s), a benzodiazepine(s), and combinations thereof. In certain embodiments, at least one of the one or more additional therapeutic agents is an antidepressant, e.g., an oral antidepressant. 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., the patient, had an inadequate response.

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 the one or more antidepressants are administered as a chronic treatment.

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, on background therapy as described above for a specified 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 more).

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 the patient while on background therapy as described above for a specified 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 more). In some embodiments, treatment with compound I, or a pharmaceutically acceptable salt thereof, is given when the patient has been on background therapy as described above for a period of time including or spanning at least 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 range including and/or spanning any of the aforementioned values.

Therapeutically effective amounts/dosage levels and dosage regimens for additional therapeutic agents as defined herein, e.g., antidepressant(s), antipsychotic(s), mood stabilizer(s), benzodiazepine(s), can be readily determined by one of skill in the art and administered according to his or her prescribed dosing regimen, e.g., as prescribed by the treating physician and/or by his or her labeling. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for marketing are publicly available, e.g., as listed on the package label, in standard dosing guidelines, in standard dosing reference books, such as the [Physician's Desk Reference] (Medical Economics Company or online at http:///www.pdrel.com), or from other sources.

Examples of antidepressants that may be used in combination or background therapy according to the present invention are those approved by the FDA for major depressive disorder.

As disclosed elsewhere herein, examples of antidepressants that may be used in combination or background therapies according to the present invention 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 (RIMA)), and multimodal antidepressants, as described herein.

In an embodiment, the antidepressant is selected from the group consisting of fluoxetine, duloxetine, desvenlafaxine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine tranylcypromine, selegiline, moclobemide, perindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipopezine, noxiptylline, vilazodone, vortioxetine, and bupropion.

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.

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.

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

As disclosed herein, compound I, or a pharmaceutically acceptable salt thereof, can be administered together with another antidepressant (as enumerated 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.

In various embodiments, as disclosed elsewhere herein, the subject, e.g., the patient, is not administered any other antidepressant during the course of administration of compound I, or a pharmaceutically acceptable salt thereof.

In various embodiments, as disclosed elsewhere herein, compound I is administered as a free base.

In various embodiments, as disclosed elsewhere herein, the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder, and seasonal affective disorder. In certain embodiments, the depressive disorder is major depressive disorder. In further embodiments, the major depressive disorder is treatment-resistant depression.

As disclosed elsewhere herein, all of the above-mentioned embodiments and the following embodiments relating to the combination therapy of the present invention are equally applicable to:

Compound I, or a pharmaceutically acceptable salt thereof, for use in combination therapy according to the present invention;

Use of compound I, or a pharmaceutically acceptable salt thereof, in combination therapy according to the present invention;

A pharmaceutical composition comprising compound I, or a pharmaceutically acceptable salt thereof, for use in combination therapy according to the present invention; and

Use of a pharmaceutical composition comprising compound I, or a pharmaceutically acceptable salt thereof, in combination therapy according to the present invention.

Additional embodiments of the present invention

In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

In another aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

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

In an embodiment, the depressive disorder is selected from major depressive disorder, in particular treatment-resistant depression, suicidality of 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 of major depressive disorder, and seasonal affective disorder. In a particular embodiment, the depressive disorder is major depressive disorder. In a further embodiment, the major depressive disorder is treatment-resistant depression.

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

In another aspect, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of major depressive disorder, wherein the major depressive disorder has failed to respond to at least two antidepressant treatments, 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. In embodiments, the at least two antidepressants are two different antidepressants.

In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, for example by subcutaneous injection, in a dose 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.

In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, for example by subcutaneous injection, in a dose of about 0.1 mg to about 15 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 1 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.3 mg to about 1 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 1 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 5 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 10 mg. In an embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to 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.

In additional embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg, about 4 mg, or about 10 mg.

In certain embodiments, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, e.g., treatment-resistant depression, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In certain embodiments, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, wherein the major depressive disorder has not responded to at least one antidepressant treatment in the current major depressive episode, and wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In certain embodiments, the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, wherein the major depressive disorder has not responded to at least two prior antidepressant treatments in a current major depressive episode, and wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In another aspect, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of major depressive disorder, wherein the major depressive disorder has failed to respond to at least two antidepressant treatments, 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 in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg. In embodiments, the at least two antidepressants are two different antidepressants.

In certain embodiments, the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg.

In certain embodiments, the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive disorder and a current major depressive episode of at least 8 weeks duration in a subject, e.g., a patient, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of about 0.1 mg to about 15 mg, for example, about 0.1 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.5 mg to about 1 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg, or about 1 mg to about 15 mg. In certain embodiments, the major depressive episode has a duration of at least 8 weeks, but less than 24 months.

In an embodiment, the depressive disorder is characterized as treatment-resistant depression. In an embodiment, a diagnosis of TRD is confirmed by meeting DSM-5 criteria for MDD and by failure to adequately respond to at least two different antidepressant medications at adequate doses and durations for the current depressive episode. In certain embodiments, the subject, e.g., the patient, has failed to respond to two or more, but no more than five, prior antidepressant treatments, wherein the two failed treatments are two different antidepressants at adequate doses and durations as measured by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), e.g., ≥ 6 weeks duration.

In embodiments, the subject, e.g., the patient, is characterized as having a <50% response to at least one antidepressant treatment, e.g., the subject has a current major depressive episode of ≥8 weeks duration and has been receiving antidepressant treatment at an adequate and stable dose, i.e., an effective dose, for at least 4 weeks according to the MGH-ATRQ. In embodiments, the subject, e.g., the patient, has a single episode major depressive disorder. In embodiments, the subject, e.g., the patient, has a recurrent major depressive disorder.

In certain embodiments, the subject is a human patient.

In certain embodiments, the subject is an adult patient.

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

In certain embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once every two weeks or less frequently.

In a further embodiment, the treatment further comprises administration of one or more additional therapeutic agents, e.g., one or more standard of care medications, prescribed for use in the treatment of a psychiatric disorder, e.g., a depressive disorder. In an embodiment, the treatment further comprises administration of the one or more additional therapeutic agents for a period of at least about 4 weeks, e.g., at least about 6 weeks, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof. In an embodiment, the treatment with the one or more additional therapeutic agents continues following treatment with Compound I, or a pharmaceutically acceptable salt thereof. In an embodiment, the one or more additional therapeutic agents is selected from the group consisting of antidepressant(s), antipsychotic(s), mood stabilizer(s), benzodiazepine(s), and combinations thereof. In a particular embodiment, at least one of the one or more additional therapeutic agents is an antidepressant, e.g., an oral antidepressant.

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

In another embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered adjunctively with other antidepressant(s) currently being administered to the subject, e.g., the patient, including a current antidepressant(s) to which the subject, e.g., the patient, had an inadequate response. In another embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered adjunctively with antidepressant(s) not previously administered to the subject, e.g., the patient. In yet another embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in therapy with antidepressant(s) previously administered to the subject, e.g., the patient.

In certain embodiments, the invention 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., a patient, wherein the subject, e.g., the patient, has not responded to at least one antidepressant treatment for the current major depressive episode, and the treatment comprises 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, then subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., the patient, at a dose of from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, and optionally, continuing treatment with the first antidepressant.

In certain embodiments, the invention 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., a patient, wherein the subject, e.g., the patient, has not responded to at least two prior antidepressant treatments for a current major depressive episode, and the treatment comprises 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, then subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., the patient, at a dose of from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, and optionally, continuing treatment with the first antidepressant.

In a further embodiment, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of treatment-resistant depression, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of from about 0.1 mg to about 15 mg, for example from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, and wherein the treatment further comprises administration of one or more additional therapeutic agents, such as an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, or a combination thereof.

As described herein, compound I can be used as an adjunctive therapy, or in other words, as an add-on, or in combination with one or more therapeutic agents, for example one or more antidepressants, for example the patient may already or also be administered one or more antidepressants. Accordingly, in a further particular embodiment, the invention relates to compound I, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, as an adjunctive therapy with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In a further particular embodiment, the invention relates to compound I, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, with an effective amount of one or more therapeutic agents, for example one or more antidepressants. In a further specific embodiment, the invention relates to compound I, or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneously administering 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 a further specific embodiment, the invention further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct subcutaneously administering an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, as an adjunctive treatment with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. In a further specific embodiment, the invention further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct administering 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 a further specific embodiment, the invention further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct administering 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 can be selected from any of the antidepressants disclosed herein.

In a further embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided 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.

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

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

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

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

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

In certain embodiments, the invention also 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 in a dose of from about 0.1 mg to about 15 mg, for example, from about 0.1 mg to about 1 mg, from about 0.3 mg to about 1 mg, from about 0.5 mg to about 1 mg, from about 1 mg to about 5 mg, from about 1 mg to about 10 mg, from about 1 mg to about 15 mg, and wherein the treatment further comprises administration of one or more oral antidepressants. In embodiments, the patient is an adult.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.2 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.3 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.4 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.6 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.7 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.8 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.9 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 2 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 3 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 4 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 5 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 6 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 7 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 8 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 9 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 10 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 11 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 12 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 13 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 14 mg.

In a further embodiment, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 15 mg.

In additional embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg, about 4 mg, or about 10 mg.

In an embodiment, 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, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMA)), and multimodal antidepressants.

In an embodiment, the antidepressant is selected from the group consisting of fluoxetine, duloxetine, desvenlafaxine, venlafaxine, milnacipran, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, isocarboxazid, phenelzine tranylcypromine, selegiline, moclobemide, perindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipopezine, noxiptyl, vilazodone, vortioxetine, and bupropion.

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

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

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

In certain embodiments, the antidepressant is an oral antidepressant.

Additional embodiments of the present invention are outlined below:

Embodiment a

Embodiment 1a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a depressive disorder, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 2a. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in the treatment of a depressive disorder, wherein the pharmaceutical composition is administered subcutaneously.

Embodiment 3a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a depressive disorder, wherein the treatment comprises the steps of:

(a) Determining or having determined the baseline MADRS score of the subject, e.g., the patient; and

(b) subcutaneously administering to the subject, e.g., the patient, compound I, or a pharmaceutically acceptable salt thereof, wherein the amount of compound I, or a pharmaceutically acceptable salt thereof, improves the MADRS score by at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to a measured baseline MADRS score, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to the subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 4a. A compound for use according to embodiment 3a, or a pharmaceutically acceptable salt thereof, wherein the subject, e.g., the patient, is evaluated at regular intervals after step (b) to determine relative efficacy, wherein the evaluation comprises measuring the MADRS score of the subject, e.g., the patient.

Embodiment 5a. A compound for use according to any one 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 of 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 of major depressive disorder, and seasonal affective disorder.

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

Embodiment 7a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder is treatment-resistant depression.

Embodiment 8a. A compound for use according to embodiment 7a, or a pharmaceutically acceptable salt thereof, for treating treatment-resistant depression, including partial resistance.

Embodiment 9a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of depressive symptoms, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 10a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of depressive symptoms of major depressive disorder, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 11a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of depressive symptoms of major depressive disorder with acute suicidal ideation or behavior, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 12a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of depressive symptoms of treatment-resistant depression, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 13a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in a method of reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 14a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a major depressive episode, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 15a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in preventing major depressive episodes, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 16a. A 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, for example at least 6 weeks, at least 8 weeks.

Embodiment 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 the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 18a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a single-agent major depressive disorder, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 19a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive disorder, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 20a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive disorder and a current major depressive episode having a duration of at least 4 weeks, for example at least 6 weeks, for example at least 8 weeks, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

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, for example at least 8 weeks, but less than 24 months.

Embodiment 22a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the depressive disorder or depressive episode has not responded adequately to at least one antidepressant treatment, for example in the current depressive episode.

Embodiment 23a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in which the depressive disorder or depressive episode has had a partial response to at least one antidepressant treatment, for example in the current depressive episode.

Embodiment 24a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in the treatment of a depressive disorder or depressive episode, for example in a current depressive episode that has not responded adequately to at least two prior antidepressant treatments.

Embodiment 25a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in a depressive disorder or depressive episode, for example in a current depressive episode, which has had a partial response to at least two prior antidepressant treatments.

Embodiment 26a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in the treatment of a depressive disorder or depressive episode, for example a current depressive episode that has not responded adequately to at least two, but not more than five, prior antidepressant medications.

Embodiment 27a. A compound for use according to any one of Embodiments 24a to 26a, or a pharmaceutically acceptable salt thereof, wherein at least two antidepressant treatments are two different antidepressants.

Embodiment 28a. A compound for use according to any one of Embodiments 22a to 27a, or a pharmaceutically acceptable salt thereof, wherein the antidepressant treatment(s) is administered for a duration of at least 4 weeks, for example for a duration of at least 6 weeks.

Embodiment 29a. A compound for use according to any one of Embodiments 22a to 28a, 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 (RIMA)), and multimodal antidepressants.

Embodiment 30a. A compound for use according to 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.

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

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

Embodiment 33a. A compound for use according to any of the preceding embodiments, wherein the treatment further comprises evaluating the subject, e.g., the patient, at regular intervals after treatment with compound I, or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine whether continued treatment is necessary.

Embodiment 34a. Object, for example A compound for use according to embodiment 33a, or a pharmaceutically acceptable salt thereof, wherein the 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.

Embodiment 35a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 0.0048 mg/kg to about 0.32 mg/kg, in particular 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.

Embodiment 36a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of from about 0.1 mg to about 15 mg.

Embodiment 37a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 1 mg.

Embodiment 38a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.3 mg to about 1 mg.

Embodiment 39a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 1 mg.

Embodiment 40a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 5 mg.

Embodiment 41a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 10 mg.

Embodiment 42a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 15 mg.

Embodiment 43a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

Embodiment 44a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg, about 4 mg, or about 10 mg.

Embodiment 45a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the 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.

Embodiment 46a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once without repetition.

Embodiment 47a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once every two weeks or less frequently.

Embodiment 48a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once every three weeks or less frequently.

Embodiment 49a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once a month or less frequently.

Embodiment 50a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once every six weeks or less frequently.

Embodiment 51a. A compound for use according to 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.

Embodiment 52a. A compound for use according to any one of the preceding embodiments, wherein the scores in one or more depression assessment instruments selected from the group consisting of the Montgomery-Osberg Depression Rating Scale (MADRS), the Mini-International Neuropsychiatric Interview (M.I.N.I.), e.g. version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicidality Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI) are improved after treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 53a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode with a duration of at least 4 weeks, for example at least 6 weeks, at least 8 weeks.

Embodiment 54a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound is administered to a treatment-resistant subject, e.g., a patient, or a pharmaceutically acceptable salt thereof.

Embodiment 55a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, who is partially resistant to the drug.

Embodiment 56a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, who has had an inadequate response to, or failed to respond to, other antidepressant treatments prior to treatment with compound I, or a pharmaceutically acceptable salt thereof, in a current major depressive episode.

Embodiment 57a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, who has not responded adequately or has failed to respond adequately to at least one antidepressant in a current major depressive episode, or a pharmaceutically acceptable salt thereof.

Embodiment 58a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, who has not responded adequately or has failed to respond adequately to at least two antidepressants in a current major depressive episode, or a pharmaceutically acceptable salt thereof.

Embodiment 59a. A compound for use according to any one of Embodiments 56a to 58a, or a pharmaceutically acceptable salt thereof, wherein the inappropriate reaction or reaction failure comprises a partial reaction.

Embodiment 60a. A compound for use according to any one of Embodiments 56a to 59a, or a pharmaceutically acceptable salt thereof, wherein the current major depressive episode has a duration of at least about 4 weeks, for example at least about 6 weeks, at least about 8 weeks, in particular at least about 8 weeks, but not more than 24 months.

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

Embodiment 62a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound 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, or at least about 25 at baseline.

Embodiment 63a. A compound for use according to any of the preceding embodiments, wherein the treatment further comprises determining or has determined a MADRS total score after subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, for example 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 64a. A compound for use according to any of the preceding embodiments, wherein the subject, e.g., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a decreased MADRS total score 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 65a. A compound for use according to any of the preceding embodiments, wherein the subject, e.g., the patient, has a greater than 30%, for example, greater than 35%, greater than 40%, greater than 45%, greater than 50% improvement in 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., the patient, has a greater than 30%, for example, greater than 35%, greater than 40%, greater than 45%, greater than 50% improvement in MADRS total score after 24 hours, 7, 14, 21 and/or 28 days of subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 66a. A compound for use according to any of the preceding embodiments, wherein the subject, e.g., the patient, has a MADRS total score of less than 12 following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a MADRS total score of less than 12 24 hours, 7, 14, 21 and/or 28 days following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 67a. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with one or more additional therapeutic agents for the treatment of a psychiatric disorder, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 68a. A use according to embodiment 67a, wherein the compound, or a pharmaceutically acceptable salt thereof, is for use according to any one of embodiments 1a to 66a.

Embodiment 69a. A use according to any one of Embodiments 1a to 66a, wherein the treatment further comprises administration of one or more additional therapeutic agents.

Embodiment 70a. Use according to embodiment 69a, wherein treatment with compound I, or a pharmaceutically acceptable salt thereof, is additional to one or more standard care medications prescribed for use in the treatment of a psychiatric disorder.

Embodiment 71a. Psychiatric disorder is a depressive disorder, use according to any one of embodiments 67a to 70a.

Embodiment 72a. Depressive disorder is major depressive disorder, use according to embodiment 71a.

Embodiment 73a. Major depressive disorder is treatment-resistant depression, major depressive disorder with suicidality, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with self-harm, or seasonal affective disorder, use according to embodiment 72a.

Embodiment 74a. A compound for use according to any one of Embodiments 67a to 73a, wherein the treatment comprises administering one or more additional therapeutic agents for a period of at least about 4 weeks, for example at least about 6 weeks, prior to treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 75a. A compound for use according to any one of Embodiments 67a to 74a, or a pharmaceutically acceptable salt thereof, wherein treatment with one or more additional therapeutic agents continues after treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 76a. A compound for use according to any one of Embodiments 67a to 75a, or a pharmaceutically acceptable salt thereof, wherein one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof.

Embodiment 77a. A compound for use according to 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, for example an oral antidepressant.

Embodiment 78a. A compound for use according to any one of Embodiments 67a to 77a, or a pharmaceutically acceptable salt thereof, wherein one or more additional therapeutic agents are one or more antidepressants.

Embodiment 79a. A compound for use according to any one of Embodiments 76a to 78a, or a pharmaceutically acceptable salt thereof, wherein the disorder has not responded adequately to, or has failed to respond adequately to, at least one, for example at least two, of additional therapeutic agents or standard-of-care medications during a current major depressive episode.

Embodiment 80a. A compound for use according to any one of Embodiments 76a to 79a, 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)), a multimodal antidepressant, and combinations thereof.

Embodiment 81a. A compound for use according to 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.

Embodiment 82a. A compound for use according to 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.

Embodiment 83a. A compound for use according to 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, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 84a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the upper arm or abdominal region.

Embodiment 85a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered as a single subcutaneous injection.

Embodiment 86a. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition, optionally comprising at least one pharmaceutically acceptable excipient.

Embodiment 87a. A compound for use according to any one of the preceding embodiments, wherein compound I is administered as a free base, or a pharmaceutically acceptable salt thereof.

Embodiment 88a. A compound according to any one of the preceding embodiments, wherein the compound I is formulated for delivery from a subcutaneous injection device, or a pharmaceutically acceptable salt thereof.

Embodiment 89a. A compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, formulated for delivery from a subcutaneous injection device as a single subcutaneous injection.

Embodiment 90a. A compound for use according to 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, e.g., a patient, who has failed to respond to two or more, but no more than five, prior antidepressant treatments, wherein the two failed treatments are two different antidepressants at appropriate doses and durations, e.g., at least 6 weeks duration, as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

Embodiment 91a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a <50% response to at least one antidepressant treatment during a major depressive episode of, e.g., ≥ 8 weeks duration, at an effective and stable dose for at least 4 weeks according to the MGH-ATRQ.

Embodiment 92a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 diagnosis of recurrent major depressive disorder (MDD) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and a current major depressive episode of at least 8 weeks duration.

Embodiment 93a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, characterized as having treatment-resistant or treatment-refractory depression.

Embodiment 94a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a human patient.

Embodiment 95a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to an adult patient.

Embodiment 96a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a history of treatment failure with esketamine, ketamine or arketamine.

Embodiment 97a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, suffering from an episode of depression, e.g., a major depressive episode, wherein the subject, e.g., the patient, has not responded to treatment with at least one antidepressant for the current depressive episode.

Embodiment 98a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, suffering from an episode of depression, e.g., a major depressive episode, wherein the subject, e.g., the patient, has not responded to treatment with at least two antidepressants for the current depressive episode.

Embodiment 99a. A compound for use according to any one of Embodiments 97a and 98a, or a pharmaceutically acceptable salt thereof, wherein at least one antidepressant is an oral antidepressant.

Embodiment 100a. A compound for use according to any one of Embodiments 97a to 99a, or a pharmaceutically acceptable salt thereof, wherein the antidepressant has been administered for a duration of at least 4 weeks, for example for a duration of at least 6 weeks.

Embodiment 101a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is either male or female.

Embodiment 102a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 an acute depressive episode that has persisted for more than 2 years.

Embodiment 103a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is currently undergoing depressive episode treatment or who has not received electroconvulsive therapy within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 104a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 undergone transcranial magnetic stimulation within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof, for a current depressive episode.

Embodiment 105a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 vagus nerve stimulation within 1 year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof, in a current depressive episode.

Embodiment 106a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 undergone deep brain stimulation within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof, in a current depressive episode.

Embodiment 107a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a previous or current diagnosis of major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features as determined by, for example, the SCID-5.

Embodiment 108a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 withdrawal symptoms requiring treatment for an acute alcohol or substance use disorder or addiction.

Embodiment 109a. A compound for use according to 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 had an addiction treatment within 1 month prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 110a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 borderline personality disorder or antisocial personality disorder as defined by DSM-5 criteria.

Embodiment 111a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a clinical diagnosis of autism, dementia, or intellectual disability.

Embodiment 112a. A compound for use according to 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 1 year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 113a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 exhibit suicidal ideation as determined by a yes response to Q4 or Q5 by the CSSRS at baseline.

Embodiment 114a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 evidence of significant renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) of ^< 40 mL/min/1.73 m 2 at baseline.

Embodiment 115a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a history of hypersensitivity to compound I, or a pharmaceutically acceptable salt thereof, or a drug of a similar mechanism of action, i.e., a drug affecting the NMDA receptor.

Embodiment 116a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 an active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

Embodiment 117a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 seizures, except for childhood febrile seizures.

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

a) Within 6 months prior to treatment with compound I or a pharmaceutically acceptable salt thereof;

History of myocardial infarction, angina, or coronary artery bypass grafting.

b) History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g., double-fiber bundle block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound I or its pharmaceutically acceptable salt.

Embodiment 119a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a resting QTcF ≥450 msec (male) or ≥460 msec (female) at baseline.

Embodiment 120a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 exhibit 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:

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

b) Concomitant medication(s) with a “known risk of TdP” that cannot be discontinued or replaced by a safer alternative medication.

Embodiment 121a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 mean systolic blood pressure > 140 mmHg or a diastolic blood pressure > 90 mmHg at baseline; or no history of hypertensive crisis.

Embodiment 122a. A compound, or a pharmaceutically acceptable salt thereof, for use according to 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 a history of hemorrhagic stroke or a known cerebrovascular disorder (e.g., an aneurysm or arteriovenous malformation) or a known aneurysmal vascular disease of another location (e.g., the aorta).

Embodiment 123a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any 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 pregnant or lactating female.

Embodiment 124a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any 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 female of childbearing potential who is not using highly effective contraception.

Embodiment 125a. A compound for use according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound is administered to a subject, e.g., a patient, who is not a sexually active male and who does not intend to use a condom during sexual intercourse while taking compound I, or a pharmaceutically acceptable salt thereof, and for one week after discontinuing treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 126a. A compound, or a pharmaceutically acceptable salt thereof, for use according to any 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 medications as defined by Table 1 during treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 127a. A therapeutic agent for use in the treatment of psychiatric disorders, for example depressive disorders, for example major depressive disorder, for example 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, seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 128a. A therapeutic agent for use according to embodiment 127a, wherein the therapeutic agent is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof.

Embodiment 129a. A therapeutic agent for use according to any one of Embodiments 127a and 128a, wherein the therapeutic agent is an antidepressant, for example an oral antidepressant.

Embodiment 130a. A therapeutic agent for use according to any one of Embodiments 127a to 129a, wherein the therapeutic agent is administered for a period of at least about 4 weeks, for example at least about 6 weeks, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 131a. A therapeutic agent for use according to any one of Embodiments 127a to 130a, wherein treatment with the therapeutic agent continues after treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 132a. A therapeutic agent for use according to 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)), and a multimodal antidepressant.

Embodiment 133a. A therapeutic agent for use according to 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.

Embodiment 134a. A therapeutic agent for use according to any one of Embodiments 128a to 133a, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium members, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 135a. A therapeutic agent for use according to any one of Embodiments 127a to 134a, wherein treatment with compound I, or a pharmaceutically acceptable salt thereof, is according to any one of Embodiments 1a to 66a and 84a to 126a.

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

Embodiment 137a. A compound for use according to embodiment 136a, wherein the use is according to any one of embodiments 33a to 66a, 80a to 82a and 84a to 126a, or a pharmaceutically acceptable salt thereof.

Certain features described in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features described in the context of a single implementation may also be implemented in multiple implementations separately or in any suitable subcombination. Furthermore, although features may be described above as operating in a particular combination, one or more features from a claimed combination may in some cases be removed from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.

Embodiment b:

Embodiment 1b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 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 use in the treatment of a depressive disorder, wherein the pharmaceutical composition is administered subcutaneously.

Embodiment 3b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a depressive disorder, wherein the treatment comprises the following steps:

(a) Determining or having determined the baseline MADRS score of the subject, e.g., the patient; and

(b) subcutaneously administering to the subject, e.g., the patient, compound I, or a pharmaceutically acceptable salt thereof, wherein the amount of compound I, or a pharmaceutically acceptable salt thereof, improves the MADRS score by at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to a measured baseline MADRS score, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to the subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 4b. A use according to embodiment 3b, wherein the subject, e.g., the patient, is assessed at regular intervals after step (b) to determine relative effectiveness, wherein the assessment comprises measuring the MADRS score of the subject, e.g., the patient.

Embodiment 5b. Use according to any one of the preceding embodiments, wherein the depressive disorder is selected from major depressive disorder, in particular treatment-resistant depression, suicidality of 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 of major depressive disorder, and seasonal affective disorder.

Embodiment 6b. Use according to any one of the preceding embodiments, wherein the depressive disorder is major depressive disorder, such as acute MDD.

Embodiment 7b. Use according to any one of the preceding embodiments, wherein the depressive disorder is treatment-resistant depression.

Embodiment 8b. Use according to embodiment 7b, wherein the treatment-resistant depression comprises partial resistance.

Embodiment 9b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of depressive symptoms, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 10b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depressive symptoms of major depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 11b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depressive symptoms of major depressive disorder accompanied by acute suicidal ideation or behavior, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 12b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depressive symptoms of treatment-resistant depression, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 13b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in a method of reducing at least one depressive symptom in a subject, for example a patient, suffering from a depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 14b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of major depressive episodes, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 15b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in preventing major depressive episodes, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 16b. The use according to any one of Embodiments 14b and 15b, wherein the major depressive episode lasts for at least 4 weeks, for example, at least 6 weeks, at least 8 weeks, for example, about 8 weeks.

Embodiment 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, in particular acute MDD, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 18b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of single-agent major depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 19b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of recurrent major depressive disorder, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 20b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of recurrent major depressive disorder and current major depressive episodes having a duration of at least 6 weeks, for example at least 8 weeks, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 21b. Use according to any one of Embodiments 14b to 20b, wherein the major depressive episode lasts for at least 6 weeks, for example at least 8 weeks, but less than 24 months.

Embodiment 22b. Use according to any of the preceding embodiments, wherein the depressive disorder or depressive episode has not responded adequately to at least one antidepressant treatment, for example in the current depressive episode.

Embodiment 23b. Use according to any of the preceding embodiments, wherein the depressive disorder or depressive episode is, for example, a current depressive episode that has had a partial response to at least one antidepressant treatment.

Embodiment 24b. Use according to any of the preceding embodiments, wherein the depressive disorder or depressive episode has not responded adequately to at least two prior antidepressant treatments, for example in the current depressive episode.

Embodiment 25b. Use according to any of the preceding embodiments, wherein the depressive disorder or depressive episode is, for example, a current depressive episode that has had a partial response to at least two prior antidepressant treatments.

Embodiment 26b. Use according to any of the preceding embodiments, wherein the depressive disorder or depressive episode has not responded adequately to at least two, but not more than five, antidepressant treatments in the current depressive episode.

Embodiment 27b. A use according to any one of Embodiments 24b to 26b, wherein at least two antidepressant treatments are two different antidepressants.

Embodiment 28b. Use according to any one of Embodiments 22b to 27b, wherein the antidepressant treatment(s) has been administered for a duration of at least 4 weeks, for example for a duration of at least 6 weeks.

Embodiment 29b. The use according to any one of Embodiments 22b to 28b, 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 (RIMA)), and multimodal antidepressants.

Embodiment 30b. A use according to 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.

Embodiment 31b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of treatment-resistant depression, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 32b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of major depressive disorder in a subject, e.g., a patient, wherein the subject, e.g., the patient, meets DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 33b. A use according to any of the preceding embodiments, wherein the treatment further comprises evaluating the subject, e.g., the patient, at regular intervals after treatment with compound I, or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine whether continued treatment is necessary.

Embodiment 34b. Object, for example Use according to embodiment 33b, wherein the 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.

Embodiment 35b. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered in an amount of from about 0.0048 mg/kg to about 0.32 mg/kg, in particular 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.

Embodiment 36b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 15 mg.

Embodiment 37b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg to about 1 mg.

Embodiment 38b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.3 mg to about 1 mg.

Embodiment 39b. The use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.5 mg to about 1 mg.

Embodiment 40b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 5 mg.

Embodiment 41b. The use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 10 mg.

Embodiment 42b. The use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg to about 15 mg.

Embodiment 43b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

Embodiment 44b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of about 1 mg, about 4 mg, or about 10 mg.

Embodiment 45b. A 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.

Embodiment 46b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered once without repetition.

Embodiment 47b. A compound for use according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein the compound I, or a pharmaceutically acceptable salt thereof, is administered once every two weeks or less frequently.

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.

Embodiment 49b. A 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.

Embodiment 50b. A 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.

Embodiment 51b. The use according to any one 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.

Embodiment 52b. Use according to any one of the preceding embodiments, wherein the score in one of the depression assessment tools selected from the group consisting of the Montgomery-Osberg Depression Rating Scale (MADRS), the Mini-International Neuropsychiatric Interview (M.I.N.I.), e.g. version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicidality Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI) improves after treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 53b. A use according to any one of the preceding embodiments, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, having recurrent major depressive disorder and a current major depressive episode with a duration of at least 4 weeks, for example at least 6 weeks, at least 8 weeks.

Embodiment 54b. A use according to any one of the preceding embodiments, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is resistant to treatment.

Embodiment 55b. A use according to any one of the preceding embodiments, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is partially resistant.

Embodiment 56b. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the compound is administered to a subject, e.g., a patient, who has had an inadequate response or failed to respond to other antidepressant treatments prior to treatment with compound I, or a pharmaceutically acceptable salt thereof, in a current major depressive episode.

Embodiment 57b. A use according to any of the preceding embodiments, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who has not responded adequately or has failed to respond adequately to at least one antidepressant in a current major depressive episode.

Embodiment 58b. A use according to any one of the preceding embodiments, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who has not responded adequately or has failed to respond adequately to at least two antidepressants in a current major depressive episode.

Embodiment 59b. A use according to any one of Embodiments 56b to 58b, wherein the inappropriate reaction comprises a partial reaction.

Embodiment 60b. Use according to any one of embodiments 56b to 59b, wherein the current major depressive episode has a duration of at least about 4 weeks, for example at least about 6 weeks, at least about 8 weeks, in particular at least about 8 weeks, but not longer than 24 months.

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

Embodiment 62b. A 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, 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, or at least about 25 at baseline.

Embodiment 63b. The use according to any one of the preceding embodiments, wherein the treatment further comprises determining or had determined a MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, for example 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 64b. A use according to any one of the preceding embodiments, wherein the subject, e.g., the patient, has a decreased 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., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, compared to a baseline assessment, 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 65b. The use according to any one of the preceding embodiments, wherein the subject, e.g., the patient, has a greater than 30%, for example, greater than 35%, greater than 40%, greater than 45%, greater than 50% improvement in 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., the patient, has a greater than 30%, for example, greater than 35%, greater than 40%, greater than 45%, greater than 50% improvement in MADRS total score after 24 hours, 7, 14, 21 and/or 28 days of subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 66b. A use according to any one of the preceding embodiments, wherein the subject, e.g., the 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., the patient, has a MADRS total score of less than 12 after 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 67b. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with one or more additional therapeutic agents for the treatment of a psychiatric disorder depressive disorder, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 68b. A use according to embodiment 67b, wherein the compound, or a pharmaceutically acceptable salt thereof, is for use according to any one of embodiments 1b to 66b.

Embodiment 69b. A use according to any one of Embodiments 1b to 66b, wherein the treatment further comprises administration of one or more additional therapeutic agents.

Embodiment 70b. Use according to embodiment 69b, wherein treatment with compound I, or a pharmaceutically acceptable salt thereof, is additional to one or more standard care medications prescribed for use in the treatment of a psychiatric disorder.

Embodiment 71b. Psychiatric disorder is a depressive disorder, use according to any one of embodiments 67b to 70b.

Embodiment 72b. Depressive disorder is major depressive disorder, use according to embodiment 71b.

Embodiment 73b. Major depressive disorder is treatment-resistant depression, major depressive disorder with suicidality, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, major depressive disorder with self-harm, or seasonal affective disorder, use according to embodiment 72b.

Embodiment 74b. A use according to any one of Embodiments 67b to 74b, wherein the treatment comprises administering one or more additional therapeutic agents for a period of at least about 4 weeks, for example at least about 6 weeks, prior to treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 75b. The use according to any one of embodiments 67b to 75b, wherein treatment with one or more additional therapeutic agents continues after treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 76b. A use according to any one of embodiments 67b to 76b, wherein the one or more additional therapeutic agents are selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof.

Embodiment 77b. A use according to any one of embodiments 67b to 77b, wherein at least one of the one or more additional therapeutic agents is an antidepressant, for example an oral antidepressant.

Embodiment 78b. A use according to any one of embodiments 67b to 78b, wherein the one or more additional therapeutic agents is one or more antidepressants.

Embodiment 79b. The use according to any one of embodiments 76b to 78b, wherein the disorder has not responded adequately to, or has failed to respond to, at least one additional therapeutic agent or at least one standard of care medication, for example at least two, during the current major depressive episode.

Embodiment 80b. A use according to 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.

Embodiment 81b. The use according to embodiment 80b, 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.

Embodiment 82b. A use according to 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.

Embodiment 83b. Use according to any one of embodiments 76b to 82b, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 84b. A use according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the upper arm or abdominal region.

Embodiment 85b. A 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.

Embodiment 86b. A 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.

Embodiment 87b. A use according to any one of the preceding embodiments, wherein compound I is administered as a free base.

Embodiment 88b. A use according to any one of the preceding embodiments, wherein compound I is formulated for delivery from a subcutaneous injection device.

Embodiment 89b. A use according to any one of the preceding embodiments, wherein compound I is formulated for delivery from a subcutaneous injection device as a single subcutaneous injection.

Embodiment 90b. A use according to 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 failed to respond to two or more, but no more than five, prior antidepressant treatments, wherein the two failed treatments are two different antidepressants at appropriate doses and durations, e.g., at least 6 weeks duration, as determined by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

Embodiment 91b. A use according to 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 a <50% response to at least one antidepressant treatment during a major depressive episode of ≥ 8 weeks duration, e.g., at an effective and stable dose for at least 4 weeks according to the MGH-ATRQ.

Embodiment 92b. A use according to 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 diagnosis of recurrent major depressive disorder (MDD) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and a current major depressive episode of at least 8 weeks duration.

Embodiment 93b. A use according to any one of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, characterized as having treatment-resistant or treatment-refractory depression.

Embodiment 94b. A use according to any preceding embodiment, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a human patient.

Embodiment 95b. A use according to any preceding embodiment, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to an adult patient.

Embodiment 96b. A use according to 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 treatment failure with esketamine, ketamine or arketamine.

Embodiment 97b. A use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, suffering from an episode of depression, e.g., a major depressive episode, wherein the subject, e.g., the patient, has not responded to treatment with at least one antidepressant for the current depressive episode.

Embodiment 98b. A use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, suffering from an episode of depression, e.g., a major depressive episode, wherein the subject, e.g., the patient, has not responded to treatment with at least two antidepressants for the current depressive episode.

Embodiment 99b. A use according to any one of embodiments 97b and 98b, wherein at least one antidepressant is an oral antidepressant.

Embodiment 100b. Use according to any one of embodiments 97b to 99b, wherein the antidepressant has been administered for a duration of at least 4 weeks, for example for a duration of at least 6 weeks.

Embodiment 101b. A use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is either male or female.

Embodiment 102b. A use according to 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 an acute depressive episode lasting more than 2 years.

Embodiment 103b. A use according to any of the preceding embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, who is currently undergoing depressive episode treatment or who has not received electroconvulsive therapy within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 104b. A use according to 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 the current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 105b. A use according to 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 vagus nerve stimulation in the current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 106b. A use according to 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 undergone deep brain stimulation in the current depressive episode or within the past year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 107b. A use according to 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 a previous or current diagnosis of major depressive disorder, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features as determined by, for example, the SCID-5.

Embodiment 108b. A use according to 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 withdrawal symptoms requiring treatment for an acute alcohol or substance use disorder or addiction.

Embodiment 109b. A use according to 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 had an anti-addiction treatment within 1 month prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 110b. A use according to 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 borderline personality disorder or antisocial personality disorder as defined by DSM-5 criteria.

Embodiment 111b. A use according to 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 a clinical diagnosis of autism, dementia, or intellectual disability.

Embodiment 112b. A use according to 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 suicide attempts or suicidal behavior within 1 year prior to treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 113b. A use according to 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 exhibit suicidal ideation as determined by a baseline CSSRS response to Q4 or Q5.

Embodiment 114b. Use according to 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 evidence of significant renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) of <40 mL/min/1.73 m ² at baseline.

Embodiment 115b. A use according to 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 a history of hypersensitivity to compound I, or a pharmaceutically acceptable salt thereof, or a drug of a similar mechanism of action, i.e., a drug affecting the NMDA receptor.

Embodiment 116b. A use according to 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 an active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection.

Embodiment 117b. A use according to 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 seizures, except for childhood febrile seizures.

Embodiment 118b. A use according to 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 a cardiac or cardiac repolarization abnormality, including any of the following:

a) Within 6 months prior to treatment with compound I or a pharmaceutically acceptable salt thereof;

History of myocardial infarction, angina, or coronary artery bypass grafting.

b) History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g., double-fiber bundle block, Mobitz type II, and third-degree AV block) within 6 months prior to treatment with Compound I or its pharmaceutically acceptable salt.

Embodiment 119b. A use according to 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 a resting QTcF ≥450 msec (male) or ≥460 msec (female) at baseline.

Embodiment 120b. A use according to 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 exhibit 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:

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

b) Concomitant medication(s) with a “known risk of TdP” that cannot be discontinued or replaced by a safer alternative medication.

Embodiment 121b. A use according to 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 mean systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg at baseline; or no history of hypertensive crisis.

Embodiment 122b. A use according to 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 a history of hemorrhagic stroke or a known cerebrovascular disorder (e.g., an aneurysm or arteriovenous malformation) or a known aneurysmal vascular disease of another location (e.g., the aorta).

Embodiment 123b. A use according to any 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 pregnant or lactating woman.

Embodiment 124b. A use according to any 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 female of childbearing potential who is not using highly effective contraception.

Embodiment 125b. A use according to any 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 and who does not intend to use a condom during sexual intercourse while taking compound I, or a pharmaceutically acceptable salt thereof, and for one week after discontinuing treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 126b. A use according to any 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 medications as defined by Table 1 during treatment with compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 127b. Use of a therapeutic agent in the manufacture of a medicament for the treatment of psychiatric disorders, for example depressive disorders, for example major depressive disorder, for example 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, seasonal affective disorder, wherein the treatment additionally comprises subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 128b. A therapeutic agent for use according to embodiment 127b, wherein the therapeutic agent is selected from the group consisting of antidepressants, antipsychotics, mood stabilizers, benzodiazepines, and combinations thereof.

Embodiment 129b. A therapeutic agent for use according to any one of Embodiments 127b and 128b, wherein the therapeutic agent is an antidepressant, for example an oral antidepressant.

Embodiment 130b. A therapeutic agent for use according to any one of Embodiments 127b to 129b, wherein the therapeutic agent is administered for a period of at least about 4 weeks, for example at least about 6 weeks, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 131b. A therapeutic agent for use according to any one of Embodiments 127b to 130b, wherein treatment with the therapeutic agent continues after treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 132b. A therapeutic agent for use according to 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)), and a multimodal antidepressant.

Embodiment 133b. A therapeutic agent for use according to 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.

Embodiment 134b. A therapeutic agent for use according to any one of Embodiments 128b to 133b, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium members, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 135b. A therapeutic agent for use according to 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.

Embodiment 136b. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of treatment-resistant depression in an adult patient, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously, and wherein the treatment is administered in combination with at least one oral antidepressant.

Embodiment 137b. A use according to embodiment 136a, wherein the use is according to any one of embodiments 33a to 66a, 80a to 82a and 84a to 126a.

embodiment c

Embodiment 1c. 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.

Embodiment 2c. 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 pharmaceutical composition comprising a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

Embodiment 3c. A method for reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, comprising subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 4c. A method for long-term treatment of 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.

Embodiment 5c. A method of treating treatment-resistant depression in a subject, e.g., a patient, having major depressive disorder, comprising subcutaneously administering a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 6c. A method of subcutaneously administering compound I, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, e.g., a patient, comprising the step of subcutaneously administering compound I under the skin of the subject.

Embodiment 7c. A method of treating a depressive disorder in a subject, for example a patient, in need of treatment for a depressive disorder, comprising the steps of:

a. Determining or determining the baseline MADRS score of the subject, e.g., the patient; and

b. A method 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 amount of compound I, or a pharmaceutically acceptable salt thereof, improves the MADRS score by at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to a measured baseline MADRS score, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 8c. The method of embodiment 7c, wherein the subject, e.g., the patient, is evaluated at regular intervals after step (b) to determine relative effectiveness, wherein the evaluation comprises measuring the MADRS score of the subject, e.g., the patient.

Embodiment 9c. A method according to any preceding embodiment, wherein the subject, for example a patient, is diagnosed or has been diagnosed with a depressive disorder.

Embodiment 10c. A method according to any preceding embodiment, wherein the subject, for example a patient, is diagnosed or has been diagnosed with a major depressive disorder.

Embodiment 11c. A method according to any preceding embodiment, wherein the subject, for example a patient, is diagnosed or has been diagnosed with treatment-resistant depression (TRD).

Embodiment 12c. A method according to any one of the preceding embodiments, wherein scores are improved on one or more depression assessment instruments selected from the group consisting of the Montgomery-Osberg Depression Rating Scale (MADRS), the Mini-International Neuropsychiatric Interview (M.I.N.I.), e.g., version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicidality Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI).

Embodiment 13c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of about 1 mg to about 15 mg, wherein the dosage amount refers to the free base of compound I.

Embodiment 14c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of about 1 mg to about 10 mg, wherein the dosage amount refers to the free base of compound I.

Embodiment 15c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously in a dose of about 1 mg, about 4 mg, or about 10 mg, wherein the dosage amount refers to the free base of compound I.

Embodiment 16c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once a week.

Embodiment 17c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, twice a week.

Embodiment 18c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once every two weeks.

Embodiment 19c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once every three weeks.

Embodiment 20c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, a) once a month; or b) once every six weeks to a subject, e.g., a patient.

Embodiment 21c. A method according to any one 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 1 1 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.

Embodiment 22c. A method according to any one of the preceding embodiments, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder.

Embodiment 23c. The depressive disorder is major depressive disorder, a method according to any one of the preceding embodiments.

Embodiment 24c. A method according to any one of the preceding embodiments, wherein the depressive disorder is treatment-resistant depression.

Embodiment 25c. A method according to any one of the preceding embodiments, wherein the subject, eg, the 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.

Embodiment 26c. A method according to embodiment 25c, 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 (RIMA)), and multimodal antidepressants.

Embodiment 27c. A method according to 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.

Embodiment 28c. A method according to any one of the preceding embodiments, wherein the subject, for example a patient, is experiencing a major depressive episode.

Embodiment 29c. A method according to 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.

Embodiment 30c. A method according to embodiment 29c, wherein the subject, for example a patient, has not responded to at least one antidepressant in a current major depressive episode.

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

Embodiment 32c. A method according to embodiment 29c, wherein the subject, for example the patient, has not responded to at least two antidepressant medications in a current major depressive episode.

Embodiment 33c. The method of embodiment 32c, wherein at least two antidepressants are not identical.

Embodiment 34c. A method according to any one of embodiments 32c and 33c, wherein at least one of the at least two antidepressants is an oral antidepressant.

Embodiment 35c. A method according to any one of embodiments 28c to 34c, wherein the current major depressive episode has a duration of at least about 4 weeks, for example at least 6 weeks, or about 8 weeks.

Embodiment 36c. A method according to any one of the preceding embodiments, wherein the treatment is in combination with at least one additional therapeutic agent.

Embodiment 37c. A method according to any of the preceding embodiments, wherein the subject, e.g., a patient, is treated with compound I, or a pharmaceutically acceptable salt thereof, in addition to treatment with one or more standard care medications prescribed for a psychiatric disorder, e.g., a depressive disorder.

Embodiment 38c. A method according to any one of embodiments 36c and 37c, wherein the treatment comprises at least one additional antidepressant, antipsychotic, mood stabilizer, or a combination thereof.

Embodiment 39c. A method according to any one of embodiments 36c to 38c, wherein at least one additional therapeutic agent is at least one antidepressant.

Embodiment 40c. A method according to any one of Embodiments 36c to 39c, wherein the subject, e.g., the patient, continues treatment with at least one additional therapeutic agent after receiving treatment with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 41c. A method according to any one of embodiments 38c to 40c, wherein at least one 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 (RIMA)), and multimodal antidepressants.

Embodiment 42c. A method according to embodiment 41c, wherein at least one additional 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.

Embodiment 43c. A method according to any one of embodiments 38c to 42c, wherein the antipsychotic or mood stabilizer is selected from lithium, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 44c. A method according to any one of the preceding embodiments, wherein the subject, e.g., a patient, has a MADRS score of at least about 20, at least about 21, at least about 22, at least about 23, or at least about 24 prior to administration of compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 45c. A method according to any one of the preceding embodiments, further comprising determining or having determined a MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, for example 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, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 46c. A method according to any one of the preceding embodiments, wherein the subject, e.g., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a decreased MADRS total score after 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, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 47c. A method according to any one of the preceding embodiments, wherein the subject, e.g., the patient, has an improvement in MADRS total score of greater than about 30%, for example greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, compared to a baseline assessment, following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, for example, the subject, e.g., the patient, has an improvement in MADRS total score of greater than about 30%, for example greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, compared to a baseline assessment, following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, at least about 24 hours, at least about 7 days, at least about 14 days, at least about 21 days, and/or at least about 28 days, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 48c. A method according to any one of the preceding embodiments, wherein the subject, e.g., the patient, has a MADRS total score of less than 12 after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a MADRS total score of less than 12 after 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, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 49c. A method according to any one of the preceding embodiments, wherein the subject, e.g., the patient, is treated with a treatment selected from ketamine, compound I, or a pharmaceutically acceptable salt thereof, electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, amantadine, a monoamine oxidase inhibitor, citalopram, escitalopram, a medication known to have a risk of torsade de pointes according to www.qtdrug.org, amitriptyline, nortriptyline, quetiapine, benztropine, diphenhydramine, trazodone, cannabis, medical marijuana, a psychostimulant, e.g., amphetamine, methylphenidate, modapanil, armodafinil, and an opioid, e.g., an antidepressant treatment, in combination with, e.g., not treated simultaneously.

Embodiment 50c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the upper arm or abdominal region.

Embodiment 51c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously as a single subcutaneous injection.

Embodiment 52c. A method according to any one of the preceding embodiments, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered as a free base.

Embodiment 53c. A composition comprising compound I in combination with a carrier, the composition being configured for subcutaneous distribution to a patient.

Embodiment 54c. The composition of embodiment 53c, wherein the carrier comprises, consists of, or consists essentially of water for injection.

Embodiment 55c. A composition according to embodiment 53c or 54c, comprising a tonicity-enhancing agent and/or being isotonic.

Embodiment 56c. A device comprising a composition according to any one of Embodiments 53c to 55c, comprising a chamber configured to hold the composition and a piercing element configured to subcutaneously discharge the composition into a patient.

Embodiment 57c. The device of embodiment 56c further comprising an actuator that can be activated to inject the composition into a patient.

Embodiment 58c. The device of embodiment 57c, wherein the operating device is a button or a plunger.

Embodiment 59c. A device according to any one of embodiments 56c to 58c, wherein the piercing element is a needle.

Embodiment 60c. A kit comprising a composition of any one of embodiments 53c to 55c and/or a device of any one of embodiments 56c to 59c.

Embodiment 61c. A kit according to embodiment 60c, further comprising instructions for use.

Certain features described in the context of separate implementations may also be implemented in combination in a single implementation. Conversely, various features described in the context of a single implementation may also be implemented in multiple implementations separately or in any suitable subcombination. Furthermore, although features may be described above as operating in a particular combination, one or more features from a claimed combination may in some cases be removed from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.

Example

abbreviation

Example 1 Absorption, bioavailability and pharmacokinetics

Compound I showed low oral bioavailability in animals (<10% in mice, rats, or dogs). Following subcutaneous administration, bioavailability was surprisingly higher (61% in mice and 70% in rats). The subcutaneous route of administration surprisingly showed higher bioavailability compared to oral gavage administration.

In a rat PK study comparing different routes of administration, compound I exposure (based on AUClast) was highest following s.c. administration, followed by intratracheal, intranasal, and then buccal administration.

Example 2 Preclinical studies using s.c. Compound I

NMDA receptor blockers such as MK-801, also known as ketamine and dizocilpine, are known to reverse haloperidol-induced catalepsy in rats. The pharmacodynamic effects of compound I were measured by quantifying the extent to which it reversed haloperidol-induced catalepsy in this model. Locomotor activity was measured in rats as a surrogate model for the potential to induce psychotogenic effects.

Rat haloperidol-induced catalepsy (rod test):

Using the rod test, laxity was assessed by placing the rat's forepaw on a horizontal metal rod raised 6" above a Plexiglas platform and recording the time spent grasping the rod for up to 60 seconds per trial. The test was terminated when the animal's forepaw returned to the platform or after 60 seconds.

In this test, rats were treated by subcutaneous injection of vehicle (negative control) or compound I (0.1, 0.3, and 10 mg/kg). CP-101,606 (traxoprodil), an NMDA receptor antagonist specific for the NR2B subunit, served as a positive control at 10 mg/kg (subcutaneous injection). Testing was started 30 minutes after dosing.

Compound I was found to dose-dependently reduce rod holding time at all doses tested (Fig. 2) (the minimum effective dose was 0.1 mg/kg) and reverse haloperidol-induced catalepsy.

Data are presented as mean ± SEM (N = 10). Data were analyzed by one-way ANOVA. *p < 0.05 compared with haloperidol (hal) + vehicle.

Move test

Locomotor activity is a measure that can detect changes across a number of activity measures in addition to basic exploratory driving. It is frequently used as a preclinical surrogate for psychotogenic effects. In this test, rats are placed in a locomotor activity chamber and the distance traveled is measured from a horizontal photocell beam cutoff, which is automatically recorded by a computer system.

In this test, rats were first placed in the chamber for a 30-minute baseline measurement. Rats were then treated by subcutaneous injection with vehicle (negative control), compound I (1, 3, 10, and 30 mg/kg), or ketamine (1, 3, 10, and 30 mg/kg, positive control). They were immediately placed back into the same chamber for an additional 60-minute test session.

Compound I increased locomotor activity at doses of 3, 10, and 30 mg/kg s.c. starting 20 min after injection, which persisted throughout the duration of the test session (Fig. 3B). Ketamine induced robust hyperlocomotion at doses that reversed haloperidol-induced catalepsy (10 and 30 mg/kg) (Fig. 3A). The effects of compound I were qualitatively different (described as exploratory by the observer) and moderate compared to those induced by ketamine.

Rat quantitative electroencephalography (qEEG)

Quantitative EEG (qEEG) experiments provide real-time assessment of EEG frequencies when animals are at rest or under drug administration, thus interpreting the effects of various CNS-active compounds on brain activity. Previous studies have demonstrated that NR2B-selective NAMs have a distinct EEG spectral fingerprint in preclinical species, defined by a reduction in the mid- to low-frequency bands, most notably the alpha, beta, and beta sub-bands (Keavy et al, 2016; Nagy et al, 2016).

In this test, rats were treated with subcutaneous injections of vehicle (negative control) or compound I (0.1, 0.3, and 1 mg/kg). EEG recordings were started 60 min before dosing (habituation phase) and continued for up to 2 h after dosing.

The results (Fig. 4) demonstrate that compound I preferentially modulates mid-frequency spectral output specifically within the beta (primarily driven by the beta1 sub-band) and alpha frequency bands, while having no significant effect over vehicle on relative gamma output, confirming its selectivity as an NR2B NAM in vivo.

Data are presented as mean ± SEM (N = 10). Data were analyzed by one-way ANOVA.

In summary, these nonclinical data demonstrate that compound I administered subcutaneously to rats is active and selective for the NR2B subunit and reverses haloperidol-induced catalepsy, a model of target binding and pharmacodynamic activity.

In summary, preclinical data are considered to support subcutaneous administration of compound I in patients in clinical studies.

Example 3 Clinical study using subcutaneous doses of compound I

Phase 1 study in HV using subcutaneous doses of compound I

This is a randomized, participant- and investigator-blinded, placebo-controlled, single ascending dose (SAD) study to investigate the safety, tolerability, and PK of subcutaneously administered Compound I in healthy participants. The study is ongoing and will involve approximately 32 non-Japanese and 12 Japanese participants. Study participants (non-Japanese) have already been enrolled in three sequential cohorts and received a single subcutaneous dose of 1, 4, or 12 mg Compound I or placebo. Eight participants in each cohort completed treatment and the randomization ratio for Compound I versus placebo was 3:1. Subsequently, 12 Japanese participants will be enrolled in a single cohort and receive subcutaneous doses of Compound I or placebo. The exact dose of Compound I in the Japanese cohort will be determined based on the results of the cohorts with non-Japanese participants.

Preliminary results from the first SAD (single ascending dose) cohort (1, 4, and 12 mg subcutaneous compound I or placebo) indicate that the safety and tolerability of compound I were acceptable across the dose range tested in the study.

purpose

The primary objective of this non-confirmatory study was to evaluate the safety and immediate efficacy of a single subcutaneous injection of compound I as an add-on to standard pharmacological antidepressant (SoC) treatment in participants with TRD as assessed by the MADRS (Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Brit J Psychiat; 134:382-9), a validated and widely used scale in trials of depressive disorders, assessed approximately 24 hours after study drug administration.

Objectives, Endpoints and Estimates

[Table 3-1] Purpose and related endpoints

The clinical study aimed to establish the efficacy (versus placebo) of s.c. compound I given as an add-on to standard-care pharmacological antidepressant (SoC) treatment on changes in depressive symptoms 24 hours after injection of compound I in participants with TRD who have already failed to respond adequately to at least two conventional antidepressant medications.

reason

The justification for the primary estimator is that it would allow estimating the rapid effect of Compound I in a population of depressed participants who are considered treatment-resistant based on the above definition. Since conventional antidepressants may require several weeks to achieve a reduction in depressive symptoms, a rapid response would be clinically valuable.

The first-order estimator is described by the following properties:

1. Group: Participants with treatment-resistant depression who have failed to achieve an adequate treatment response to at least two previous antidepressant medications.

2. Primary variable: Change in MADRS total score from baseline to 24 hours post-dose.

3. Treatment of interest: Randomized treatment (compound I or placebo treatment) administered as a single s.c. injection on day 1. The dose of concomitant medications allowed for depression (i.e., SoC) should be maintained stable throughout the trial.

4. Handling of intercurrent events (IEs) prior to MADRS assessment at 24 hours:

· New doses or changes in concomitant medications/therapies with potential confounding effects: Hypothetical strategies

· Taking Prohibited Medicines: Hypothetical Strategies

· Taking relief medications: a hypothetical strategy

· IE related to pandemic: Hypothetical strategies

· IEs that lead to study discontinuation due to adverse events (AEs), lack of efficacy, or other reasons: Treatment Policy

Participants who are taking prohibited or rescue medications, or who are receiving new or modified concomitant treatments with potential confounding effects will remain in the study and will be assessed as scheduled.

Summary measures: Differences in variable means between study drug and placebo.

The Multiple Comparison Procedure-Modeling (MCP-Mod) approach will be used to assess the primary objective.

Study Design

As presented in Figure 1, this is a non-confirmatory, randomized, double-blind, placebo-controlled, parallel-group trial in participants with TRD to evaluate the efficacy, safety, tolerability and pharmacokinetics of a single subcutaneous Compound I administration in addition to standard of care (“SoC”) treatment with pharmacological antidepressants. Approximately 56 participants will be randomized at a total of 20-25 sites worldwide.

Participants will be randomly assigned in a 1:1:1:1 ratio to one of four treatment arms:

· Single dose of compound I s.c. 1 mg

· Single dose of compound I s.c. 4 mg

· Single dose of compound I s.c. 10 mg

· Single dose of placebo sc

The screening period begins when the participant signs the informed consent form and may last up to 28 days. Eligibility of the participant will be determined based on assessments performed during the screening period and also on Day 1 prior to randomization. Except for laboratory results, all other baseline assessments, including the primary efficacy measure (MADRS), will be performed on Day 1 prior to randomization and reviewed for eligibility criteria prior to dosing. On Day 1/prior to dosing, eligible participants will be randomized to one of the treatment arms.

Treatment is administered as a single s.c. injection on day 1, followed by a safety observation at the clinical site for at least 4 hours after administration. Study participants will be continuously observed by site staff for the first 30 minutes after administration for the occurrence of adverse events, particularly CNS (central nervous system) or cardiovascular AEs. Safety assessments will include the performance of a physical examination (PE), ECG, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), CADSS, MOAA/S, C-SSRS, and memory assessment using orientation questions. Local tolerability will be assessed by visual inspection of the injection site. Injection site abnormalities reaching the threshold for mild changes will also be assessed quantitatively.

Participants will be permitted to leave the clinical site as early as 4 hours after dosing if all of the following criteria are met:

· Participants neither reported nor exhibited any adverse CNS events (dissociation, amnesia, sedation)

· No increase in suicidal intensity or new onset of suicidal ideation as assessed by the C-SSRS

· No clinically relevant QTcF prolongation (QTcF≥500 msec or QTcF increase from baseline≥60 msec)

· Absence of any clinically relevant blood pressure (BP) abnormality (90 ≤ systolic BP (SBP) ≥ 180 mmHg or 50 ≤ diastolic BP (DBP) ≥ 105 mmHg or an increase or decrease in SBP of at least 20 mmHg from baseline or an increase or decrease in DBP of at least 15 mmHg) or any BP increase accompanied by symptoms such as headache, dizziness, nausea, visual disturbances, or other neurological symptoms

· The investigator did not identify any other AEs that required continued monitoring.

If a participant is unable to be discharged from the clinical site 4 hours after dosing, extended safety monitoring will be performed as described below.

The follow-up period after dosing will continue for 4 weeks (28 days) after treatment. Site visits to assess efficacy and safety are scheduled on Day 2 (24 hours after dosing) and then weekly during the follow-up period (i.e., on Days 8, 15, 22, and 29). The assessment to assess the primary objective will be conducted on Day 2 (24 hours after dosing). A telephone call will be conducted 3 days after each site visit. The end-of-study (EOS) visit will be completed on-site on Day 29, and a safety follow-up phone call will be conducted by phone on Day 31 (30 days after dosing). The total duration of the study, including screening, is approximately 8 weeks (56 days).

Extended safety monitoring in AE case on day 1

If extended monitoring beyond the minimum 4 hours of monitoring on Day 1 is required, the following will be assessed:

· Monitoring of CNS adverse events (dissociation, amnesia, sedation):

· If any dissociative AE, amnesia, or somnolence/sedation is present, participants should be monitored on-site until these AEs have fully resolved. If dissociative AEs or cognitive symptoms do not resolve within 6 hours of onset, participants will need to remain on-site for overnight monitoring and may be discharged on Day 2 after assessments have been completed and the AEs have resolved. The times of onset and resolution of dissociative and cognitive AEs should be determined as precisely as possible. The following assessments are recommended to track CNS AEs whenever possible (e.g., whenever the participant is awake):

· If dissociative AEs are present, it is recommended that CADSS be administered hourly until the total score returns to baseline or normal levels (i.e., a total score of 4 or less)

· If memory gaps/amnesia are present, this should be assessed with orientation questions at least once per hour until the amnesia resolves.

· Sedation/drowsiness should be assessed by hourly questioning or administration of the MOAA/S until the AE resolves

· Monitoring suicidal ideation or behavior:

· If moderate to severe suicidal ideation or any suicidal behavior is present, the investigator should admit the participant at least overnight, based on the rating scale or investigator judgment.

· If suicidal ideation is mild, based on the rating scale or investigator judgment, the participant may be allowed to leave the clinical setting, but in such cases, arrangements should be made to have a family member or friend stay with the participant for at least 24 hours. If these arrangements are not possible, it is recommended that the participant be admitted at least overnight.

· Monitoring of QTcF prolongation:

· If initial QTcF prolongation is confirmed by a repeat ECG at least 10 minutes later, close observation of the participant should be initiated at the investigator's discretion

· ECG should be performed every 30 minutes until QTcF is less than 500 msec and the increase from baseline is less than 60 msec

· Serum electrolyte levels should be determined and corrected if necessary (especially hypokalemia, hypomagnesemia).

· Consultation with a cardiologist may be conducted at the investigator's discretion.

· Monitoring for increased blood pressure:

· Although blood pressure increases should be monitored, initial treatment is not recommended unless clinically indicated. Blood pressure increases associated with Compound I treatment are usually transient, with blood pressure typically returning to predose values within 3 to 4 hours

· 1.5 hours after administration, if SBP is ≥160 mmHg and/or DBP is ≥100 mmHg, assessments should continue every 30 minutes until:

1. If blood pressure is <160 mmHg SBP and <100 mmHG DBP,

2. Based on the clinical judgment of the investigator, the participant is clinically stable or

3. Participants will be referred for appropriate medical care when clinically indicated.

4. If blood pressure remains ≥160 mmHg SBP and/or ≥100 mmHg DBP 4 hours after administration, participants should be referred for immediate medical attention.

Rationale for study design and overall study design

The primary objective of the study was to investigate the efficacy of compound I following intravenous administration in participants with treatment-resistant depression. The design of the study was chosen to adequately assess the primary objective and followed the American Psychiatric Association (APA) Practice guideline for the treatment of patients with major depressive disorder (Alan J. Gelenberg, Marlene P. Freeman, John Markowitz (2010) Practice guideline for treatment of patients with major depressive disorder p. 1-118).

The randomized, placebo-controlled design is intended to limit the effects of expectation bias and measurement bias. The parallel design was chosen because it ensures unbiased comparisons between treatment arms. This design also avoids any potential carryover effects that may occur in different designs, such as crossover.

Three compound I arms with different doses are included in the study to enable estimation of the dose-response and exposure-response relationships of the antidepressant effects of compound I.

The relatively long follow-up period (4 weeks or 28 days) is intended to assess the duration of the antidepressant effect of compound I. This information will be used to select the dosing interval for the pivotal phase 3 study.

The study included a schedule of frequent visits to assess safety and efficacy, with weekly site visits to clinical sites and telephone calls in between.

In a previous written PoC study in participants with treatment-resistant depression, the efficacy of compound I was assessed following i.v. administration. The results of the present study with s.c. compound I will be compared with the written PoC study in a similar population using i.v. compound I to explore whether there are any major differences in the safety and efficacy of compound I when administered via the s.c. or i.v. route. It is therefore important to ensure that the 2 studies have essentially the same design, utilize the same primary endpoint, and recruit the same participant population.

Rationale and timing for selection of efficacy assessments

For the primary objective, efficacy will be determined using the MADRS Montgomery and Osberg 1979, a standard for the assessment of major depressive episodes. The 24-hour post-dose time point was chosen for the primary analysis to collect information on Compound I. Achieving a rapid antidepressant effect is clinically meaningful because participants with major depression are at risk for suicide or self-harm, whereas conventional antidepressant medications can take weeks to achieve efficacy. The primary endpoint and its timing will also be the same as in the writing PoC study, to allow comparison of the results of the two studies.

Basis for safety assessment

The safety assessment and its frequency were chosen based on the written FIH and PoC studies in healthy volunteers and the ongoing SAD study with s.c. compound I.

The most common AEs associated with Compound I include dissociative events/amnesia and sedation. These will be monitored using AE collection, CADSS, and MOAA/S, which have been used to identify associated events in previous studies with Compound I.

Other potential risks associated with compound I include QTc prolongation and increased blood pressure. These events are related to the Cmax of compound I, which tends to decrease during the first 4 hours after administration. Therefore, frequent ECG and BP measurements will be performed during the first 4 hours after injection to detect any potential effects on QTc and BP.

Additional safety assessments include standard laboratory tests (hematology, blood chemistry, and urinalysis), physical examination, and monitoring of AEs and SAEs. Participants with major depressive disorder or treatment-resistant depression will be monitored for suicidal thoughts and behaviors using the Columbia Suicide Severity Rating Scale (C-SSRS) at each visit because they are at risk for suicide.

Selection of patient population

The study is intended to investigate compound I in participants with treatment-resistant depression who may potentially benefit from rapid-acting antidepressant medication. Treatment resistance will be defined based on retrospective assessment of prior treatment regimens and outcomes by the investigators and supported by medical records. The same approach was used in the original PoC study and is modified here to ensure that the participants enrolled in the two studies represent the same participant population.

Other eligibility criteria are defined to ensure a homogeneous study population and to minimize risks associated with study participation.

Evidence for treatment duration

Rapid response is significant in treatment-resistant depression, a population that fails to respond to conventional antidepressants used for an adequate duration and at an adequate dose. Depressive disorders often result in suicidal thoughts or behaviors that put patients at risk. However, conventional antidepressant treatment can take several weeks to achieve therapeutic benefit. Therefore, rapid-acting and safe antidepressant treatments are needed. To evaluate whether compound I can rapidly improve symptoms of treatment-resistant depression after s.c. administration, a single-dose treatment is sufficient.

Another objective of the study was to evaluate the duration of efficacy of s.c. Compound I. To evaluate the duration of efficacy, single-dose treatment is the most appropriate method because it provides direct information on the efficacy of a single injection without any confounding effects of repeated dosing.

In the PoC study, compound I was superior to placebo in reducing depressive symptoms as measured by the MADRS total score at 24 hours after the first dose. Compound I was also significantly better than placebo after repeated dosing for 6 weeks at a dose of 0.16 mg/kg every other week or at a dose of 0.32 mg/kg every week. The other two dose groups (0.16 mg/kg every week and 0.32 mg/kg every other week) also showed numerical improvements in the MADRS score. Nevertheless, the PoC results demonstrate that the initial response to compound I (24 hours after the first dose) and the outcome of repeated dosing (6-week outcome) were similar, suggesting that the initial response may have longer-term consequences. In the PoC study, the maximum improvement in the MADRS score in the active treatment group was already observed after the first dose. There was no further accumulation of the effect after subsequent doses. This suggests that, surprisingly, a single dose is sufficient to estimate the maximum drug effect.

Rationale for selection of control drug (comparator/placebo) or combination drug

The use of a double-blind placebo arm for the Compound I arm is intended to provide a comparison group for unbiased collection of efficacy, safety, and tolerability data. Based on the high degree of placebo response in depressive disorder trials, placebo is necessary to assess the efficacy of investigational drugs (Kirsch I (2019) Placebo Effect in the Treatment of Depression and Anxiety. Front Psychiatry; 10:407).

Purpose and timing of interim analysis

An interim analysis for internal modeling purposes will be conducted after approximately 28 participants have completed the study on Day 29 (or discontinued before Day 29). The purpose of this interim analysis will be separate from the study objectives. This interim analysis for internal modeling purposes will be conducted by an unblinded pharmacological panel. The unblinded results of the interim analysis for internal modeling purposes will not be communicated to the blinded study team.

Additional interim analyses may be performed at any time during the study to support decision-making related to the current clinical study, the sponsor's clinical development plan, or if any new safety concerns arise.

Research group

Approximately 56 participants with TRD will be randomized in a 1:1:1:1 ratio to receive compound I: 1 mg, 4 mg, or 10 mg or placebo in addition to standard pharmacological antidepressant SoC treatment at a total of 20 to 25 sites worldwide.

TRD is defined based on a retrospective assessment of antidepressant treatment failure according to treatment history as specified in the inclusion criteria below.

Investigators must ensure that all participants considered for the study meet the following eligibility criteria. To ensure that the study population is representative of all eligible subjects, no additional criteria should be applied by the investigator.

Participant selection should be established by careful examination of all eligibility criteria at screening and relevant eligibility criteria at baseline. Relevant records of eligibility criteria (e.g., checklists) should be maintained at the study site with source documentation.

Any deviation from the entry criteria will exclude patients from study enrollment.

Inclusion criteria

Participants eligible for inclusion in this study must meet all of the following criteria:

1. A signed informed consent form must be obtained prior to participating in the study.

2. Male and female participants aged 18 to 65 years (inclusive) at screening.

3. Participants have a diagnosis of recurrent MDD as defined by DSM-5 criteria at screening and a current major depressive episode of at least 8 weeks duration as confirmed by both the MINI and an appropriate clinical psychiatric assessment.

4. MADRS ≥ 24 at screening and before randomization on day 1.

5. Failure to respond to two or more but not more than five antidepressant treatments, where the two failed treatments are two different antidepressants, at least one of which was used in the current depressive episode at an appropriate dose and duration (≥ 6 weeks duration, dose defined by agent) as identified by the MGH-Antidepressant Treatment Response Questionnaire based on patient report and prior psychiatric history, assessed by the investigator, and further documented in the medical record. Patients with a history of treatment failure with esketamine, ketamine, or arketamine are excluded.

6. Participants must agree to receive standard pharmacological care for MDD (as determined by the treating physician(s) based on clinical judgment and local treatment guidelines) for the duration of the study.

7. If the participant is taking any other type of psychotropic medication, the dose of these medications needs to be stable, where a stable dose of psychotropic medication is defined as no change in the dose or type of, for example, antipsychotics or mood stabilizers (if applicable) for at least 6 weeks prior to baseline.

8. Antidepressants must be at a stable dose for at least 4 weeks prior to baseline. No new antidepressants were initiated within 6 weeks prior to baseline. No psychotherapy was initiated within 4 weeks prior to baseline.

9. Able to communicate smoothly and understand and comply with research requirements.

Exclusion criteria

Participants who meet any of the following criteria are ineligible for inclusion in this study:

1. Participants with a current acute depressive episode lasting more than 2 years, or who have received electroconvulsive therapy (ECT), vagal brain stimulation (VNS), or deep brain stimulation (DBS) within the past year prior to screening.

2. Any previous or current diagnosis of MDD, bipolar disorder, schizophrenia, or schizoaffective disorder with psychotic features as assessed at screening from the M.I.N.I, Module C (Manic and Hypomanic Episodes) and Module K (Psychotic Disorders and Mood Disorders with Psychotic Features).

3. Participants with acute alcohol or substance use disorder or withdrawal symptoms requiring addiction treatment as determined by the SCID-5 at screening, or participants who had received treatment (inpatient or outpatient) for addiction treatment within 1 month prior to screening.

4. Participants with current borderline personality disorder or antisocial personality disorder assessed at screening, based on DSM-5 criteria and investigator judgment.

5. Current clinical diagnosis of autism, dementia, or intellectual disability.

6. Participants with a history of suicide attempt or suicidal behavior within the past year prior to screening and participants with suicidal ideation with intent, as documented by a yes response to Q4 or Q5 on the C-SSRS at screening or baseline.

7. Participants with evidence of significant renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) of <40 mL/min/1.73 m2 at screening.

8. Use of other investigational drugs at screening or within 30 days or 5 half-lives after screening, whichever is longer.

9. History of hypersensitivity to any study treatment or excipients or drugs with a similar mechanism of action (i.e., drugs affecting NMDA receptors).

10. Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID-19 infection based on medical history and/or available medical records.

11. History of seizures. Note: Childhood febrile seizures are not excluded.

12. Abnormalities of the heart or cardiac repolarization, including any of the following:

· History of myocardial infarction, angina pectoris, or coronary artery bypass grafting within 6 months prior to starting study treatment

· History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, or high-grade atrioventricular (AV) block (e.g., double-fiber bundle block, Mobitz type II, and third-degree AV block).

13. Resting QTcF ≥450 msec (men) or ≥460 msec (women) at screening or baseline.

14. Risk factors for torsades de pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of heart failure, or history of clinically significant/symptomatic bradycardia, or any of the following:

· Long QT syndrome, family history of idiopathic sudden cardiac death or congenital long QT syndrome

· Concurrent medication(s) with a “known TdP risk” that cannot be discontinued or replaced by a safer alternative medication

15. Participants had a mean systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg at screening or before the first dose on Day 1; or a history of hypertensive crisis.

16. History of hemorrhagic stroke or known cerebrovascular disease (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease elsewhere (e.g., aorta).

17. Pregnancy (including a positive human chorionic gonadotropin [hCG] test) or lactation at screening or baseline.

18. Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant, unless they are using highly effective contraception during treatment and for 1 week after discontinuation of the investigational drug. Highly effective contraception includes:

· Complete abstinence from heterosexual intercourse (if this is preferred by the subject and is consistent with their usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation) and withdrawal are not acceptable methods of contraception.

· Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to taking the investigational drug. In the case of oophorectomy alone, only if the woman's reproductive status is confirmed by follow-up hormone level assessment.

· Male sterilization (at least 6 months prior to screening). For female participants in the study, the male partner who had a vasectomy must be the participant’s only partner.

· Use of an intrauterine device (IUD) or intrauterine system (IUS) If an IUD or IUS is used, the device or system must be in place for at least 3 months prior to receiving study treatment and be well tolerated by the patient.

Oral (estrogen and progesterone), injectable or implantable hormonal contraceptives, and other forms of hormonal contraception are not approved for contraception.

Where local regulations deviate from the contraceptive methods listed above and require more extensive measures to prevent pregnancy, local regulations will apply and will be described in the ICF.

Women were considered postmenopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or had undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to treatment with Compound I. If they had undergone oophorectomy alone, they were considered not of childbearing potential only if their reproductive status was confirmed by follow-up hormone level assessments. If they had undergone oophorectomy alone, they were considered not of childbearing potential only if their reproductive status was confirmed by follow-up hormone level assessments.

19. Sexually active males who do not intend to use condoms during sexual intercourse while taking the investigational drug and for 1 week after stopping the study treatment. Condoms are required for all sexually active male participants to prevent conception and to prevent the investigational drug from being transmitted to their partner through semen. In addition, male participants should not donate sperm during the above-mentioned period.

20. Participants taking medications prohibited by the protocol (see Table 3-4)

21. Any other medical condition that, in the opinion of the investigator, would jeopardize the safety of the participant, affect compliance, or make the patient an unsuitable candidate for the study (e.g., known liver disease/impaired liver function, active malignancy, etc.).

General: If safety laboratory assessments at screening and/or baseline are outside the ranges specified above, the assessments may be repeated once before randomization. If the repeat values remain outside the ranges specified, the participant will be excluded from the study.

Research treatment

Study treatment will consist of Compound I or placebo. Compound I 20 mg will be supplied centrally as a lyophilized powder in vials (pharmaceutical form).

Compound I 20 mg will be reconstituted with water for injection to obtain an injectable solution for all Compound I doses. Placebo will consist of 0.9% sodium chloride infusion bags supplied by the site.

The s.c. injection of study treatment (day 1) must be administered while the participant is on site.

Details on storage and management requirements for study treatment, and guidelines to follow for participant numbering, prescribing/dispensing, and administration of study treatment are outlined in the Pharmacy Manual.

Clinical trial and control drugs

[Table 3-2] Clinical trial and control drugs

The investigational treatment for this study was Compound I. Because of manufacturing differences between Compound I and placebo, blinding will need to be maintained by unblinded, qualified site personnel independent of the clinical trial staff.

Additional research treatment

Treatments other than the investigational drug, the control drug (placebo), and standard antidepressant pharmacological care were not included in this trial.

In the study, standard-of-care pharmacological treatment consisted of antidepressants or combinations of antidepressants with other medications used to improve depressive disorder. Antidepressants used as background treatment during the study are recommended to be FDA-approved for the MDD indication (see Table 3-3 below).

[Table 3-3] Antidepressants recommended for use as background treatment during the study

* Table taken from FDA-approved medications to treat major depressive disorder (MDD). 2021

Treatment Arm/Arm

Participants will be randomly assigned in a 1:1:1:1 ratio to one of four treatment arms on day 1:

· Single dose of compound I 1 mg, 1 sc injection

· Single dose of compound I 4 mg, 1 sc injection

· Single dose of compound I 10 mg, 1 sc injection

· Placebo, single dose of 1 sc injection

Duration of treatment

Participants will receive a single s.c. injection on day 1.

combination therapy

All medications, procedures, and significant non-pharmacological treatments (including physical therapy and blood transfusions, and SARS-CoV-2 vaccines) administered to participants after enrollment in the study must be recorded on the Concomitant Medications/Significant Non-Pharmacological Treatments CRF.

The investigator should instruct the participant to inform the study site of any new medications that the participant takes after enrollment in the study. All medications, procedures, and significant non-pharmacological treatments administered to the participant after enrollment in the study should be recorded. The start and stop dates and times of each medication should be recorded as accurately as possible.

Each concomitant medication should be individually evaluated against all exclusion criteria/prohibited medications.

All permitted concomitant baseline psychotropic medications used to treat depression must be documented as standard of care (SoC) and remain unchanged throughout the study. Any changes in SoC (dose change or start of new medication) after randomization must be documented in the medical record and reported in the eCRF.

Certain benzodiazepines, specifically lorazepam or alprazolam (as authorized by country), will be permitted for episodic or chronic use. They should not be taken within 12 hours before or within 4 hours after the dose, unless they are used as rescue medications, not exceeding 2 mg in a 24-hour period. Such use of lorazepam or alprazolam will be documented as concomitant medication(s), and the time of administration should be documented in the medical record and reported in the eCRF.

Any vaccine should not be administered within 2 days prior to randomization.

For participants taking strong CYP2D6 inhibitors (e.g., berberine, bupropion, dacomitinib, fluoxetine, paroxetine, quinidine), the immediate post-s.c. administration period should be monitored with a temporary warning. All safety observations should be carefully monitored for increased or unexpected frequency and severity.

Based on nonclinical information, compound I is predicted to be eliminated predominantly by oxidative metabolism via CYP2D6 (64% clearance). Inhibition of this elimination pathway could result in increased exposure to compound I. The following investigations were conducted to evaluate potential drug-drug interactions for the major elimination pathway via CYP2D6:

· The influence of strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine and bupropion) on the exposure of iv injected Compound I was investigated in drug-drug interaction (DDI) simulations by SimCYP ^® software. Simulated Cmax values were up to 1.3-fold higher in the presence of fluoxetine or paroxetine, and AUC values were up to 2-fold higher for all CYP2D6 genotypes (poor, extensive or very poor). The mean exposure values obtained in the presence of strong CYP2D6 inhibitors are within the exposure range investigated in the FIH study after iv infusion (doses: 0.016, 0.048, 0.16, 0.24, 0.32 and 0.48 mg/kg). For the strong CYP2D6 inhibitor bupropion, no drug-drug interaction was assumed. In the sc SAD study with HV, after sc administration of the highest dose (12 mg), the exploratory mean AUClast and Cmax values were 257 h*ng/mL and 77.4 ng/mL, respectively, which are comparable to the exposure values after iv infusion of 0.16 mg/kg compound I in the FIH study. As discussed above, the mean exposure values after sc administration of the highest dose (10 mg) in this study are within the exposure range investigated in the FIH study in the presence of strong CYP2D6 inhibitors.

· In addition, in the PoC study, Compound I doses (0.16 and 0.32 mg/kg), approximately 70% of participants received at least one CYP2D6 inhibitor (a weak to strong CYP2D6 inhibitor or a combination of these). The Cmax values at both doses and the AUC values at 0.16 mg/kg did not exceed the exposure range determined in the FIH study.

Based on overall clinical experience, the overall safety data suggest that compound I is generally safe and well tolerated, and that adverse events observed are transient. For the proposed compound I doses of 10 mg or less, the risk of overdose or unexpected AEs due to increased exposure by CYP2D6 inhibition is considered low. In conclusion, CYP2D6 inhibitors are acceptable as concomitant medications. Nevertheless, caution should be exercised when administering strong CYP2D6 inhibitors.

Based on preclinical information, compound I may affect the elimination of compounds that are predominantly eliminated via CYP3A4 and CYP2D6. The influence of compound I on the exposure of midazolam (a CYP3A4 substrate) and desipramine (a CYP2D6 substrate) was investigated in drug-drug interaction (DDI) simulations by SimCYP ^® software. No increase in exposure of either probe substrate was estimated at the highest compound I dose tested of 0.48 mg/kg after iv infusion. Therefore, at sc doses of ≤ 10 mg compound I, the risk of overdosage or unexpected adverse events of co-administered sensitive CYP3A4 and CYP2D6 substrates is considered not significant.

Prohibited drugs

The use of the treatments listed in the table below is not permitted at the time points listed. This list of medications is not exhaustive. Each medication should be evaluated for its potential additive effect(s) of sedation, dissociation, suicidality, cardiovascular and respiratory effects, as well as its effects on memory and cognitive function. Medications with potential effects should be avoided for at least 1 half-life of the medication prior to each study visit and for 1 half-life after each study drug administration.

[Table 3-4] Prohibited drugs or treatments

Rescue medicine

Rescue medication will not be supplied by the client.

The following relief medications may be considered and should be documented in the medical record and eCRF:

For agitation and restlessness or aggressive behavior (as judged by the investigator or local clinical practice): as needed, midazolam (maximum dose of 2.5 mg orally or intramuscularly), any short-acting benzodiazepine (e.g., lorazepam), or antipsychotics (e.g., quetiapine, olanzapine, promethazine, or dipiperone).

Prohibited medications (see Table 3-4) may be administered as rescue medications whenever clinically justified.

Handling of research treatments and other treatments

Prescription and Dosage Guidelines for Research Treatment

Study participants will receive one of the following study treatments as a single s.c. injection: Compound I (1 mg, 4 mg, 10 mg) or placebo.

The study treatment will be administered as a single s.c. injection in the supraumbilical (i.e., cephalad) abdominal area, but not within 5 cm of the umbilicus. The injection should not be administered in sites with scars, inflammation, proliferative skin diseases (including nevi), tattoos, burns, or other skin abnormalities. The injection should be administered by trained staff with appropriate technique, taking into account the participant’s body type (e.g., thickness of local subcutaneous tissue). For lean participants, the use of the skin-fold technique is recommended. The injection will be administered slowly (over 15 to 30 seconds). Caution should be taken not to administer the study treatment as an intramuscular injection, as this may alter the PK and consequently the safety and efficacy profile of Compound I.

Study treatment (compound I or placebo) will be assigned by the IRT and recorded in the IRT system.

Each study site will be supplied with a kit of the clinical trial treatment (Compound I).

Efficacy Evaluation

Handling of efficacy assessments by independent field evaluators

The primary efficacy endpoint of Compound I compared to placebo is assessed based on the MADRS scale, SIGMA version.

Administration of Compound I is associated with a number of transient adverse events, including sedation, dissociative symptoms, memory lapses/amnesia, and cardiovascular events. To minimize the risk of introducing bias, efficacy and safety assessments will be performed by trained and qualified site personnel. The independent site assessors performing the MADRS, CGI-I, and CGI-C will be different from the assessors assessing vital signs, adverse events, ECG results, MOAA/S, CADSS, and C-SSRS. The independent site assessors for MADRS, CGI-I, and CGI-C will not be permitted to access or review participant safety records and, therefore, will not be permitted to provide clinical care to participants. Clinical care of participants will be conducted by the investigator or a designee at the study site, and not by the MADRS, CGI-I, and CGI-C assessors.

Whenever possible, every effort should be made to use the same independent rater for the MADRS, CGI-S, and CGI-I at each site to assess the same participants throughout the study. If this is not possible, review of appropriate pre-assessments and communication with the pre-assessor should be performed as needed. Any clinically relevant safety findings from the scales or interviews should be communicated to the investigator.

During the study, the roles of the investigators and independent field evaluators, including backups, are not interchangeable across participating sites.

Montgomery-Osberg Depressive Disorder Rating Scale (MADRS), SIGMA version

The Montgomery-Asberg Depression Rating Scale (MADRS, SIGMA version) is a clinician-rated scale designed to measure the severity of depressive disorders and to detect changes due to antidepressant treatment: the test consists of 10 items, each of which is scored from 0 (absent or normal) to 6 (severe or persistent symptoms), for a total score of 60. Higher scores indicate more severe symptoms. The MADRS assesses overt sadness, reported sadness, internal tension, sleep, appetite, concentration, listlessness, interest levels, pessimistic thoughts, and suicidal ideation (Khan A, Khan SR, Shankles EB, et al (2002) Relative sensitivity of the Montgomery-Asberg Depression Rating Scale, the Hamilton Depression rating scale and the Clinical Global Impressions rating scale in antidepressant clinical trials. Int Clin Psychopharmacol p. 281-5). The test has shown high inter-rater reliability. In this study, the following recall periods will be used: “last 7 days with baseline,” “over the past 4 hours,” “last 7 days,” and “since last assessment” for the primary endpoint. Whenever possible, the MADRS should be administered to the same participants by the same rater throughout the study.

The MADRS is a standardized scale used in registry studies of depressive disorders. It is relatively quick to administer, does not focus predominantly on the somatic symptoms of depressive disorders, but rather addresses core mood symptoms such as sadness, tension, listlessness, pessimistic thinking, and suicidal ideation. The MADRS is sensitive to changes in treatment effects over time, and is considered the gold standard registry scale for depression.

Additional evaluation

Clinical Outcome Assessment (COA)

During public health emergencies declared by local or regional authorities that restrict or prohibit field study visits, i.e., pandemics, endemics, or natural disasters, COA data may be collected remotely.

Clinical Research Outcomes Report (ClinRO)

ClinRO will be used to establish a diagnosis of depression and to assess and document the patient's treatment history at screening. It will also be used to measure the effect of Compound I on suicidality and disease severity with the following tools:

· M.I.N.I.

· SCID-5

· MGH-ATRQ

· C-SSRS

· CGI (CGI-S and CGI-I)

Mini International Neuropsychiatric Interview (M.I.N.I.), version 7.0.2

The M.I.N.I. is a brief structured clinical interview for major psychiatric disorders in the DSM-5 and ICD-10. It is divided into diagnostic modules that contain screening questions corresponding to criteria for each disorder, allowing the physician to assess whether diagnostic criteria have been met.

The full M.I.N.I. version will be provided on-site. The M.I.N.I. will be administered on-site by qualified personnel at the time of screening.

Module A (Major Depressive Episode), Module B (Suicidality), Module C (Manic and Hypomanic Episodes), Module K (Psychotic Disorders and Mood Disorders with Psychotic Features), Module I (Alcohol Use Disorders), Module J (Substance Use Disorders, Non-Alcohol), Module P (Antisocial Personality Disorder), and Module Y (Borderline Personality Disorder) should be used for eligibility purposes as defined in the Eligibility Criteria. Other modules should be used as needed. The results of the interview should be added to the source records to confirm eligibility criteria.

Structured Clinical Interview for DSM-5 (SCID-5)

The SCID-5 is a semi-structured interview guide for DSM-5 disorders. It is administered by qualified personnel familiar with the DSM-5 classification and diagnostic criteria. The version used in this test is the SCID-5-Clinical Trial Version (SCID-5-CT). It guides the clinician step-by-step through the DSM-5 diagnostic process and enables the assessment of whether diagnostic criteria have been met. The interview questions are provided with their corresponding DSM-5 criteria to assist in assessing the presence or absence of each criterion. The SCID-5-CT covers the most commonly encountered DSM-5 diagnoses in clinical settings.

SCID-5-CT will be performed only at screening.

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

The MGH-ATRQ examines the adequacy of the duration and dose of previous and current antidepressant treatment in a stepwise manner (Chandler 2010). When assessing the duration and dose of antidepressants, investigators should always inquire about the level of compliance with each treatment. In addition, the MGH-ATRQ assesses the degree of improvement on the scale from 0% (no improvement at all) to 100% (completely improved).

The MGH-ATRQ will be administered at screening. Treatments with a response of “less than 25% improvement” will be considered failed treatments. All current and previous treatments (both failed and successful) used in the episode for each participant should be listed on the MGH-ATRQ and entered on the corresponding CRF page. All treatments listed on the MGH-ATRQ and ongoing at screening should also be entered on the concomitant medication CRF page.

Columbia University Suicide Severity Rating Scale (C-SSRS)

The CSSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal behavior. In this study, the following recall periods will be used: “1 month/1 year” and “since last assessment.”

Clinical Global Impression (CGI)

The CGI is a three-item observer-rated scale that measures symptom severity, treatment response, and treatment efficacy in studies of the treatment of patients with mental disorders (Guy (1976) ECDEU assessment manual for psychopharmacology (Internet)). The CGI provides an overall clinician-determined summary measure that takes into account all available information, including the patient's history, psychosocial situation, symptoms, behavior, and knowledge of the impact of symptoms on the patient's ability to function. The CGI is assessed by an experienced clinician who is familiar with the disorder under study and the likely course of the treatment. The CGI is assessed without regard to the clinician's belief that any clinical change is due to the medication or not and without considering the cause of the symptoms.

Two items will be used for the study: the CGI-S to assess disease severity, and the CGI-I to assess change from treatment initiation. The following recall periods will be used for the CGI-S: “past 4 hours,” “last 7 days,” and “since last assessment.” The CGI-S and CGI-I will be administered electronically/on paper by qualified field personnel.

Patient-Reported Outcomes (PRO)

Participant impressions of the impact of Compound I on disease severity will be assessed by PGIC.

Participant refusal to complete all or any part of the PRO measure should be documented in the study data capture system and should not be considered a protocol deviation. Participant questionnaires should be written in the language most familiar to the participant. Participants should be provided with sufficient space and time to complete the PRO measure(s). Participants should be aware that the completed measure(s) will not be reviewed by the investigator/study staff.

Patient Global Impression of Change (PGIC)

The PGIC scale aims 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 includes a number of scores that demonstrate optimal patient preference, discrimination ability, and test-retest ability, tailored to specific conditions and disease parameters.

Digital Health Technologies (selected countries)

The Cambridge Automated Neuropsychological Test Battery (CANTAB) assessments (i.e., cognitive tests and affective bias tasks) will be administered on-site, on tablets provided by the vendor, using pre-installed applications. Testing will be conducted on-site, where equipment and trained personnel are available. Assessments will be administered during the following study visits: Screening (training only), predose on Day 1, Day 2 (24 hours postdose), Days 8, 15, 22, and 29. Site staff will be required to complete training provided by the vendor prior to administering the tests to participants. For more information, refer to the training materials provided by the vendor. The tablets will be returned at the end of the study.

The test battery will consist of the Digit Symbol Substitution Task (DSST) and the Emotion Bias Task (EBT) and will take approximately 6-7 minutes to complete.

The DSST is a global measure of cognitive ability that requires the effective completion of multiple cognitive domains. It measures attention and processing speed. The task presents the participant with a set of abstract symbols related to numbers. When a specific number is highlighted on the screen, the participant must draw the corresponding abstract symbol using the index finger on the touchscreen. The participant is instructed to complete as many symbols as possible within 90 seconds. Outcome measures include total correct, incorrect, and latency (movement latency and reaction latency).

The EBT is an assessment that measures whether people can recognize facial emotions in others. Participants are asked to view images of faces that are altered between happy and sad emotions of varying intensity. They are then asked to indicate whether they perceive the faces on the screen to be happy or sad. Many of the faces may appear ambiguous, meaning that participants must choose which emotion they perceive to be among those presented on the screen. The task will take approximately 4 minutes to complete and will follow a generally consistent format, with a very brief presentation of the face on the screen, followed by a screen with a 'sad' or 'happy' button that can be used to select a response. No feedback will be provided regarding response decisions. The primary outcome measure for the EBT is the bias score (the proportion of trials in which happy is selected compared to the alternative emotion, scaled from 0 to 10). This is used to determine the degree and direction of the participant's cognitive bias in recognizing facial emotions (happy or sad). In addition, measures of latency and measures of the number of times each emotion is selected are also available.

Pharmacokinetics

Pharmacokinetic (PK) samples will be collected at -1 h, 0 h (treatment), 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 4 h, and 24 h. Plasma concentrations of compound I will be determined by a validated LC-MS/MS method. The lower limit of quantification (LLOQ) of compound I in plasma is considered to be 0.1 ng/mL. Concentrations below the LLOQ will be reported as “0” and missing data will be labeled as such in the bioanalytical data report. Samples collected from placebo-treated participants will not be measured. The following pharmacokinetic parameters of compound I will be determined using actual recorded sampling times and non-compartmental method(s) using Phoenix WinNonlin (version 8 or later): Primary PK parameters: AUClast, Tmax, and Cmax; Secondary PK Parameters: Where data permit, additional PK parameters will be estimated, e.g., T1/2, area under the curve from time 0 to infinity (AUCinf), AUC0-t (if necessary, time range to be defined during PK analysis), CL/F, Vz/F (data are not limited). The linear trapezoidal rule will be used to calculate AUC. The regression analysis of the final elimination step for potential determination of T1/2 will include at least 3 data points after Cmax. If the R ² value of the regression analysis of the final step is less than 0.75, the PK parameters resulting from the estimation of the final elimination step (e.g., CL/F, Vz/F, AUCinf) will not be reported.

Biomarker

The purpose of the genetic studies may be to better understand the safety and efficacy of compound I, learn more about human diseases, or help develop methods to detect, monitor, and treat diseases. Nonclinical information suggests that compound I is predominantly eliminated by oxidative metabolism via the polymorphic enzyme CY2D6. CYP2D6 genotype status supports understanding of PK and its potential variability at a given dose. Knowledge of CYP2D6 genotype may be used to better understand exposure-response analyses. In the future, patients may be selected or excluded based on CYP2D6 genotype status. Blood samples will be collected from consenting patients to assess CYP2D6 and other polymorphisms.

Other evaluations

Local tolerability at the injection site will be assessed by clinical assessment of the following parameters by the investigator or a delegated person: erythema/redness, induration/swelling, ecchymosis/bruising, and pain. The presence of erythema, induration, and ecchymosis will be assessed visually. If any of these abnormalities are greater than 2.5 cm in size, the exact size of the lesion should also be measured. Lesion size will be estimated and recorded as the largest diameter of the best-fitting oval shape. Lesions will be graded and recorded in the eCRF as described below: mild lesion: 2.5–5 cm, moderate lesion: 5.1–10 cm, severe lesion: >10 cm.

Harmful incident

An adverse event (AE) is any untoward medical occurrence (e.g., any undesirable and unintended sign [including abnormal laboratory results], symptom, or disease) that occurs in a clinical trial participant after giving written informed consent to participate in the study. Thus, an AE may or may not be temporally or causally related to the use of the medicinal (investigational) product. The occurrence of an AE should be sought by non-directive questioning of the participant at each visit during the study. An adverse event may also be detected when the participant volunteers during or between visits, or through physical examination results, laboratory test results, or other assessments.

AEs should be documented under the relevant signs, symptoms, or diagnoses, along with the following information (to the extent possible): Severity ratings are as follows: Mild: Usually transient in nature and does not usually interfere with normal activities; Moderate: Sufficiently uncomfortable to interfere with normal activities; Severe: Inhibits normal activities.

Pre-existing medical conditions at the time of informed consent should be recorded in the participant's medical history. Adverse events (including laboratory abnormalities constituting AEs) should be described using diagnoses whenever possible, rather than individual underlying signs and symptoms. Adverse event monitoring should continue for at least 30 days after the last dose of study treatment. Once an adverse event is detected, it should be followed until it has resolved or is judged to be permanent (e.g., continuing until the end of the study) and assessed at each visit (or more frequently if necessary) for any change in severity, suspected relationship to interventions required for treatment, and outcome.

An abnormal laboratory value or test result constitutes an adverse event only if it meets at least one of the following criteria: causes clinical signs or symptoms, is considered clinically significant, and requires treatment. Clinically significant abnormal laboratory values or test results should be identified by review of values that are outside the normal range/clinically important range, a significant change from baseline or a previous visit, or values that are considered atypical in participants with an underlying medical condition. Alert ranges for laboratory and other test abnormalities are included in Tables 3-5.

[Table 3-5] Clinically Important Values for Vital Signs

Dissociation refers to a lack of connection between oneself and one's environment. It is not the same as "psychosis", which refers to fixed false beliefs (delusions) or false sensory experiences (hallucinations), but can be compared to the normal cognitive process of dreaming (being disconnected from one's own body and the real world). Déjà vu and déjà antoine are classic dissociative experiences. The two main forms of dissociation are depersonalization and derealization. In depersonalization, one feels disconnected from oneself, while in derealization, one feels disconnected from the world. This experience is often described as a feeling of unreality, as if there were a film between oneself and one's experience of the world. Dissociation is not the same as hallucination, since there is no false sensory experience (e.g. hearing voices that do not exist). Rather, normal sensory experiences occur as if there is some disconnection between the observer and the experienced object, not quite normal. In extreme cases, depersonalization can involve the feeling that one is not oneself, or perhaps that multiple selves can be identified within oneself. Harry can affect cognitive processes. Memories are not false, but they are remembered as if they were not completely real. In severe cases, actual events can be forgotten.

Amnesia is the loss of memory. Dissociative amnesia means that something is not remembered because of dissociation, that is, a lack of connection between oneself and the world. All other types of amnesia occur in the absence of dissociation. In assessing dissociative AEs or cognitive AEs of interest (e.g., amnesia or sedation), those AEs of particular interest will be described in detail in writing in the original document by the participant and the investigator. The terms reported should be as specific as possible to the participant's experience. The investigator will carefully record the time of onset and resolution of these AEs. Safety measures should be administered hourly for the first 4 hours after the onset of the event, more frequently than every hour.

To ensure participant safety and improve reliability in determining the hepatotoxic potential of an investigational drug, a standardized process for the identification, monitoring, and evaluation of hepatic events should be followed. Liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP, and G-GT) should be used to determine hepatotoxic potential.

Once participants are exposed to study treatment, the following 2 categories of abnormal renal laboratory alert values must be assessed during the study period: increase in serum creatinine ≥ 25% from baseline while normohydrated; any of the following: urine protein-creatinine ratio (PCR) ≥ 1 g/g or ≥ 100 mg/mmol, or new-onset dipstick proteinuria ≥ 3+, or new-onset dipstick hematuria ≥ 3+ (after excluding menstruation, urinary tract infection (UTI), strenuous exercise, or trauma). Abnormal renal event results must be confirmed within 24 to 48 hours of the first evaluation.

Claims (64)

A method for treating a depressive disorder in a subject, e.g., a patient, in need of treatment for a depressive disorder, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating a depressive disorder in a subject, e.g., a patient, in need of treatment for a depressive disorder, comprising a therapeutically effective amount of compound I,

A method comprising the step of subcutaneously administering to a subject, e.g., a patient, a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. A method for reducing at least one depressive symptom in a subject, e.g., a patient, suffering from a depressive disorder, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating major depressive disorder in a subject, e.g., a patient, in need thereof, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method according to claim 4, wherein the major depressive disorder is acute. A method of treating major depressive disorder in a subject, e.g., a patient, in need thereof, wherein the subject, e.g., the patient, meets DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), said method comprising administering a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating treatment-resistant depression in a subject, e.g., a patient, in need of treatment for treatment-resistant depression, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating depressive symptoms of major depressive disorder in a subject, e.g., a patient, in need thereof, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating a major depressive episode in a subject, e.g., a patient, in need of treatment for a major depressive episode, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for preventing a major depressive episode in a subject in need thereof, for example a patient, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method for treating recurrent major depressive disorder and a current major depressive episode in a subject, e.g., a patient, in need thereof, comprising a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method according to any one of claims 9 to 11, wherein the major depressive episode lasts for at least 4 weeks, for example at least 6 weeks, for example at least 8 weeks. A method according to any one of claims 9 to 12, wherein the major depressive episode lasts at least 8 weeks but not longer than 24 months. A method of treating major depressive disorder in a subject, e.g., a patient, in need thereof, wherein the subject, e.g., the patient, has failed to respond to at least two antidepressant treatments, at least one of which is used to treat a current major depressive episode, said method comprising administering to the subject a therapeutically effective amount of compound I,

Or a method comprising the step of subcutaneously administering a salt thereof acceptable to a subject, for example a patient. A method in claim 14, wherein at least two antidepressant treatments are two different antidepressant treatments. A method according to any one of claims 1 to 15, wherein the treatment further comprises administering to the subject, e.g., the patient, one or more additional therapeutic agents. A method according to any one of claims 1 to 16, wherein the treatment further comprises administering to the subject, e.g., the patient, one or more pharmacological standard-of-care treatments. A method according to any one of claims 1 to 17, wherein the subject, e.g., the patient, is treatment resistant. A method according to any one of claims 1 to 18, wherein the subject, e.g., the patient, is partially resistant. A method according to any one of claims 1 to 19, wherein the subject, eg, the patient, fails to adequately respond to at least one antidepressant treatment. A method according to any one of claims 1 to 20, wherein the subject, e.g., the patient, has failed to adequately respond to at least two antidepressant treatments. A method according to any one of claims 1 to 21, wherein the subject, for example, the patient, is at risk of suicide. A method according to any one of claims 16 to 22, wherein the one or more additional therapeutic agents or standard care treatments comprises an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, or a combination thereof. A method according to any one of claims 16 to 23, wherein the one or more additional therapeutic agents or standard care treatments are one or more additional antidepressants. A method according to any one of claims 16 to 24, wherein at least one of the one or more additional therapeutic agents or standard care treatments is an oral antidepressant. A method according to any one of claims 23 to 25, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium, for example lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone. A method for treating treatment-resistant depression in an adult patient in need of treatment for treatment-resistant depression, comprising a therapeutically effective amount of compound I,

Or a method comprising subcutaneously administering to a subject, e.g., a patient, at least one oral antidepressant together with a salt thereof that is pharmaceutically acceptable. A method according to any one of claims 14 to 27, 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 (RIMA)), and multimodal antidepressants. 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. A method according to any one of claims 16 to 29, wherein the subject, eg, the patient, continues treatment with one or more additional therapeutic agents or standard of care treatments following treatment with compound I, or a pharmaceutically acceptable salt thereof. A method according to any one of claims 1 to 30, comprising the following steps:
(a) determining or having determined the baseline MADRS score of the subject, e.g., the patient; and
(b) subcutaneously administering to the subject, e.g., the patient, a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, wherein the amount of compound I, or a pharmaceutically acceptable salt thereof, improves the MADRS score by at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% compared to a measured baseline MADRS score, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of compound I, or a pharmaceutically acceptable salt thereof. A method in claim 31, wherein the subject, e.g., the patient, is evaluated at regular intervals after step (b) to determine relative effectiveness, wherein the evaluation comprises measuring the MADRS score of the subject, e.g., the patient. A method according to any one of claims 1 to 32, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 0.1 mg to 15 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 33, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dosage of 0.1 mg to 1 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 34, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 0.3 mg to 1 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 35, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 0.5 mg to 1 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 36, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 1 mg to 5 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 37, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 1 mg to 10 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 38, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 1 mg to 15 mg, wherein the dosage refers to the free base of compound I. A method according to any one of claims 1 to 39, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dosage 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 dosage amount refers to the free base of compound I. A method according to any one of claims 1 to 40, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered in a dose of 1 mg, 4 mg, or 10 mg, wherein the dosage amount refers to the free base of compound I. A method according to any one of claims 1 to 41, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once a week. A method according to any one of claims 1 to 42, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, twice a week. A method according to any one of claims 1 to 43, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once every two weeks. A method according to any one of claims 1 to 44, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, once every three weeks. A method according to any one of claims 1 to 45, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., a patient, a) once a month; or b) once every six weeks. A method according to any one of claims 1 to 46, 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. A method according to any one of claims 1 to 47, wherein the depressive disorder is selected from major depressive disorder, treatment-resistant depression, suicidality of 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 of major depressive disorder, and seasonal affective disorder. In claim 48, the depressive disorder is major depressive disorder, method. A method according to claim 49, wherein the major depressive disorder is acute. A method according to claim 48, wherein the depressive disorder is treatment-resistant depression. In claim 51, the method comprises treatment-resistant depression including partial resistance. A method according to any one of claims 1 to 52, wherein the score improves compared to baseline on one or more depression assessment instruments selected from the group consisting of the Montgomery-Osberg Depression Rating Scale (MADRS), the Mini-International Neuropsychiatric Interview (M.I.N.I.), e.g., version 7.0.2, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicidality Severity Rating Scale (C-SSRS), and the Clinical Global Impression (CGI). A method according to any one of claims 1 to 53, wherein the subject, e.g., the 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. A method according to any one of claims 1 to 54, further comprising determining or having determined a MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, e.g., 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, thereby assessing the efficacy of the treatment, wherein the baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 55, wherein the subject, e.g., the patient, has a decreased MADRS total score after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a decreased MADRS total score about 24 hours, about 7 days, about 14 days, about 21 days, and/or about 28 days after subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 56, wherein the subject, e.g., the patient, has a greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50% improvement in MADRS total score following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the patient, has a greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50% improvement in 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, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof. The method of any one of claims 1 to 57, wherein the subject, e.g., the patient, has a MADRS total score of less than 12 following subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof, as compared to a baseline assessment, for example, the subject, e.g., the 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, wherein baseline is the MADRS total score for the subject, e.g., the patient, prior to subcutaneous administration of Compound I, or a pharmaceutically acceptable salt thereof. A method according to any one of claims 1 to 58, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered subcutaneously to the upper arm or abdominal area. A method according to any one of claims 1 to 59, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered as a subcutaneous injection. A method according to any one of claims 1 to 60, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered as a single subcutaneous injection. A method according to any one of claims 1 to 61, wherein compound I, or a pharmaceutically acceptable salt thereof, is administered as a free base. A method according to any one of claims 1 to 62, wherein compound I, or a pharmaceutically acceptable salt thereof, is formulated for delivery from a subcutaneous injection device. A method according to any one of claims 1 to 63, wherein compound I, or a pharmaceutically acceptable salt thereof, is formulated for delivery from a subcutaneous injection device as a single subcutaneous injection.