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.

Field of the Disclosure

The present disclosure relates to treatments for major depressive disorder (MDD), including treatment resistant depression. The disclosure further relates to a subcutaneous dosage and/or regimen of Compound (I), or a pharmaceutically acceptable salt thereof, for the treatment of a depression 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 combinations of any of the foregoing). Several embodiments pertain to a subcutaneous dosage 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 receptor including, but not limited to, depression 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, and/or combinations of any of the foregoing). Several embodiments relate to the use of Compound (I), or a pharmaceutically acceptable salt thereof, in the treatment of treatment resistant depression in patients with major depressive disorder.

Background of the Disclosure

Depression is a serious and life-threatening condition with high rates of morbidity and a chronic disease course. It is a common illness worldwide, with more than 264 million people affected (WHO (2020) World Health Organization: Depression (Depression. Key facts) (Internet) Available from: https://crediblemeds.org/). When long-lasting and with moderate or severe intensity, depression causes the affected person to suffer greatly, impairing the ability to work, self-care, and maintain relationships.

Despite a broad availability of antidepressant medication, about a third of patients suffering from major depressive disorder (MDD) fail to respond fully to antidepressant treatment of adequate duration and dose, and the majority fail to maintain long-term response to standard antidepressants (Rush AJ, Trivedi MH, Wisniewski SR, et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry; 163(11): 1905 -17). This chronicity of symptoms predisposes patients to treatment resistance. Treatment-resistant depression (TRD) is defined as a lack of clinically meaningful improvement after treatment with at least two different antidepressant agents prescribed in adequate dosages for adequate durations.

Patients suffering from TRD are very likely to have suicidal ideation and experience a disproportionate burden of illness causing significant impairment and increased morbidity (Shelton RC, Osuntokun 0, Heinloth AN, et al (2010) Therapeutic options for treatment resistant depression. CNS Drugs; 24(2): 131-61).

Therefore, there is a large unmet medical need for rapid-acting antidepressants that are either more effective or better tolerated, treatments that can effectively interrupt a depressive episode and are able to prevent future depressive episodes.

Summary of the Disclosure

Ketamine, which is a N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective in TRD in off-label research, but is limited by psychotomimetic side effects. Further, ketamine has been shown to be rapid-acting and reduce suicidality. The efficacy of ketamine provides the 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 for MDD with acute suicidal ideation or behavior by the Food and Drug Administration (FDA) and for moderate to severe episode of MDD as acute short-term treatment in conjunction with an oral antidepressant for the rapid reduction of symptoms which according to clinical judgement constitute a psychiatric emergency by the European Medicines Agency (EMA]). While both ketamine and SPRAVATO® have demonstrated a certain level of efficacy and shown rapid mode of action, their safety profiles are not without adverse effects, meaningful both for patients and clinicians.

Targeting a specific subset of NMDA receptors is one approach to potentially mitigate adverse effects of NMDA receptor inhibition while retaining the antidepressant efficacy. The infusion of traxoprodil, a negative allosteric modulator selective for the NR2B subtype of NMDA receptors, also known as CP-101,606, is efficacious in TRD patients with the magnitude and duration of response comparable to those of ketamine with 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 TRD patients and was generally safe.

Conventional pharmacotherapies for major depressive disorder (MDD) include antidepressants that belong 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, and after failing, may attempt another of these therapies only to fail again, and thus are termed “treatment-resistant”. The rationale of presenting a new dosage regimen for a given drug is that the development of such dosage regimen needs to balance patient compliance, therapeutic efficacy and side effects of said drug; a goal not easily attained, hence requiring substantial skills.

Therefore, there is a large unmet medical need for rapid-acting antidepressants that are either more effective or better tolerated, treatments that can effectively interrupt a depressive episode and are able to prevent future depressive episodes.

In several embodiments, provided herein are novel methods for treating a depressive disorder. In several embodiments, the depressive disorder is a major depressive disorder. In several embodiments, the depressive disorder is treatment resistant depression. In several embodiments, the depressive disorder is one where a potentially rapid acting antidepressant effect can be beneficial (including but not limited to, for example, a major depressive disorder, treatment resistant depression, or other depressive disorders disclosed herein). In several embodiments, a rapid response is meaningful in those suffering from treatment resistant depression, which includes a population that failed to respond to conventional antidepressants used for adequate duration of time and at adequate dose. Depression disorder often leads to suicidal thoughts or behavior, putting patients at risk. Additionally, even where conventional antidepressants would work eventually, conventional antidepressant treatment might take a few weeks to achieve treatment benefit. There is thus a need for rapid acting, safe antidepressant treatments. Several embodiments disclosed herein solve the above or other problems disclosed herein. Compound (I), or a compound of formula (I), as used herein, is 6-((lS)-2-((3aR, 5R, 6a.S')-5-('2 -fluorophenoxy) hexahydrocyclopenta[c]pyrrol-2(117)-yl)-l- hydroxyethyl)pyridin-3-ol, of the following formula: having the INN name onfasprodil. Onfasprodil is a NR2B-NMDA receptor non-allosteric modulator (NAM), which can be prepared as described in WO2016/049165, which is incorporated herein by reference in its entirety.

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 is intended to allow patients to rapidly achieve a significant antidepressant effect, especially in patients having treatment resistant depression.

Several embodiments disclosed herein provide methods for treating a depressive disorder, in particular, major depressive disorder, especially treatment resistant depression, using Compound (I) and/or novel formulations comprising Compound (I). In several embodiments, advantageously, Compound (I) is provided in a form that is fast-acting and has a rapid onset of activity in a patient. In several embodiments, the methods for treating a depressive disorder (e.g., a major depressive disorder, treatment resistant depression, etc.) have increased efficacy where Compound (I), provided as a rapid acting formulation (e.g., a subcutaneous formulation). A rapid response (such as achieved using Compound (I) as disclosed herein) is meaningful in treatment of resistant depression, even in a population that failed to respond to conventional antidepressants used for adequate duration of time and at adequate dose. In several embodiments, as disclosed herein, the compositions of Compound (I) disclosed herein are effective in treating a depressive disorder (e.g., major depressive disorder, treatment resistant depression, etc.) in a population that failed to respond to conventional antidepressants used for adequate duration of time and at adequate dose. In several embodiments, an adequate duration of time is one in which the conventional antidepressant would have been expected to have reached full efficacy in a patient.

Thus, there remains a need for achieving a rapid antidepressant effect, as patients with major depression are at risk of suicide or self-harm, while conventional antidepressant drugs might take several weeks to reach efficacy.

Moreover, patients having major depressive disorder with suicidality, often require 4-5 days of hospitalization. Compound (I), having rapid onset of efficacy, can reduce the number of days a patient is hospitalized (or eliminate hospitalization altogether) and therefore provide a benefit over other antidepressants that take at least 4 weeks for a patient to respond to treatment. In several embodiments, treatment using Compound (I), as disclosed herein, reduces hospitalization periods by equal to or at least about: 1 day, 2 days, 3 days, 4 days, 5 days, or ranges including and/or spanning the aforementioned values. For example, in several embodiments, treatment using Compound (I), as disclosed herein, reduces hospitalization periods 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 several embodiments, treatment using Compound (I) allows patients to rapidly achieve a significant improvement of their depressive symptoms, and suicidality.

The disclosure is also aimed at alleviating one or more depressive symptoms in patients with major depressive disorder, particularly, treatment resistant depression. The disclosure is based in part, in treating major depressive disorder in a patient in need of adjunctive therapy for major depressive disorder, particularly treatment resistant depression.

The disclosure is also aimed at alleviating one or more depressive symptoms in patients with suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. In several embodiments, the disclosure overcomes these shortcomings by providing a subcutaneous dosage of Compound (I).

In a first aspect, there is provided a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously to the subject, e.g., patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof. In a second aspect, there is provided a method of treating depression disorder, in a subject, e.g. , patient, in need thereof, the method comprising administering subcutaneously to the subject, e.g., 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, there is provided a method of reducing at least one depressive symptom in a subject, e.g., patient, suffering from depression disorder, the method comprising administering subcutaneously to the subject, e.g., patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

In other aspects of the disclosure, the methods comprise adjunctive treatment with one or more antidepressants, comprising administering a therapeutically effective amount of the one or more antidepressants to a subject, e.g., patient, in need thereof. The one or more antidepressants can include, for example, at least one member of lithium, a conventional antidepressant, a herbal antidepressant, a mood stabilizer, an antipsychotic agent, and a benzodiazepine.

The one or more antidepressants can include, for example, 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 (RIMAs)), multimodal antidepressants, or combinations thereof.

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

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

Brief Description of the Drawings

Figure 1 depicts the periods in 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 either with vehicle (negative control), Compound (I) (at 1, 3, 10, and 30 mg/kg) or ketamine (at 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 rat locomotor activity after treatment by subcutaneous injection either with vehicle (negative control), Compound (I) (at 1, 3, 10, and 30 mg/kg) or ketamine (at 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 by subcutaneous injection either with vehicle (negative control) or Compound (I) (at 0.1, 0.3, and 1 mg/kg). Data are presented as mean ± SEM (N=10). Data were analyzed by One-Way ANOVA.

Detailed Description of the Disclosure

Several embodiments disclosed herein pertain to a subcutaneous dosage 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-NMDA receptor. In several embodiments, the disease or disorder mediated by negative allosteric modulation or inhibition of NR2B-NMDA receptor is a depression disorder. In several embodiments, the disclosure 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). Further diseases or disorders mediated by negative allosteric modulation or inhibition of NR2B-NMDA receptor, for which the subcutaneous dosage of the disclosure may also be useful, include 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 selfharm in major depressive disorder, seasonal affective disorder. Several embodiments disclosed herein pertain to methods of treating depression disorder, in a subject, e.g., patient, in need thereof. In several embodiments, the method comprises administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient, in need thereof. In several embodiments, the depression disorder is major depressive disorder. In several embodiments, the major depressive disorder is treatment resistant depression. Several embodiments pertain to the use of Compound (I), or a pharmaceutically acceptable salt thereof, in the treatment of treatment resistant depression in patients with major depressive disorder.

Disorders (DSM-V) of the American Psychiatric Association provide a diagnostic tool for the identification of the disorders described herein. The person skilled in the art will recognize that alternative nomenclatures, nosology, and classification systems for psychiatric disorders described herein exist, and that these evolve with medical and scientific progresses.

Definitions

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Features disclosed under one heading (such as a composition) can be used in combination with features disclosed under a different heading (e.g, methods of treatment). Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated.

Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; 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 “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps but may 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. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those 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 having skill 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. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

When referring to various features, the terms “or ranges including and/or spanning the aforementioned values” may be used. These terms (and variations thereof) are meant to include any range that includes or spans any of the aforementioned values. For example, with regard to % improvement in mood, the % may be expressed as “equal to or at least about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.” This language includes not only the particular % provided and the range exceeding that value (e.g., equal to or at least about 1%, equal to or at least about 5%, equal to or at least about 10%, and equal to or at least about 20%) but also the % ranges spanning those values (e.g., from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, and 10% to 20%). Similarly, with regard to the % improvement in mood, the % may be expressed as “equal to or less than about: 1%, 5%, 10%, 20%, or ranges including and/or spanning the aforementioned values.” This language includes not only the particular % provided and the range below that value (e.g., equal to or less than about 1%, equal to or less than about 5%, equal to or less than about 10%, and equal to or less than about 20%) but also the % ranges spanning those values (e.g., from 1% to 20%, 1% to 10%, 1% to 5%, 5% to 20%, 5% to 10%, and 10% to 20%). Compound (I), a compound of formula (I), formula (I), as used herein, is 6-((lS)-2-((3a7?,57?,6aS)-5- (2 -fluorophenoxy )hexahydrocyclopenta[c]pyrrol-2(l/Z)-yl)-l-hydroxyethyl)pyri din-3-ol, of the following formula: and having the INN name onfasprodil. Onfasprodil is a highly potent, selective and reversible low molecular weight negative allosteric modulator (NAM) targeting the NR2B sub-unit of the N-methyl-D- aspartate receptors (NMDARs). Evidence suggests that the NR2B-selective negative allosteric modulators (NAMs) MK-0657 (also known as CERC-301) and CP-101,606 have low frequencies of dissociative adverse events. Although, the relative contribution of each individual subtype of NMDARs to the adverse effects of pan-NMDAR inhibition is poorly understood due to the lack of selective inhibitors for the various subtypes, taken together, this suggests that achieving safe, yet rapid-onset antidepressant efficacy is feasible with a compound selectively inhibiting NR2B -containing NMDA receptor.

As used herein, the terms “salt”, “salts” or “salt form” refers to an acid addition or base addition salt of a respective compound, e.g. , the compounds specified herein (e.g. , Compound (I) or further pharmaceutical active ingredient, for example, as defined herein). “Salts” include in particular “pharmaceutically acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds and, which typically are not biologically or otherwise undesirable. The compounds, as specified herein (e.g., Compound (I) or further pharmaceutical active ingredient, for example, as defined herein), may be capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The compound of the disclosure is capable of forming acid addition salts, 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 acids and organic acids.

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

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 and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, 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, secondaiy, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

Pharmaceutically acceptable salts can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of the compound with a stoichiometric amount of the appropriate base (such as 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 the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 22 ^nd edition, Mack Publishing Company (2013); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2 ^nd edition).

Some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. In embodiment, the term “about”, refers to a range of values ± 10% of a specified value.

As used herein, the term “adjunct therapy”, also known as adjunctive treatment, adjunctive therapy, add-on therapy, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy. In an embodiment, the primary or initial therapy in the context of the present disclosure is an antidepressant therapy, e.g., as disclosed herein. There are also non-pharmacologic treatments, such as psychotherapy and transcranial magnetic stimulation, that are also available and options for adjunctive therapy.

As used herein, unless otherwise noted, the term “antidepressant”, “antidepressant therapy”, “conventional antidepressant”, and the like, shall mean any pharmaceutical agent, which can be used to treat depression. Antidepressant, antidepressant therapy, or conventional antidepressant also includes those listed under the List of Antidepressant Medications, in the MGH Antidepressant Treatment Response Questionnaire (ATRQ), which is incorporated herein by reference in its entirety. In certain instances, antidepressant therapy can be augmented with antipsychotic drugs. Suitable examples include, without limitation, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants; natural products such as Kava- Kava, St. John’s Wort, and the like; dietary supplements such as S-adenosylmethionine, and the like; neuropeptides such as thyrotropin-releasing hormone and the like; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like; and hormones such as triiodothyronine, and the like. 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®), des venlafaxine (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 isocarboxazid, (e.g., Marplan®), phenelzine (e.g., Nardil®), tranylcypromine (e.g., Parnate®) and selegiline (e.g., Eldepryl®, Emsam®). Examples of reversible inhibitors of monoamine oxidase include moclobemide. (e.g., Aurorix®), pirlindole (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., Adapm®, Sinequan®, Quitaxon®, Aponal®), imipramine (e.g., Tofranil®), trimipramine (e.g., Surmontil®), amoxapine (e.g., Asendin®), desipramine (e g., Norpramin®), maprotiline (e.g., Ludiomil®), nortriptyline (e.g., Pamelor®), protriptyline (e.g., Vivactil®).®), pipofezine (e.g., Azafen®), noxiptiline (e.g., Agedal®, Elronon®). 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 an embodiment, the “antidepressant”, “antidepressant therapy”, “conventional antidepressant” is FDA approved for the treatment of MDD.

The term “antipsychotic” includes, but is not limited to:

(a) typical or traditional antipsychotics, such as phenothiazines (e.g, chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixo), butyrophenones (e.g, haloperidol), 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” isselected 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 effective dosage levels and dosage regimens for the antidepressant (for example, 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), may be readily determined by one of ordinary skill in the art. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician’s Desk Reference (Medical Economics Company or online at http://Zwww.pdrel.com) or other sources.

The term “AUClasf ’, as used herein, refers to the area under the plasma concentration -time curve from time zero to time of last measurable concentration. “Time zero” in a general context refers to the time of subcutaneous injection of the intended dose.

Except where otherwise indicated herein, the term “baseline” or “baseline assessment” herein means a time immediately prior to initiation of treatment with Compound I, or a pharmaceutically acceptable salt thereof.

The terms “combination therapy”, “concomitant”, and “concomitant administration” shall mean treatment of a patient in need thereof by administering Compound (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agent(s), e.g., as adjunctive therapy, wherein the additional therapeutic agent(s) are administered by any suitable means. The agents may be administered simultaneously, or sequentially in any order during the entire or portions of the treatment period. The terms “combination therapy”, “concomitant”, and “concomitant administration” also encompass adjunct therapy, as defined herein. The terms “combination therapy”, “concomitant”, and “concomitant administration”, also encompass treatment with Compound (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents, such as a standard of care medicament prescribed for a psychiatric disorder, e.g. , depression disorder, e.g., as defined herein. In an embodiment, Compound (I) is administered in a regimen with one to five additional therapeutic agent(s) (e.g., 1, 2, 3, 4, or 5 additional therapeutic agents). In another embodiment, Compound (I) is administered in a regimen with one, two, three, four, or five additional therapeutic agent(s). In another embodiment, Compound (I) is administered in a regimen with one or two additional therapeutic agent(s). In another embodiment, Compound (I) is administered in a regimen with one other therapeutic agent. In a further embodiment, Compound (I) is administered in a regimen with the additional therapeutic agent(s) currently being administered to the patient, including current antidepressant(s) to which the patient had an inadequate response. In yet a further embodiment, Compound (I) is administered in a regimen with one or more additional therapeutics agent not previously administered to the patient. In still other embodiments, Compound (I) is administered in a regimen with one or more additional therapeutic agents previously administered to the patient. Where Compound (I) and the additional therapeutic agent(s) are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different and more typically different. The additional therapeutic agent(s) may be dosed as prescribed by the attending physician and/or by its label and Compound (I) is dosed as described herein. Typically, a patient is under concurrent treatment with both an antidepressant and Compound (I), where both are administered by their prescribed dosing regimens. The Compound (I) and antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms. In an embodiment, 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 a particular embodiment, the one or more additional therapeutic agent(s) is one or more antidepressants.

The term “depressive episode” or “major depressive episode”, as used herein, refers to the characteristics of a major depressive disorder, as defined herein.

A “major depressive episode” may be defined as at least two weeks of depressed mood or loss of interest, which may be accompanied by other symptoms of depression, in particular, symptoms of a major depressive disorder sufficient to meet criteria for major depression as specified in the Diagnostic and Statistical Manual of Mental Disorders. 5 ^th Edition: DSM 5. The symptoms must persist for most of the day (i.e., for at least two thirds of the patients' waking hours), nearly every day (i.e., for at least ten out of fourteen days) for at least two consecutive weeks. A “depressed mood” is often described by the patient as 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 by the patient as feeling less interested in hobbies or not feeling any enjoyment in activities that were previously considered to be pleasurable.

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

As used herein, the term “Cmax” shall refer to the observed maximum plasma concentration assayed after any administration, e.g , single or repeated administration. In some embodiments the method disclosed herein further comprises measuring plasma levels in the patient.

The term “depression disorder”, as used herein, means a clinical disorder that includes a predominantly sad or depressed mood and is accompanied by psychological and/or physical symptoms. The depression disorder may be mild depression disorder, moderate depression disorder, severe depression disorder, clinical depression disorder or postpartum depression disorder. Exemplary depression disorders include, but are not limited to, major depressive disorder, including 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 self-harm in major depressive disorder, persistent depressive disorder, seasonal affective disorder, perinatal depression, e.g., postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, mid-life depression, late-life depression, depression due to identifiable stressors, treatment resistant depression, partially resistant depression, and combinations thereof, each of which are contemplated to be treated using the methods and compositions described herein. There exist a number of methods and techniques well known to those skilled in the art for diagnosing depression disorder, for assessing the status or severity of such conditions or symptoms thereof over time, and for monitoring the change in status or severity of such conditions or symptoms thereof over time, including in response to treatment or therapy. In an embodiment, the depression disorder is major depressive disorder. In a further embodiment, the depression disorder is treatment resistant depression. In another embodiment, the depression disorder is seasonal affective disorder.

The term “depressive symptom ”, as used herein, refers to one or more symptoms associated with depression disorder, in particular, major depressive disorder, which include persistent anxious or sad feelings, feelings of 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 appetite loss, difficulty thinking, concentrating or making decisions, thoughts of suicide, and suicide attempts. The presence, number, severity, frequency, and duration of these symptoms may vary from individual to individual and from time to time for a given individual. Depressive symptoms can manifest in depression disorders, e.g., major depressive disorder.

The terms “drug”, “active substance”, “active ingredient”, “pharmaceutically active ingredient”, “active agent” or “therapeutic agent” are to be understood as meaning a compound in free form or in the form of a pharmaceutically acceptable salt, in particular 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 because of inadequate efficacy, e.g., if the patient indicated that their current symptoms had little to no improvement. The previous or current antidepressant treatment has been used for adequate duration of time and at adequate dose, e.g. , a therapeutically effective dose. For example, the previous or current antidepressant treatment has been used for a duration of at least 4 weeks, e.g., at least 6 weeks. In several embodiments, a patient that failed to respond to a medication is one that was treated with that medication for a period of equal to or at least about: 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or ranges including and/or spanning the aforementioned values. The inadequate response can be assessed by a clinician skilled in treating the disease in question.

“Inadequate response” as used herein refers to a patient experiencing a less than about 50% reduction in depressive symptom severity from the start of initiating treatment. Typically, the inadequate response is during a current/active episode of the depression. In some embodiments, an inadequate response refers to a patient experiencing about 26 to less than about 50% reduction in depressive symptom severity from the start of initiating treatment. In other embodiments, an inadequate response refers to a patient experiencing 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% reduction in depressive symptom severity from the start of initiating treatment. In some embodiments, the inadequate response refers to a patient experiencing a reduction of 25% or less in depressive symptom severity from the start of initiating treatment, a reduction of 10% or less in depressive symptom severity from the start of initiating treatment, a reduction of 5% or in depressive symptom severity from the start of initiating treatment, a reduction of 0% in depressive symptom severity from the start of initiating treatment. A patient's response may be measured by one or more scales described herein and/or by physician/clinical judgment. In some embodiments, an inadequate response is measured by MGH-ATRQ, MADRS, or SHAPS. In further embodiments, an inadequate response is measured by MGH-ATRQ.

As used herein, the term “major depressive disorder”, or MDD, is defined, for example, with reference to 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 as 1) a psychiatric disorder meeting five or more of the following symptoms that have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (i) depressed mood or (ii) loss of interest or pleasure: i) depressed/sad mood; ii) loss of interest and pleasure; iii) significant weight loss when not dieting or weight gain or a decrease or increase in appetite; iv) insomnia or hypersomnia; v) psychomotor agitation or retardation; vi) fatigue or loss of energy; vii) feelings of worthlessness or excessive or inappropriate guilt; viii) diminished ability to think or concentrate or indecisiveness; ix) recurrent thoughts of death or suicidal ideation, planning or attempt; 2) the symptoms cause clinically significant distress or impairment in social, occupational or other functioning; 3) the episode is not better accounted for by a psychotic disorder; 4) the episode is not attributable to the physiological effects of a substance or to another medical condition; 5) there has never been a manic or hypomanic episode (Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition, American Psychiatric Association, 2013). The tables vide infra further define the criteria for Major Depressive Episodes/Disorders:

In principle, the term major depressive disorder, as used according to the present disclosure may refer to an acute major depressive disorder or to a chronic major depressive disorder. In a particular embodiment, the major depressive disorder is acute major depressive disorder.

The term “medications with a known risk of Torsades de Pointes” refers to any medication that can prolong the QT interval and cause Torsades de Pointes. Examples of drugs known to cause Torsades de Pointes are listed in www.qtdrugs.org.

As used herein, the term “non-responder” or “non-responsive” means a patient that does not experience a clinically meaningful improvement after treatment (e.g., a 50% or less change from baseline for a given depression assessment test, a 25% or less change from baseline for a given depression assessment test, a 10% or less change from baseline for a given depression assessment test, a 5% or less change from baseline for a given depression assessment test, a 0% change from baseline for a given depression assessment test (or ranges including and/or spanning the aforementioned values), or an improvement that is not statistically significant. In several embodiments, the depression assessment test is the MADRS. In several embodiments, the depression assessment test is the MGH-ATRQ. In several embodiments, the depression assessment test is the Hamilton Depression Scale (HAM-D). In several embodiments, the depression assessment test is the clinical global impression - severity scale (CGI-S). To the extent the patient is said to have a partial response to treatment, this refers to some minor to moderate symptomatic improvement since the initiation of treatment, but some of the initial symptoms are still present and troubling to the patient and these persistent symptoms still affect behavior and function. For instance, the patient's motivation, productivity, and interest in his or her usual activities may still be impaired. In one embodiment, the patient is better than at baseline but continues to be symptomatic, such that further antidepressant treatment is required. In another embodiment, the patient experiences <50% but >25% decrease from baseline depression scale scores, including, for example, but not limited to MADRS, MGH-ATRQ, HAM-D, CGI-S.

As used herein, the term “patient” refers to a subject, who is diseased and would benefit from the treatment. In an embodiment, the subject, e.g., patient, has major depression disorder. Mild depression disorder, moderate depression disorder and severe or major depression disorder can be characterized according to the total score of depressive symptom severity of the Montgomery-Asberg Depression disorder Rating Scale (MADRS). For example, the patient has measured MADRS with a score of 24 or more 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) and a current major depressive episode of at least 4 weeks, e.g, at least 6 weeks, e.g.. at least 8 weeks, in duration as defined by Diagnostic and Statistical Manual of Mental Disorders, Firth Edition (DSM-5) criteria and confirmed by both SCID-5 and adequate clinical psychiatric evaluation. In a particular embodiment of the disclosure, the patient is in need of adjunctive therapy for treatment resistant depression. In a particular embodiment, the patient is an adult. The term “adult” as used herein refers to a human that is about 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 to be administered to a subject, e.g, patient, in order to treat a particular condition (i.e. disease, disorder or condition or at least one of the clinical symptoms thereof) affecting the subject, e.g., patient.

As used herein, the term “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington’s Pharmaceutical Sciences, 22 ^nd Ed. Mack Printing Company, 2013, pp. 1049-1070). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

As used herein, “pregnancy” is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

The term “preparatory behavior”, as used herein, means acts or preparation toward making a suicide attempt, but before potential for harm has begun. This can include anything beyond a verbalization or thought, such as assembling a method (e.g., buying a gun, collecting pills) or preparing for one’s death by suicide (e.g., writing a suicide note, giving things away).

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 assisting people to modify their behaviors, cognitions, emotions, and/or other personal characteristics in directions that the participants deem desirable.

The term “self-harm”, as used herein, means willful self-inflicting of painful, destructive, or injurious acts without intent to die.

As used herein, the term “standard of care treatment” refers to a physician-prescribed treatment for a patient suffering from a psychiatric disorder, for example, a major depressive disorder, including, but not limited to, patients with suicidality and/or suicidal ideation, that have been assessed to be at imminent risk of suicide.

Typically, the standard of care treatment is provided as prescribed by the treating physician or other health care profession and is concomitant with the Compound (I) treatment, e.g., standard of care treatment is provided during the same treatment period as the Compound (I) treatment. The standard of care treatment may also precede treatment with Compound (I) and may continue after treatment with Compound (I) is discontinued. With respect to antidepressants used in the standard of care treatment, the Compound (I) and the antidepressant(s) may be administered via the same or different routes of administration.

A “subject” or “individual” are used interchangeably and refer to either a human or non-human animal. The term includes mammals such as humans. In some embodiments, the subject is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. 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 of suffering from, or potentially capable of suffering from a disease described herein. In some embodiments, the subject is a human suffering from, at risk of suffering from, or potentially capable of suffering from a disease described herein. In some embodiments, the subject is a patient, i.e., a subject suffering from or at risk of suffering from a disease described herein or a subject in need of a treatment for a disease described herein. In some embodiments, the patient is a human suffering from a depression 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 self-directed injurious behavior with any intent to die as a result of the behavior.

The term “suicidality”, as used herein, refers to thoughts of suicide (suicidal ideation) and suicide, suicide attempts and preparatory acts (suicidal behavior).

The term “suicide attempt”, as used herein, means a nonfatal self-directed potentially injurious behavior with any intent to die as a result of the behavior. A suicide attempt may or may not result in injury.

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

The term “suicidal ideation”, as used herein, refers to passive thoughts about wanting to be dead or active thoughts about killing oneself, not accompanied by preparatory behavior. Suicidal ideation refers to thinking about or planning suicide. Thoughts can range from creating a detailed plan to having a fleeting consideration but does not include the final act of suicide. Passive suicidal ideation is when there are thoughts of suicide or self-harm but no plan to carry it out. Active suicidal ideation is when there are thoughts of suicide or self-harm, and there is a plan to carry it out.

The terms “suicidal ideation with intent” or “suicidal ideation with suicidal intent”, as used herein, refers to the passive thoughts about wanting to be dead or active thoughts about killing oneself with the desire, aim, purpose, or goal for a self-destructive act to end 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 one of a number of standardized questionnaires, clinical instruments, or symptom inventories utilized to measure severity of suicidal ideation. Such suicidal ideation symptoms rating scales include, but are not limited to, Scale for Suicidal Ideation (SSI), the Suicide Status Form (SSF), Sheehan Suicidal Tracking Scale (S-STS) or the Columbia Suicide Severity Rating Scale (C-SSRS).

The term “suicidal ideation with no intent”, as used herein, refers to the passive thoughts about wanting to be dead or active thoughts about killing oneself, but with no intention to do so.

The term “stable dose”, as used herein, refers as no changes in dose or type of agent.

The term “treat” “treating” “treatment” or “therapy”, as used herein, means obtaining beneficial or desired results, for example, clinical results. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms in patients with major depressive disorder or treatment resistant depression, as defined herein, such as. One aspect of the treatment is, for example, that said treatment should have a minimal adverse effect on the patient, e.g. the agent used should have a high level of safety, for example without producing the side effects of previously known treatment regimens. The term “alleviation”, for example in reference to a symptom of a condition, as used herein, refers to reducing at least one of the frequency and amplitude of a symptom of a condition in a patient.

As used herein, the term “treating depression disorder” can refer to a reduction of the symptoms of a depression disorder, such as major depressive disorder, for example, as measured by reduction in the Montgomery-Asberg Depression disorder Rating Scale (MADRS) score. In some aspects, the term “treating depression disorder” refers to a change from baseline, as measured by the MADRS score. In some aspects, the term “treating depression disorder” refers to a remission, as measured by reduction in the MADRS score. In some aspects, the term “treating depression disorder” refers to a 50% or greater improvement, for example, as measured the MADRS score. In some aspects, treating depression disorder, such as MDD, refers to a reduction of at least 50% in MDD severity on a standardized rating scale, such as those disclosed herein, e.g., MADRS. The term depression disorder, in particular, refers to major depressive disorder, e.g., treatment resistant depression. While the MADRS scale is often used herein as a scale for measuring depression, the term “treating depression disorder” can also (or alternatively) refer to an improved score in any measure of depression disclosed herein (e.g., Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, Mini International Neuropsychiatric Interview, Cambridge Automated Neuropsychological Test Battery, Digit Symbol Substitution Task, Emotional Bias Task, etc.). In several embodiments, an improvement may be an increased score where the scale provides higher scores for improvements in depression measures. Alternatively, in several embodiments, an improvement of score may be a decreased score where the scale provides higher scores for enhanced 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 where the patient has not responded (e.g. , has failed to respond or has achieved a partial response) to adequate doses of at least one antidepressant, in particular, at least two different antidepressants, in particular, two antidepressants but not more than five in the current depressive episode. In other embodiments, TRD is defined as major depressive disorder in a patient hat has not responded to at least two oral antidepressants of adequate dose and duration, e.g., at least 6 weeks duration, in the current depressive episode. For example, the treatment resistant depression may be a depression disorder that is resistant or non-responsive to one or more antidepressants, for example, as described herein, such as 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. The classes of antidepressants listed above are not exhaustive. Treatment resistant depression can be assessed by the Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), which is a self-rated scale used to determine treatment resistance in major depressive disorder.

One skilled in the art will recognize that the 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 antidepressant is determined prospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined prospectively. In another embodiment, at least one of the failures to respond to an adequate course of antidepressant is determined retrospectively. In another embodiment, at least two of the failures to respond to an adequate course of antidepressant are determined retrospectively in a current depressive episode.

The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject that is being sought by a medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated. In some embodiments of the present disclosure, the therapeutically effective amount of Compound (I) is between about 0.1 mg and about 15 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 0.1 mg and about 1 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 0.3 mg and about 1 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 0.5 mg and about 1 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 1 mg and about 5 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 1 mg and about 10 mg. In other embodiments, the therapeutically effective amount of Compound (I) is between about 1 mg and about 15 mg. In yet other embodiments, the therapeutically effective amount of Compound (I) is about 0.1, 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 yet other embodiments, the therapeutically effective amount of Compound (I) is 1 mg. In yet other embodiments, the therapeutically effective amount of Compound (I) is 4 mg. In yet other embodiments, the therapeutically effective amount of Compound (I) is 10 mg.

As used herein, “women of child-bearing potential” refers to all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking Compound I and for 1 week post last treatment. Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

• Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking Compound I. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.

• Use of an intrauterine device (IUD) or intrauterine system (IUS). In case of use of an IUD or IUS, the device or system should have been placed and be well tolerated by the patient for a minimum of 3 months before taking the study treatment.

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception other forms of hormonal contraception are not allowed for the purpose of contraception.

Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to treatment with Compound I. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.

As used herein, the term “subject, e.g., patient,” refers to a mammalian organism, preferably a human being (male or female). In particular, the subject is a patient.

As used herein, a subject, e.g., patient, is “in need of’ a treatment if such subject, e.g, patient, would benefit biologically, medically or in quality of life from such treatment.

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

Methods of Treating Depression

The present disclosure provides methods of treating major depressive disorder (MDD). The methods generally involve administering subcutaneously a therapeutically effective amount of Compound I to an individual having MDD. In various embodiments, treatment is in conjunction with one or more antidepressant therapies, e.g., one or more oral antidepressants.

In some embodiments, a diagnosis of MDD is confirmed by meeting the 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- Asberg Depression Rating Scale (MADRS) >20, e.g., >21, >22, >23, >24, >25.

Disclosed herein are methods of treating a depressive disorder, e.g., major depressive disorder, in a patient in need thereof comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the patient. The present disclosure is also drawn to methods of treating treatment resistant depression, in a patient in need thereof comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the patient.

The present disclosure is particularly drawn to methods of treating of treatment resistant depression in an adult patient, in need thereof, the method comprising administering subcutaneously to the patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, in conjunction with at least one oral antidepressant.

The present disclosure provides methods of treating depressive symptoms in a subject, e.g., patient, with depression, the method comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient. The present disclosure also provides methods of treating depressive symptoms in a subject, e.g., patient, with major depressive disorder, the method comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient. The present disclosure also provides methods of treating depressive symptoms in a subject, e.g., patient, with major depressive disorder with acute suicidal ideation or behavior, the method comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient. The present disclosure further provides methods of treating depressive symptoms in a subject, e.g., patient, with treatment resistant depression the method comprising administering subcutaneously Compound I, or a pharmaceutically acceptable salt thereof, to the subject, e.g, patient.

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

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

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

In some embodiments, the subject, e.g., 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. losifescu, 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., patient, is characterized as having sub-optimal response to at least one antidepressant treatment. For example, the subject has <50% response to at least one antidepressant treatment (>8 weeks at an adequate and stable dose for at least 4 weeks) per the MGH-ATRQ. In some embodiments, the subject, e.g., patient, has a single episode major depressive disorder. In some embodiments, the subject, e.g., patient, has recurrent major depressive disorder. In some embodiments, the subject, e.g., patient, has chronic major depressive disorder. In some embodiments, the subject, e.g., 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 in the current depressive episode has not responded adequately to at least two different antidepressants of adequate dose and duration. Typically, the methods disclosed herein further comprise administering to the subject, e.g., patient, one or more additional antidepressant treatments, such as oral antidepressants.

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

In some embodiments, the present disclosure also provides a method of treating a subject, e.g. , patient, who meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), the method comprising administering subcutaneously to the subject, e.g., patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject, e.g., patient, failed >1 and <8 trials in the current episode per the MGH ATRQ and/or has <50% response to current antidepressant treatment (>8 weeks of major depressive episode) at an adequate or effective and stable dose for at least 4 weeks) per the MGH ATRQ. In some embodiments, the subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, is used for an outpatient group of depressed subjects, e.g., patients, who are considered treatment resistant. The methods disclosed herein advantageously eliminate the necessity of patient presentation to a hospital or clinic for subcutaneous administration. As a result, the subject, e.g., patient, can undergo administration of a composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, at home. In some embodiments, the methods disclosed herein do not require close monitoring of the subject, e.g., patient, in a medically supervised healthcare setting.

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

In various embodiments, this disclosure presents a method of administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g., patient, in need thereof, the method comprising selecting a subject, e.g., patient, who suffers from a depression disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having depression disorder.

In various embodiments, provided herein is a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient, in need thereof. As disclosed elsewhere herein, in several embodiments, the method comprises administering a dose of Compound (I) that is equal to or less than about: 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or ranges including and/or spanning the aforementioned values. For example, in several embodiments, the method comprises administering a dose of Compound (I) ranging from 1 mg to 5 mg, 5 mg to 15 mg, 1 to 12.5 mg, or less than 15 mg. In several embodiments, the subject in need of treatment is a subject having a depression disorder. In various embodiments, provided herein is a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient, in need thereof, the method comprising selecting a subject, e.g., patient, who suffers from depression disorder.

In various embodiments, provided herein is a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having depression disorder.

In a particular embodiment, provided herein is a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising selecting a subject, e.g., patient, who suffers from depression disorder; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, provided herein is a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having depression disorder, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is subcutaneously administered at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 1 mg.

In several embodiments, as disclosed elsewhere herein, the depression disorder is a major depressive disorder. In a particular embodiment, provided herein is a method of treating major depressive disorder, in a subject, e.g., patient, in need thereof, the method comprising selecting a subject, e g., patient, who suffers from major depressive disorder; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In several embodiments, as disclosed elsewhere herein, the depression disorder is a major depressive disorder. In a particular embodiment, provided herein is a method of treating major depressive disorder, in a subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder, the method comprising administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 1 mg, of Compound (I), or a pharmaceutically acceptable salt thereof. In several embodiments, as disclosed elsewhere herein, the depression disorder is treatment resistant depression. In a particular embodiment, provided herein is a method of treating treatment resistant depression, in a subject, e g., patient, in need thereof, the method comprising selecting a subject, e.g., patient, who suffers from treatment resistant depression; and administering subcutaneously between about 0. 1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

In various embodiments, this disclosure presents a method of reducing at least one depressive symptom in a subject, e.g., patient, suffering from depression disorder, the method comprising administering subcutaneously to the subject, e.g., patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having depression disorder. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is subcutaneously administered at a dose of between about 0.1 mg and about 15 mg, e.g. , between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg.

In various embodiments, as disclosed elsewhere herein, the depression disorder is selected from major depressive disorder, treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, or combinations of any of the foregoing. In a particular embodiment, the depression disorder is major depressive disorder. In another particular embodiment, the depression disorder is treatment resistant depression. In an embodiment, major depressive disorder comprises a single major depressive episode. In an embodiment, major depressive disorder comprises a recurrent major depressive episode.

In various embodiments, as disclosed elsewhere herein, the subject, e.g., patient, is suffering from an episode of depression, e.g., major depressive episode, wherein the episode of depression, e.g., major depressive episode, has not responded to treatment with at least one antidepressant, i.e., the subject, e.g. , patient, has not responded to treatment with at least one antidepressant in the current major depressive episode. In an embodiment, the at least one antidepressant is an oral antidepressant. The antidepress ant(s) may be administered to the patient at an adequate dose, which may be determined by the attending physician and/or may be dosed as prescribed by its label. Similarly, the antidepressant has been administered for a suitable duration, e.g., as prescribed by its label. In an embodiment, the antidepressant has been administered for at least four weeks duration, e.g., for at least six weeks duration.

In various embodiments, the subject, e.g. , patient, is suffering from an episode of depression, e.g., major depressive episode, wherein the episode of depression, e.g., major depressive episode, has not responded to treatment with at least two antidepressants, i.e., the subject, e.g. , patient, has not responded to treatment with at least two antidepressants in the current major depressive episode. In an embodiment, at least one of the at least two antidepressants is an oral antidepressant. The antidepressant(s) may be administered to the patient at an adequate dose, which may be determined by the attending physician and/or may be dosed as prescribed by its label. Similarly, the antidepressant has been administered for a suitable duration, e.g., as prescribed by its label. In an embodiment, the antidepressant has been administered for at least four weeks duration, e.g, for at least six weeks duration.

In a particular embodiment, this disclosure presents a method of reducing at least one depressive symptom in a subject, e.g , patient, in need thereof, the method comprising selecting a subject, e.g, patient, who suffers from major depressive disorder; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, this disclosure presents a method of reducing at least one depressive symptom in a subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, this disclosure presents a method of reducing at least one depressive symptom in a subject, e.g , patient, in need thereof, the method comprising selecting a subject, e.g., patient, who suffers from treatment resistant depression; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, this disclosure presents a method of reducing at least one depressive symptom in a subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having treatment resistant depression; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof. In various embodiments, this disclosure presents a method of treating major depressive disorder, e.g., treatment resistant depression, the method comprising administering subcutaneously to a subject, e.g., patient, in need thereof, a therapeutically effective amount, of Compound (I), or a pharmaceutically acceptable salt thereof; wherein the subject, e.g., patient, in need thereof, is having a major depressive episode and wherein the subject, e.g. , patient has not responded to at least one antidepressant in the current major depressive episode.

In various embodiments, this disclosure presents a method for treating a depressive disorder, e.g., major depressive disorder, e.g., treatment resistant depression, in a subject, e.g., patient, in need thereof, the method comprising the steps of:

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

(b) administering subcutaneously to said subject, e.g. , 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 (e.g., decreases) by about at least 30%, e.g., by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60%, by at least about 65%, relative to the measured baseline MADRS score, wherein baseline is the MADRS total score for the subject, e g., patient, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof; and optionally

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

In various embodiments, the methods disclosed herein further comprise the step of evaluating the subject, e.g., patient, at regular intervals, after treatment with Compound (I), or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine need for continued treatment. In an embodiment, the subject, e.g., patient, is evaluated after about 2 weeks, about 4 weeks, about 6 weeks or more than about 6 weeks of treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

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

In various embodiments, this disclosure presents a method of treating treatment resistant depression in a subject, e.g., patient, in need thereof, wherein the patient has not responded to at least one, e.g., at least two, antidepressant in the 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, and thereafter administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to the patient, and optionally, continuing treatment with the first antidepressant. In various embodiments, the method of treatment further comprises the step of determining or having determined the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, e.g. , at 24 hours, 7, 14, 21 and/or 28 days, compared to baseline assessment to thereby assess efficacy of treatment, wherein baseline is the MADRS total score for the subject, e.g , patient, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof.

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

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

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

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

In various embodiments, after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, the subject (e.g. , patient) has an improved score in any measure of depression disclosed herein (e.g. , Massachusetts General Hospital Antidepressant Treatment Response Questionnaire, Mini International Neuropsychiatric Interview, Cambridge Automated Neuropsychological Test Battery, Digit Symbol Substitution Task, Emotional Bias Task, etc.) that is improved (e.g., increased or decreased as the case may be) by equal to or at least about: 25%, 30%, 40%, 50%, 60%, 70%, 80%, 100%, (or ranges spanning and/or including the aforementioned values) compared to baseline assessment. In several embodiments, the score after treatment is assessed at 24 hours, 7 days, 14 days, 21 days, and/or 28 days after initial subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof.

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

In various embodiments, the subject, e.g., patient, is from 18 to 65 years old and has depression 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., patient, does not have an acute depressive episode lasting longer than two years continuously, and has depression 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. , patient, does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, and has depression 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., patient, does not have borderline personality disorder or antisocial personality disorder, and has depression 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., patient, does not have a clinical diagnosis of autism, dementia, or intellectual disability, and has depression 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., patient does not have a history of suicidal attempt or suicidal behavior, and has depression 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., patient, is not pregnant or lactating, and has depression 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., patient, does not have a medical history of active HIV, Covid-19, and Hepatitis B or C infection, and has depression 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., patient, does not have a resting QTcF >450 msec (male) or >460 msec (female), and has depression 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, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.1 mg and about 15 mg.

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

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

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

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

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

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

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 at a dose of about 1 mg.

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

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

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 the free base.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, comprising selecting a subject, e.g. , patient, who suffers from depression disorder; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof. In an embodiment, the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g. , patient, in need of treatment is one who has been diagnosed or is diagnosed as having depression disorder; and wherein Compound (I), or a pharmaceutically acceptable salt thereof, is subcutaneously administered at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg. In an embodiment, the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder.

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

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, in need of treatment is one who suffers from depression disorder and does not have major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder. In an embodiment, the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder. In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, in need of treatment is one who suffers from depression disorder and does not have an acute depressive episode lasting longer than two years continuously. In an embodiment, the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, in need of treatment is one who suffers from depression disorder and does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification. In an embodiment, the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, in need of treatment is one who suffers from depression disorder and does not have a borderline personality disorder or antisocial personality disorder. In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and does not have clinical diagnosis of autism, dementia, or intellectual disability. In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and does not have a history of suicidal attempt or suicidal behavior. In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and is not pregnant or lactating. In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and does not have a medical history of active HIV, Covid-19, and Hepatitis B or C infection. In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder. In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and does not have a resting QTcF >450 msec (male) or >460 msec (female). In an embodiment, the subject, e.g., patient, in need of treatment is one who has been diagnosed or is diagnosed as having major depressive disorder.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and does not have a mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg. In several embodiments, after administration of Compound (I) subcutaneously, the patient’s blood pressure does not rise to a mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, wherein the subject, e.g., patient, suffers from depression disorder, and is not pregnant.

In various embodiments, depression disorder is selected from major depressive disorder, treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, and/or combinations of any of the foregoing. In a particular embodiment, the depression disorder is major depressive disorder. In a further embodiment, the major depressive disorder is treatment resistant depression.

In several embodiments, as disclosed elsewhere herein, the reduction in a depressive symptom and/or a depression disorder using Compound (I), as disclosed anywhere else herein, is measured using any one or more of the testing conditions provided herein (including those provided in the Examples section below). In several embodiments, the reduction in a depressive symptom and/or a depression disorder is measured through self-reporting, the Montgomery-Asberg Depression Rating Scale (MADRS), the Mini International Neuropsychiatric Interview (M.I.N.I.), e.g. , Version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), the Columbia Suicide Severity Rating Scale (C-SSRS), the Clinical Global Impression (CGI), or through any single measure of depression reported in the foregoing scales (e.g. , symptoms). In several embodiments, the reduction in a depressive symptom and/or a depression disorder is a reduction of any of the aforementioned scales, measures (e.g., any one or more measures of, for example, the MADRS scale), or symptoms that is equal to or at least about 50%. In several embodiments, the reduction in a depressive symptom and/or a depression disorder is a reduction (from baseline) of any of the aforementioned scales, measures, or symptoms that is equal to or at least about: a 10% reduction, a 25% reduction, a 30% reduction, a 40% reduction, a 50% reduction, a 60% reduction, a 70% reduction, a 80% reduction, a 90% reduction, a 100% reduction, or ranges including and/or spanning the aforementioned values. In several embodiments, the reduction in a depressive symptom and/or a depression disorder is measured equal to or at least about: 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I). In several embodiments, the reduction in a depressive symptom and/or a depression disorder can be measured as an improvement in score for positive outcomes (improved mood, etc ).

In several embodiments, the CADSS, MOAA/S, and AAESI are used to demonstrate safety of the administration of Compound (I). The 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 ranging from a minimum of 0 to a maximum of 92. The trained staff administering the scale will also note their subjective interpretation of the participant's mental status and overall wellbeing, and whether any findings could be related to study drug. MOAA/S is a scale used to assess participant responsiveness on a scale from 0 (= Does not respond to painful trapezius squeeze) to 5 (= Responds readily to name spoken in normal tone [awake]). Memory gaps/amnesia are AEs of Special Interest (AESI). Memory Assessment using orientation questions are assessed by qualified personnel. In several embodiments, the safety score for the patient pre and post administration changes by less than or equal to about: a 10%, a 20%, a 30%, a 40%, or ranges including and/or spanning the aforementioned values.

In several embodiments, a patient population is selected based on classification of participants into CYP2D6 metabolizer phenotypes and/or CYP3A4 metabolizer phenotypes. In some embodiments, patients on CYP2D6 inhibitors or with decreased CYP2D6 activity are excluded from patient populations. In some embodiments, patients on CYP3A4 inhibitors or with decreased CYP3A4 activity are excluded from patient populations.

In several embodiments, the local tolerability of subcutaneous injection is high (and the injection of Compound (I) results in low occurrences of, low grade lesions, or mild symptoms of the aforementioned measures). In several embodiments, subcutaneous injections of Compound (I) provide mild to moderate or no AEs in patients.

All the aforementioned embodiments and embodiments hereinafter relating to the methods of treatment are equally applicable to:

Compound (I), or a pharmaceutically acceptable salt thereof, for use in the methods of treatment according to the disclosure;

Use of Compound (I), or a pharmaceutically acceptable salt thereof, in the methods of treatment according to the disclosure;

A pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, for use in the methods of treatment according to the disclosure; and

Use of a pharmaceutical composition comprising Compound (I), or a pharmaceutically acceptable salt thereof, in the methods of treatment according to the disclosure.

Administration and Dosage In several embodiments, provided herein are methods for administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof. In the context of the disclosure, the dosing amount 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., patient, as a fixed dose.

In various embodiments, provided herein is a method of administering subcutaneously a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g., 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 Compound (I) or a pharmaceutically acceptable salt thereof, is calculated based on patrient body weight. In various embodiments, 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 and 0.32 mg/kg of patient body weight.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg.

In various embodiments, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g. , patient, in need thereof, at a dose of between about 1 mg and about 15 mg, e.g., between about 1 mg and about 10 mg. In several embodiments, the method comprises administering a subcutaneous dose of Compound (I) that is equal to or less than about: 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or ranges including and/or spanning the aforementioned values. For example, in several embodiments, the method comprises administering a subcutaneous dose of Compound (I) ranging from 1 mg to 5 mg, 1 mg to 10 mg, 5 mg to 15 mg, 1 to 12.5 mg, or less than 15 mg. In several embodiments, the subject in need of treatment is a subject having a depression disorder.

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

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

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 at a dose of about 1 mg.

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

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

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, in the upper arm or abdominal area.

In a particular embodiment, this disclosure presents a method of administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g., patient, in need thereof, comprising selecting a subject, e.g., patient, who suffers from treatment resistant depression; and administering subcutaneously between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, this disclosure presents a method of treating treatment resistant depression, the method comprising administering Compound (I), or a pharmaceutically acceptable salt thereof, to a subject, e.g., patient, in need thereof, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having treatment resistant depression at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

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

Dosing Schedule

In various embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered as a single dose without repetition. In several embodiments, Compound (I) is administered by 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 equal to or less than about: 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, or ranges 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 yet other embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered once a month. In yet other embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered once every six weeks. In various embodiments, a dose of Compound (I), or a pharmaceutically acceptable salt thereof, is administered equal to or greater than once every: week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or ranges 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 week, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, or about 2 years. In some embodiments, treatment with Compound (I), or a pharmaceutically acceptable salt thereof, continues for equal to or at least about: 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 week, 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 ranges including and/or spanning the aforementioned values.

Packages or Pharmaceutical Products

In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein Compound (I), is in particular the free base. In a further embodiment of the package or pharmaceutical product as described herein, the instructions for treatment direct administration of about 0. 1 mg and about 15 mg Compound (I), or a pharmaceutically acceptable salt thereof, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg, of Compound (I), or a pharmaceutically acceptable salt thereof.

In a further embodiment 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 a yet further embodiment 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. Furthermore, in a further particular embodiment of the package or pharmaceutical product, as described herein, the instructions for treatment direct Compound (I), or a pharmaceutically acceptable salt thereof, is for once every two weeks, once every three weeks, once a month, or once every six weeks administration. Subjects Suitable for Treatment

The disclosed methods are suitable for treatment of individuals diagnosed as having major depressive disorder. The disclosed methods are particularly suitable for treatment of individuals diagnosed as having treatment resistant or treatment refractoiy depression. Subjects that are particularly amenable to treatment with a method according to the disclosure are those that have failed to respond to at least two conventional antidepressants. Also suitable for treatment are subjects that have failed to respond to 2 or more prior antidepressant treatments but not more than 5, wherein two failed treatments are of two different antidepressants, with adequate dose and duration, e.g., > 6 weeks duration, as identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). Also suitable for treatment are subjects that have apartial response to at least one antidepressant drug. Also suitable for treatment are subjects who have <50% response to at least one antidepressant treatment (> 8 weeks duration at an adequate and stable dose for at least 4 weeks) per the MGH-ATRQ.

The disclosed methods are also suitable for subjects that have recurrent major depressive disorder (MDD) and a current major depressive episode of at least 8 weeks in duration, e.g., as defined by Diagnostic and Statistical Manual of Mental Disorders, Firth Edition (DSM-5) criteria. The diagnosis may additionally be confirmed by both SCID-5 and clinical psychiatric evaluation.

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

In various embodiments, the individual is resistant (e.g, has no response or a negative response) to at least one antidepressant drug that is different than Compound (I), or a pharmaceutically acceptable salt thereof. In yet other embodiments, the individual 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., patient, is characterized as having treatment resistant or treatment refractory depression. In various embodiments, the subject, e.g., patient, is characterized as having treatment resistant or treatment refractoiy depression and is at risk of suicide.

In various embodiments, the subject, e.g. , 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., patient, is from 18 to 65 years old.

In various embodiments, the subject, e.g., patient, does not have historical treatment failure to esketamine, ketamine or arketamine.

In various embodiments, the subject, e.g , patient, is suffering from an episode of depression, e.g, major depressive episode, wherein the episode of depression, e.g, major depressive episode, has not responded to treatment with at least one antidepressant (e.g, a conventional antidepressant), i.e., the subject, e.g , patient, has not responded to treatment with at least one antidepressant in the current major depressive episode. In an embodiment, the at least one antidepressant is an oral antidepressant. The antidepressant(s) may be administered to the patient at an adequate dose, which may be determined by the attending physician and/or may be dosed as prescribed by its label. Similarly, the antidepressant has been administered for a suitable duration, e.g, as prescribed by its label. In an embodiment, the antidepressant has been administered for at least four weeks duration, e.g., for at least six weeks duration.

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

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

In various embodiments, the subject, e g., patient, does not have an acute depressive episode lasting longer than two years continuously.

In various embodiments, the subject, e.g, patient, is not receiving electroconvulsive therapy in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

In various embodiments, the subject, e.g., patient, has not had detoxification treatment within one month prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

In various embodiments, the subject, e.g, patient, does not have borderline personality disorder or antisocial personality disorder, e.g. , based on DSM-5 criteria. In various embodiments, the subject, e.g., patient, does not have a clinical diagnosis of autism, dementia, or intellectual disability.

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

In various embodiments, the subject, e.g., patient does not present suicidal ideation with intent, e.g., as determined by CSSRS by Yes response to Q4 or Q5 at baseline.

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

In various embodiments, the subject, e.g., 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 the NMD A receptor.

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

In various embodiments, the subject, e.g. , patient, does not have a history of seizures with the exception of childhood febrile seizures.

In various embodiments, the subject, e.g., patient, does not have cardiac or cardiac repolarization abnormality, including any of the following: a) history of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. b) history of clinically significant cardiac arrhythmias (e.g. , ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

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

In various embodiments, the subject, e.g., patient, does not present risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia or any of the following: a) long QT syndrome, family history of idiopathic sudden death or congenital long QT Syndrome. b) concomitant medication(s) with a “Known Risk of TdP” that cannot be discontinued or replaced by safe alternative medication.

In various embodiments, the subject, e.g. , patient, does not have a mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg at baseline; or past history of hypertensive crisis. In various embodiments, the subject, e.g., patient, does not have a history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other location (e.g., aorta).

In some embodiments, the subject e.g., patient, is not a pregnant or nursing (lactating) woman.

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

In some embodiments, the subject e.g. , patient, is not a sexually active male not willing to use a condom during intercourse while taking Compound I, or a pharmaceutically acceptable salt, thereof, and for 1 week after stopping medication with Compound I, or a pharmaceutically acceptable salt thereof.

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

Table 1

Response measures

Several scales are known in the art that may be utilized to diagnose or monitor patients with MDD. Examples of these scales include, without limitation, the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S) scale, Clinical Global Impression-Improvement (CGI-I) scale, Patient Global Impression of Change (PGIC), The Structured Clinical Interview for DSM-5 SCID-5, Columbia Suicide Severity Rating Scale (C-SSRS), Hamilton depression rating scale (HAM-D), and Mini International Neuropsychiatric Interview (M.I.N L).

An improvement in the index or scale known in the art, such as those described below, indicates that Compound (I) is effective for the treatment of MDD. Such improvements may be determined by comparing the pre-treatment and post-treatment scores of the subject, e.g., patient, having MDD.

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

In various embodiments, MGH-ATRQ is utilized to diagnose and/or monitor the patient's depression. The MGH-ATRQ examines the adequacy of duration and dose of prior and current antidepressant treatments in a step-by-step procedure (Chandler 2010). When assessing the duration and dose of antidepressants, the examiner must always inquire about adherence to each treatment. In addition, the MGH-ATRQ assesses the degree of improvement on a scale from 0% (not improved at all) to 100% (completely improved). Montgomery Asberg Depression disorder Rating Scale (MADRS)

In some embodiments, MADRS is utilized to diagnose and/or monitor the patient. The Montgomery Asberg Depression disorder Rating Scale (MADRS, SIGMA version) is a clinician-rated scale designed to measure depression disorder severity and detects changes due to antidepressant treatment: the test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts and suicidal thoughts.

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

Hamilton depression rating scale (HAM-D)

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

Clinical Global Impressions-Severity (CGI-S)

In some embodiments, CGI-S is utilized to diagnose and/or monitor the patient. The CGI-S (Guy 1976) is a clinician-rated scale that measures the overall severity of a patient's illness in comparison with the severity in other patients the physician has observed. The patient is rated on a scale from 1 to 7 with 1 indicating a "normal state" and 7 indicating "among the most extremely ill patients". The CGI-S was administered by an investigator, sub investigator or rater with 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 depression disorder, e.g., as disclosed herein, wherein treatment of depression is determined by an improvement in the CGI-S score of the subject, e.g., patient.

Clinical Global Imprcssions-hn movement (CGI-I)

In some embodiments, CGI-I is utilized to diagnose and/or monitor the patient. The Clinical Global Impressions Improvement (CGI-I) scale (Guy 1976) is a clinician rated scale that is used to rate total improvement or worsening of mental illness, regardless of whether the investigator considered it to be a result of drug treatment or not. The patient is rated on a scale from 1 to 7, with 1 indicating that the patient was very much improved and 7 indicating that the patient was very much worse.

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

Patient Global Impression of Change (PGIC)

In some embodiments, PGIC is utilized to diagnose and/or monitor the patient. PGIC scale aims to quantify disease activity relative to baseline. Participants are asked to calculate the difference between their current and previous health state based on a Likert scale. The PGIC comprises a number of points that show optimal patient preference, discriminative ability and test-retest ability, tailored to specific conditions and disease parameters.

The Structured Clinical Interview for DSM-5 SCID-5

In various embodiments, SCID-5 is utilized to diagnose and/or monitor the patient's depression. The SCID-5 is a semi-structured interview guide for making the major DSM-5 diagnoses (formerly diagnosed on Axis I). This clinician-rated diagnostic assessment is administered by an investigator, sub-investigator, or rater who has extensive professional training and experience in the diagnosis of mental illness.

Pharmaceutical Compositions

In several embodiments, pharmaceutical compositions comprising Compound (I) are provided. In several embodiments, the pharmaceutical formulations are suitable for administration to a subject in need of treatment. In several embodiments, pharmaceutical compositions of this disclosure suitable for subcutaneous administration comprise a Compound (I) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain one or more (or all) of antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents (for example in “Remington Essentials of Pharmaceutics, 2013, 1 ^st Edition, edited by Linda Felton, published by Pharmaceutical Press 2012, ISBN 978 0 85711 105 0; in particular Chapter 30). In several embodiments, pharmaceutical excipients that may be used in combination with Compound (I) include those, for example, as described in “Handbook of Pharmaceutical Excipients, 2012, 7 ^th Edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5”). Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions as disclosed herein include one or more of water, ethanol, polyols (such as 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 may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

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

In several embodiments, the pharmaceutical composition is aqueous. In several embodiments, the pharmaceutical composition comprises water for injection. In several embodiments, Compound (I) is provided in a dry form (e.g. , a powder, a solid, etc ). In several embodiments, the dry form of Compound (I) is constituted or reconstituted with a carrier (e.g., a liquid). In several embodiments, the dry form of Compound (I) is constituted or reconstituted with a carrier prior to use, including at the point of care.

A particular pharmaceutical composition for use according to the present disclosure comprises a lyophilized formulation, which comprises Compound (I), or a pharmaceutically acceptable salt thereof, admixed with water. In an embodiment, the lyophilized formulation comprises Compound (I) as the free base. In several embodiments, Compound (I) is reconstituted prior to use.

Concomitant Therapy

In various embodiments, this disclosure presents a method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously to the subject, e.g., 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., antidepressant treatment.

In several embodiments, a subject, e.g., patient, may be under concurrent treatment with both an antidepressant and Compound (I), or a pharmaceutically acceptable salt thereof, where both are administered by their prescribed dosing regimens.

In various embodiments, a “subject, e.g. , patient, in need thereof’ may be a subject, e.g. , patient, who, prior to receiving treatment with Compound (I), or a pharmaceutically acceptable salt thereof, has been prescribed or is currently taking at least one other therapeutic agent, “a background therapy”. The background therapy can be, for example, a standard of care medicament prescribed for a psychiatric disorder, e.g., depression 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, e.g., lithium, as disclosed herein. The background therapy can be, for example, at least one additional antidepressant and an antipsychotic, e.g., an atypical antipsychotic, as disclosed herein. The background therapy may also include other concomitant medication, e.g., benzodiazepines, without prohibiting any psychotherapies. In some embodiments, the subject, e.g. , patient, in need thereof continues the background therapy after the subject, e.g. , patient, receives Compound (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the subject, e.g. , patient, in need thereof stops receiving the background therapy, e.g. , at once or gradually, before receiving Compound (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the subject, e.g., patient, is receiving the background therapy for at least 4 weeks, e.g., at least 6 weeks, prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. In a further embodiment, the subject, e.g., patient, is receiving the background therapy for at least 4 weeks, e.g., at least 6 weeks, prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof, and continues the background therapy after the subject, e.g., patient, receives Compound (I), or a pharmaceutically acceptable salt thereof. Treatment with Compound (I), or a pharmaceutically acceptable salt thereof, and the background therapy as described herein, may be useful as an augmentation strategy for the treatment of depression disorder, as described herein. The augmentation strategy is especially 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, patient, including current antidepressant(s) to which the subject, e.g., patient, had an inadequate response. In other embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered adjunctively with an antidepressant(s) not previously administered to the subject, e.g., patient. In still other embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered in a regimen with an antidepressant(s) previously administered to the subject, e.g., patient.

In some embodiments, other antidepressant therapy may include one antidepressant medication. In other embodiments, other antidepressant therapy includes two or more antidepressant medications. In further embodiments, other antidepressant therapy includes two antidepressant medications. In yet other embodiments, other antidepressant therapy includes three antidepressant medications.

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

In several embodiments, Compound (I) and the at least one other therapeutic agent, e.g., antidepressant(s) (including conventional and herbal antidepressant(s)), antipsychotic(s), mood stabilizer(s), benzodiazepine(s), may be administered via the same or different routes of administration. Examples of suitable methods of administration of the antidepressant include, but are not limited to, oral, intravenous, intranasal, intramuscular, subcutaneous, transdermal, buccal, or rectal. In a particular embodiment, the at least one other therapeutic agent is at least one other antidepressant, which is administered orally.

Thus, Compound (I), or a pharmaceutical acceptable salt thereof, may be administered as a combination therapy, e.g, as an adjunct or add-on therapy, to one or more other treatments or therapies for a psychiatric disorder, e.g., depression disorder. Compound (I), or a pharmaceutical acceptable salt thereof, may be administered in combination with one or more additional therapeutic agents, e.g., in combination with one to three additional therapeutic agents, e.g., in combination with one to two additional therapeutic agents, e.g., in combination with one additional therapeutic agent. In a particular embodiment, Compound (I), or a pharmaceutical acceptable salt thereof, is administered in a regimen with the at least one other therapeutic agent, currently being administered to the subject, e.g., patient. 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 a particular embodiment, at least one of the one or more additional therapeutic agents is an antidepressant, e.g., oral antidepressant, to which the subject, e.g., 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 the Compound (I), or a pharmaceutically acceptable salt thereof, is administered as acute treatment. In another embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered as a combination therapy with one or more additional antidepressants; wherein the Compound (I), or a pharmaceutically acceptable salt thereof, is administered as acute treatment and wherein the one or more antidepressants are administered as 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. , patient, who is on background therapy, as described above, for a certain period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, or longer).

In various embodiments, Compound (I) or a pharmaceutically acceptable salt thereof, is provided for use to treat depression disorder in a patient, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is administered as an add-on therapy to the patient who is on background therapy, as described above, for a certain period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 24 months, or longer). In some embodiments, treatment with Compound (I), or a pharmaceutically acceptable salt thereof, is given where the patient was on the background therapy, as described above, for a certain period of time equal to or greater than about: 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 week, 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 ranges including and/or spanning the aforementioned values.

Therapeutically effective amounts/dosage levels and dosage regimens for the additional therapeutic agent(s), e.g., antidepressant(s), antipsychotic(s), mood stabilizer(s), benzodiazepine(s), for example, as defined herein, may be readily determined by one of ordinary skill in the art, and are administered according to its prescribed dosing regimen, e.g., as prescribed by the attending physician and/or by its label. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician’s Desk Reference (Medical Economics Company or online at http :///www. pdrel.com) or other sources.

Examples of antidepressants which may be used in the combination or background therapy according to the disclosure are those which are FDA approved for major depressive disorder. As disclosed elsewhere herein, examples of antidepressants which may be used in the combination or background therapy according to the disclosure include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants, for example, 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, pirlindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofezine, noxiptiline, vilazodone, vortioxetine, and bupropion.

In a particular embodiment, 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 a particular embodiment, the antidepressant is selected from the group consisting of SSRIs, SNRIs, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof, e.g., 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 aforementioned antidepressants, is being used or is being prescribed to treat a current major depressive episode in a subject, e.g., 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 in conjunction with another antidepressant (as listed above) and/or an antipsychotic and/or 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., patient, is not administered any other antidepressant in course of administration with Compound (I), or a pharmaceutically acceptable salt thereof.

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

In various embodiments, as disclosed elsewhere herein, the depression disorder is selected from major depressive disorder, treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. In a particular embodiment, the depression disorder is major depressive disorder. In a further embodiment, the major depressive disorder is treatment resistant depression. As disclosed elsewhere herein, all the aforementioned embodiments and embodiments hereinafter relating to the concomitant therapy of the disclosure are equally applicable to:

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

Use of Compound (I), or a pharmaceutically acceptable salt thereof, in the concomitant therapy according to the disclosure;

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

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

Further Embodiments of the Disclosure

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

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

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

In an embodiment, the depression disorder is selected from major depressive disorder, in particular treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder. In a particular embodiment, the depression disorder is major depressive disorder. In a further embodiment, the major depressive disorder is treatment resistant depression.

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

In another aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, wherein the major depressive disorder 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 an embodiment, the at least two antidepressants are of two different antidepressants.

In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously, e.g., by subcutaneous injection, at a dose of between 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.

In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously, e.g., by subcutaneous injection, at a dose of between about 0.1 mg and about 15 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.1 mg and about 1 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.3 mg and about 1 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.5 mg and about 1 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 5 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 10 mg. In an embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 15 mg. In a further embodiment, 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 a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg, about 4 mg, or about 10 mg.

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

In a particular embodiment, the present disclosure relates 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 antidepressant therapies in a current major depressive episode, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg.

In another aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, wherein the major depressive disorder 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 at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg. In an embodiment, the at least two antidepressants are of two different antidepressants.

In a particular embodiment, the present disclosure 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 subcutaneously administered at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg.

In a particular embodiment, the present disclosure also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of recurrent major depressive disorder and a current major depressive episode of at least 8 weeks in duration in a subject, e.g., patient, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is subcutaneously administered at a dose of between about 0.1 mg and about 15 mg, e.g., between about 0.1 mg and about 1 mg, between about 0.3 mg and about 1 mg, between about 0.5 mg and about 1 mg, between about 1 mg and about 5 mg, between about 1 mg and about 10 mg, between about 1 mg and about 15 mg. In a particular embodiment, the major depressive episode is of at least 8 weeks but no more than 24 months in duration. In an embodiment, the depression disorder is characterized as treatment resistant depression. In an embodiment, a diagnosis of TRD is confirmed by meeting DSM-5 criteria for MDD and in the current depressive episode has not responded adequately to at least two different antidepressants of adequate dose and duration. In a particular embodiment, the subject, e.g., patient, failed to respond to 2 or more prior antidepressant treatments but not more than 5, wherein two failed treatments are of two different antidepressants, with adequate dose and duration, e.g., > 6 weeks duration, per the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

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

In a particular embodiment, the subject is a human patient.

In a particular embodiment, 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 by 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 yet a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered once a month. In yet a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered once every six weeks.

In a particular embodiment, 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 medicaments prescribed for use in the treatment of a psychiatric disorder, such as depression disorder. In an embodiment, the treatment further comprises administration of one or more additional therapeutic agents, for a period of about at least 4 weeks, e.g, about at least 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, after 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, such as an oral antidepressant. In an embodiment, the one or more additional therapeutic agents is selected from the group consisting of an antidepressant, antipsychotic, a mood stabilizer, a benzodiazepine, and combinations thereof. In a particular embodiment, the one or more additional therapeutic agents is selected from the group consisting of an antidepressant, antipsychotic, a mood stabilizer, 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, patient, including current antidepressant(s) to which the subject, e.g., patient, had an inadequate response. In another embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered adjunctively with an antidepressant(s) not previously administered to the subject, e.g., patient. In still another embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered in a regimen with an antidepressant(s) previously administered to the subject, e.g., patient.

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

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

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

As described herein, Compound (I) may be used as adjunctive treatment, or in other words, in conjunction, as an add-on, or in combination with one or more therapeutic agents, e.g., one or more antidepressants, for example, the patient may be already, or also, administered one or more antidepressants. Thus, in a further particular embodiment, the disclosure relates to Compound (I), or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, as adjunctive treatment with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. In a further particular embodiment, the disclosure relates to Compound (I), or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, in conjunction with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. In a further particular embodiment, the disclosure relates to Compound (I), or a pharmaceutically acceptable salt thereof, for use as described herein, comprising subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants.

In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the subcutaneous administration of an effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, as adjunctive treatment with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical product as described herein, wherein the instructions for treatment direct the administration of an effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, in conjunction with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. In a further particular embodiment, the disclosure further relates to a package or pharmaceutical as described herein, wherein the instructions for treatment direct administration of an effective amount of Compound (I), or a pharmaceutically acceptable salt thereof, in combination with an effective amount of one or more therapeutic agents, e.g., one or more antidepressants. Such one or more antidepressants can be selected from any antidepressant disclosed herein.

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

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

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

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

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

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

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

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

In a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.2 mg. In a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.3 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 11 mg. In a further embodiment, Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 12 mg.

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

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

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

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

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 (RIMAs)), 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, pirlindole, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, pipofezine, noxiptiline, vilazodone, vortioxetine, and bupropion.

In a particular embodiment, the antidepressant therapy is selected from the group consisting of serotonin reuptake inhibitors (SSRIs), selective serotonin, norepinephrine reuptake inhibitors (SNRIs), and a combination thereof.

In a particular embodiment, the antidepressant therapy is selected from the group consisting of SSRIs, SNRIs, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof.

In a particular embodiment, the antidepressant is selected form the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline, and combinations thereof.

In a particular embodiment, the antidepressant is an oral antidepressant.

Further embodiments of the present disclosure are outlined below:

Embodiments a

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

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

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

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

Embodiment 5 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depression disorder is selected from major depressive disorder, in particular treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder.

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

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

Embodiment 8a. The compound, or a pharmaceutically acceptable salt thereof, for use according to Embodiment 7a, wherein the treatment resistant depression comprises partial resistance.

Embodiment 9a. 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.

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

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

Embodiment 13 a. 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., patient, suffering from depression disorder, wherein 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 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 a major depressive episode, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 16a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 14a and 15a, wherein the major depressive episode is of at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks, in duration.

Embodiment 17a. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of major depressive disorder, in particular acute MDD, wherein 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 single episode major depressive disorder, wherein 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 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 of at least 4 weeks, e.g., at least 6 weeks, e.g., at least 8 weeks, in duration, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 21a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 14a to 20a, wherein the major depressive episode of at least 6 weeks, e.g. , at least 8 weeks, but less than 24 months, in duration.

Embodiment 22a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least one antidepressant treatment, e.g., in the current depressive episode. Embodiment 23 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode had a partial response to at least one antidepressant treatment, e.g., in the current depressive episode.

Embodiment 24a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least two antidepressant treatments, e.g., in the current depressive episode.

Embodiment 25 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode had a partial response to at least two antidepressant treatments, e.g., in the current depressive episode.

Embodiment 26a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least two antidepressant treatments but not more than five, e.g., in the current depressive episode.

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

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

Embodiment 29a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 22a to 28a, 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 ( .g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants.

Embodiment 30a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 22a to 29a, 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., patient, wherein the subject, e.g., patient, meets the DSM-5 criteria for MDD based on the Structured Clinical Interview for DSM-5 (SCID-5), and wherein the Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 33a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the treatment further comprises the step of evaluating a subject, e.g., patient, at regular intervals, following treatment with Compound (I), or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine need for continued treatment.

Embodiment 34a. The compound, or a pharmaceutically acceptable salt thereof, for use according to Embodiment 33a, wherein the subject, e.g., patient, is evaluated after about 2 weeks, about 4 weeks, about 6 weeks or more than about 6 weeks of treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 35 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein 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. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.1 mg and about 15 mg.

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

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

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

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

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

Embodiment 42a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 15 mg. Embodiment 43 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, or about 15 mg.

Embodiment 44a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg, about 4 mg, or about 10 mg.

Embodiment 45 a. The compound, or a pharmaceutically acceptable salt thereof, for 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 46a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered once without repetition.

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

Embodiment 48a. The compound, or a pharmaceutically acceptable salt thereof, for 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 49a. The compound, or a pharmaceutically acceptable salt thereof, for 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 50a. The compound, or a pharmaceutically acceptable salt thereof, for 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 1a. The compound, or a pharmaceutically acceptable salt thereof, for 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 52a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein a score is improved in one of more depression assessment instruments selected from the group consisting of Montgomery-Asberg Depression Rating Scale (MADRS), Mini International Neuropsychiatric Interview (M.I.N.I.), e.g., Version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia Suicide Severity Rating Scale (C-SSRS), and Clinical Global Impression (CGI), following treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 53a. The compound, or a pharmaceutically acceptable salt thereof, for 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., patient, with recurrent major depressive disorder and a current major depressive episode of at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks, in duration.

Embodiment 54a. The compound, or a pharmaceutically acceptable salt thereof, for 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., patient, who is treatment resistant.

Embodiment 55 a. The compound, or a pharmaceutically acceptable salt thereof, for 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., patient, who is partially resistant.

Embodiment 56a. The compound, or a pharmaceutically acceptable salt thereof, for 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., patient, who had an inadequate response or failed to respond to other antidepressant therapy prior to treatment with the Compound (I), or a pharmaceutically acceptable salt thereof, e.g., in a current major depressive episode.

Embodiment 57a. The compound, or a pharmaceutically acceptable salt thereof, for 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. , patient, who has not adequately responded or has failed to respond to at least one antidepressant, e.g., in a current major depressive episode.

Embodiment 58a. The compound, or a pharmaceutically acceptable salt thereof, for 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. , patient, who has not adequately responded or has failed to respond to at least two antidepressants, e.g., in a current major depressive episode.

Embodiment 59a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 56a to 58a, wherein the inadequate response or failure to respond comprises partial response.

Embodiment 60a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 56a to 59a, wherein the current major depressive episode is of about at least about 4 weeks, e.g., at least about 6 weeks, at least about 8 weeks, in duration, particularly, at least about 8 weeks but no more than 24 months, in duration.

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

Embodiment 62a. The compound, or a pharmaceutically acceptable salt thereof, for 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., patient, who has a MADRS score of at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at baseline.

Embodiment 63 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the treatment further comprises the step of determining or having determined the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, e.g., at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment to thereby assess efficacy of treatment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 64a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has a reduced MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g, patient, has a reduced MADRS total score at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 65 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the subject, e g., patient, has more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, improvement in the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g. , the subject, e.g., patient, has more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, improvement in the MADRS total score at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 66a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the subject, e.g, patient, has a MADRS total score less than 12 after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has a MADRS total score less than 12 at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., 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 to treat a psychiatric disorder, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 68a. The use according to Embodiment 67a, wherein the compound, or a pharmaceutically acceptable salt thereof, is for use according to any one of Embodiments la to 66a.

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

Embodiment 70a. The use according to Embodiment 69a, wherein the treatment with compound (I), or a pharmaceutically acceptable salt thereof, is in addition to one or more standard of care medicaments prescribed for use in the treatment of a psychiatric disorder.

Embodiment 71a. The use according to any one of Embodiments 67a to 70a, wherein the psychiatric disorder is a depression disorder.

Embodiment 72a. The use according to Embodiment 71a, wherein the depression disorder is major depressive disorder.

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

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

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

Embodiment 76a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 67a to 75a, wherein the one or more additional therapeutic agents is selected from the group consisting of an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, and combinations thereof.

Embodiment 77a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 67a to 76a, wherein at least one of the one or more additional therapeutic agents is an antidepressant, e.g., an oral antidepressant. Embodiment 78a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 67a to 77a, wherein the one or more additional therapeutic agents is one or more antidepressants.

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

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

Embodiment 81a. The compound or a pharmaceutically acceptable salt thereof, for use according to Embodiment 80a, wherein the antidepressant is selected from the group consisting of SSRIs, SNRIs, tricyclic antidepressants, norepinephrine dopamine reuptake inhibitors, and combinations thereof, e.g., the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline, and combinations thereof.

Embodiment 82a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 76a to 81a, 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 83 a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 76a to 82a, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

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

Embodiment 85a. The compound, or a pharmaceutically acceptable salt thereof, for 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 86a. The compound, or a pharmaceutically acceptable salt thereof, for 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 87a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein Compound (I) is administered as the free base.

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

Embodiment 89a. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein the compound (I) is formulated for delivery from a subcutaneous injection device as a single subcutaneous injection.

Embodiment 90a. The 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., patient, who has failed to respond to 2 or more prior antidepressant treatments but not more than 5, wherein two failed treatments are of two different antidepressants, with adequate dose and duration, e.g., at least 6 weeks duration, e.g., as identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

Embodiment 91a. The 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, patient, who has <50% response to at least one antidepressant treatment, e.g., during a major depressive episode > 8 weeks duration at an effective and stable dose for at least 4 weeks, e.g., per the MGH-ATRQ.

Embodiment 92a. The 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., patient, who has a diagnosis of recurrent major depressive disorder (MDD) and a current major depressive episode of at least 8 weeks in duration, e.g. , as defined by Diagnostic and Statistical Manual of Mental Disorders, Firth Edition (DSM-5) criteria.

Embodiment 93 a. The 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. , patient, who is characterized as having treatment resistant or treatment refractory depression.

Embodiment 94a. The 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 95 a. The 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. The 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., patient, who does not have historical treatment failure to esketamine, ketamine or arketamine.

Embodiment 97a. The 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., patient, who is suffering from an episode of depression, e.g., major depressive episode, wherein the subject, e.g., patient, has not responded to treatment with at least one antidepressant in the current depressive episode.

Embodiment 98a. The 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., patient, who is suffering from an episode of depression, e.g., major depressive episode, wherein the subject, e.g., patient, has not responded to treatment with at least two antidepressants in the current depressive episode.

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

Embodiment 100a. The compound for use according to any one of Embodiments 97a to 99a, wherein the antidepressant has been administered for at least four weeks duration, e.g., for at least six weeks in duration. Embodiment 101a. The 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., patient, who is male or female.

Embodiment 102a. The 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., patient, who does not have an acute depressive episode lasting longer than two years continuously.

Embodiment 103a. The 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. , patient, who is not receiving electroconvulsive therapy in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 104a. The 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., patient, who is not receiving transcranial magnetic stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 105a. The 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., patient, who is not receiving vagus nerve stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 106a. The 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., patient, who is not receiving deep brain stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 107a. The 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., patient, who does not have a prior or current diagnosis of major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder, e.g., as determined by SCID-5.

Embodiment 108a. The 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. , patient, who does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification.

Embodiment 109a. The 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., patient, who has not had detoxification treatment within one month prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 110a. The 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., patient, who does not have borderline personality disorder or antisocial personality disorder, e.g., based on DSM-5 criteria.

Embodiment Il la. The 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., patient, who does not have a clinical diagnosis of autism, dementia, or intellectual disability.

Embodiment 112a. The 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., patient, who does not have a history of suicidal attempt or suicidal behavior within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 113a. The 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., patient, who does not present suicidal ideation with intent, e.g., as determined by CSSRS by Yes response to Q4 or Q5 at baseline. Embodiment 114a. The 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. , patient, who does not show evidence of significant renal insufficiency, indicated by an estimated glomerular filtration rate (eGFR) of <40 mL/min/1.73 m ² at baseline.

Embodiment 115a. The 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., patient, who 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 the NMDA receptor.

Embodiment 116a. The 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., patient, who does not have Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or active COVID-19 infection.

Embodiment 117a. The 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., patient, who does not have a history of seizures with the exception of childhood febrile seizures.

Embodiment 118a. The 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., patient, who does not have cardiac or cardiac repolarization abnormality, including any of the following: a) history of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. b) history of clinically significant cardiac arrhythmias (e.g. , ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 119a. The 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., patient, who does not have a resting QTcF >450 msec (male) or >460 msec (female) at baseline.

Embodiment 120a. The 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., patient, who does not present risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia or any of the following: a) long QT syndrome, family history of idiopathic sudden death or congenital long QT Syndrome. b) concomitant medication(s) with a “Known Risk of TdP” that cannot be discontinued or replaced by safe alternative medication.

Embodiment 121a. The 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., patient, who does not have a mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg at baseline; or past history of hypertensive crisis.

Embodiment 122a. The 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, patient, who does not have a history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysm or arteriovenous malformation) or known aneuiysmal vascular disease in other location (e.g., aorta).

Embodiment 123a. The 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., patient, who is not a pregnant or nursing (lactating) woman.

Embodiment 124a. The 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., patient, who is not a woman of child-bearing potential who is not using highly effective contraception.

Embodiment 125a. The 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., patient, who is not a sexually active male not willing to use a condom during intercourse while taking Compound I, or a pharmaceutically acceptable salt, thereof, and for 1 week after stopping medication with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 126a. The 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., patient, who is not taking any one 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 a psychiatric disorder, e.g., depression disorder, e.g, major depressive disorder, e.g, treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, seasonal affective disorder, wherein the treatment further comprises subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 128a. The therapeutic agent for use according to Embodiment 127a, wherein the therapeutic agent is selected from the group consisting of an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, and combinations thereof.

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

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

Embodiment 131a. The 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. The therapeutic agent for use according to any one of Embodiments 128a to 131a, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants.

Embodiment 133a. The 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. The 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 a lithium member, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 135a. The therapeutic agent for use according to any one of Embodiments 127a to 134a, wherein the treatment with Compound (I), or a pharmaceutically acceptable salt thereof, is according to any one of Embodiments la 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, wherein treatment is in conjunction with at least one oral antidepressant.

Embodiment 137a. The compound, or pharmaceutically acceptable salt thereof, 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. Certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation also can be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can in some cases be excised from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.

Embodiments b:

Embodiment lb. 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 depression 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 depression 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 use in the treatment of depression disorder, wherein the treatment comprises the steps of:

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

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

Embodiment 4b. The use according to Embodiment 3b, wherein the subject, e.g, patient, is evaluated at regular intervals following step (b) to determine the relative effectiveness, wherein the evaluation comprises measuring the MADRS score of the subject, e.g., patient.

Embodiment 5b. The use according to any one of the preceding Embodiments, wherein the depression disorder is selected from major depressive disorder, in particular treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, self-harm in major depressive disorder, and seasonal affective disorder.

Embodiment 6b. The use according to any one of the preceding Embodiments, wherein depression disorder is major depressive disorder, such as acute MDD. Embodiment 7b. The use according to any one of the preceding Embodiments, wherein depression disorder is treatment resistant depression.

Embodiment 8b. The 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 use in the treatment of depressive symptoms in major depressive disorder, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment lib. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of depressive symptoms in major depressive disorder with acute suicidal ideation or 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 use in the treatment of depressive symptoms in 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, e.g., patient, suffering from depression 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 a major depressive episode, 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 a major depressive episode, 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 is of at least 4 weeks, e.g. , at least 6 weeks, at least 8 weeks, e.g. , about 8 weeks, in duration. Embodiment 17b. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of major depressive disorder, in 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 episode 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 use in 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 use in the treatment of recurrent major depressive disorder and a current major depressive episode of at least 6 weeks, e.g, at least 8 weeks, in duration, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

Embodiment 21b. The use according to any one of Embodiments 14b to 20b, wherein the major depressive episode of at least 6 weeks, e.g., at least 8 weeks, but less than 24 months, in duration.

Embodiment 22b. The use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least one antidepressant treatment, e.g., in the current depressive episode.

Embodiment 23b. The use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode had a partial response to at least one antidepressant treatment, e.g. , in the current depressive episode.

Embodiment 24b. The use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least two antidepressant treatments, e.g. , in the current depressive episode.

Embodiment 25b. The use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode had a partial response to at least two antidepressant treatments, e.g., in the current depressive episode.

Embodiment 26b. The use according to any one of the preceding Embodiments, wherein the depressive disorder or depressive episode has not adequately responded to at least two antidepressant treatments but not more than five, e.g., in the current depressive episode.

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

Embodiment 28b. The use according to any one of Embodiments 22b to 27b, wherein the at antidepressant treatment(s) have been administered for at least 4 weeks duration, e.g. , at least 6 weeks duration. 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 (RIMAs)), and multimodal antidepressants. Embodiment 30b. The 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 the Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously.

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

Embodiment 33b. The use according to any one of the preceding Embodiments, wherein the treatment further comprises the step of evaluating a subject, e.g., patient, at regular intervals, following treatment with Compound (I), or a pharmaceutically acceptable salt thereof, for evidence of therapeutic benefit to determine need for continued treatment.

Embodiment 34b. The use according to Embodiment 33b, wherein the subject, e.g., patient, is evaluated after about 2 weeks, about 4 weeks, about 6 weeks or more than about 6 weeks of treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 35b. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein 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. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 0.1 mg and about 15 mg.

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

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

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

Embodiment 40b. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 5 mg. Embodiment 41b. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of between about 1 mg and about 10 mg.

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

Embodiment 43b. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 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. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered at a dose of about 1 mg, about 4 mg, or about 10 mg.

Embodiment 45b. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered once without repetition, once a week, twice a week, once every two weeks, once every three weeks, once a month or once every six weeks.

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

Embodiment 47b. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding Embodiments, wherein 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. The use according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered once a month or less frequently.

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

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. The use according to any one of the preceding Embodiments, wherein a score is improved in one of more depression assessment instruments selected from the group consisting of Montgomery-Asberg Depression Rating Scale (MADRS), Mini International Neurop sy chi atric Interview (M.I.N.I.), e.g., Version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia Suicide Severity Rating Scale (C-SSRS), and Clinical Global Impression (CGI), following treatment with Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 53b. The use according to any one of the preceding Embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., patient, with recurrent major depressive disorder and a current major depressive episode of at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks, in duration.

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

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

Embodiment 56b. The use according to any one of the preceding Embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g. , patient, who had an inadequate response or failed to respond to other antidepressant therapy prior to treatment with the Compound (I), or a pharmaceutically acceptable salt thereof, e.g. , in a current major depressive episode.

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

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

Embodiment 59b. The use according to any one of Embodiments 56b to 58b, wherein the inadequate response comprises partial response.

Embodiment 60b. The use according to any one of Embodiments 56b to 59b, wherein the current major depressive episode is of about at least about 4 weeks, e.g., at least about 6 weeks, at least about 8 weeks, in duration, particularly, at least about 8 weeks but no more than 24 months, in duration.

Embodiment 61b. The 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. The use according to any one of the preceding Embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., patient, who has a MADRS score of at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at baseline.

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

Embodiment 64b. The use according to any one of the preceding Embodiments, wherein the subject, e.g. , patient, has a reduced MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has a reduced MADRS total score at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., 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. , patient, has more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, improvement in the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has more than 30%, e.g., more than 35%, more than 40%, more than 45%, more than 50%, improvement in the MADRS total score at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 66b. The use according to any one of the preceding Embodiments, wherein the subject, e.g. , patient, has a MADRS total score less than 12 after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has a MADRS total score less than 12 at 24 hours, 7, 14, 21 and/or 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., 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 to treat a psychiatric disorder depression disorder, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously. Embodiment 68b. The use according to Embodiment 67b, wherein the compound, or a pharmaceutically acceptable salt thereof, is for use according to any one of Embodiments lb to 66b.

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

Embodiment 70b. The use according to Embodiment 69b, wherein the treatment with compound (I), or a pharmaceutically acceptable salt thereof, is in addition to one or more standard of care medicaments prescribed for use in the treatment of a psychiatric disorder.

Embodiment 71b. The use according to any one of Embodiments 67b to 70b, wherein the psychiatric disorder is a depression disorder.

Embodiment 72b. The use according to Embodiment 71b, wherein the depression disorder is major depressive disorder.

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

Embodiment 74b. The use according to any one of Embodiments 67b to 74b, wherein the treatment comprises administration of the one or more additional therapeutic agents, for a period of about at least 4 weeks, e.g. , about at least 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 the treatment with the one or more additional therapeutic agents continues, after treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 76b. The use according to any one of Embodiments 67b to 76b, wherein the one or more additional therapeutic agents is selected from the group consisting of an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, and combinations thereof.

Embodiment 77b. The 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, e.g., an oral antidepressant.

Embodiment 78b. The 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 adequately responded or has failed to respond to at least one, e.g. , at least two, of the one or more additional therapeutic agents or standard of care medicaments, e.g. , during a current major depressive episode.

Embodiment 80b. The use according to any one of Embodiments 76b to 79b, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), multimodal antidepressants, and combinations thereof.

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, e.g, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline, and combinations thereof.

Embodiment 82b. The use according to any one of Embodiments 76b to 8 lb, 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. The use according to any one of Embodiments 76b to 82b, wherein the antipsychotic or mood stabilizer is selected from the group consisting of lithium, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

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

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

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

Embodiment 87b. The use according to any one of the preceding Embodiments, wherein Compound (I) is administered as the free base.

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

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

Embodiment 90b. The 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., patient, who has failed to respond to 2 or more prior antidepressant treatments but not more than 5, wherein two failed treatments are of two different antidepressants, with adequate dose and duration, e.g., at least 6 weeks duration, e.g, as identified by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

Embodiment 91b. The 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., patient, who has <50% response to at least one antidepressant treatment, e.g., during a major depressive episode > 8 weeks duration at an effective and stable dose for at least 4 weeks, e.g., per the MGH-ATRQ.

Embodiment 92b. The 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., patient, who has a diagnosis of recurrent major depressive disorder (MDD) and a current major depressive episode of at least 8 weeks in duration, e.g., as defined by Diagnostic and Statistical Manual of Mental Disorders, Firth Edition (DSM-5) criteria.

Embodiment 93b. The 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. , patient, who is characterized as having treatment resistant or treatment refractory depression.

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

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

Embodiment 96b. The 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, patient, who does not have historical treatment failure to esketamine, ketamine or arketamine.

Embodiment 97b. The 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., patient, who is suffering from an episode of depression, e.g., major depressive episode, wherein the subject, e.g., patient, has not responded to treatment with at least one antidepressant in the current depressive episode.

Embodiment 98b. The 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., patient, who is suffering from an episode of depression, e.g., major depressive episode, wherein the subject, e.g., patient, has not responded to treatment with at least two antidepressants in the current depressive episode.

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

Embodiment 100b. The use according to any one of Embodiments 97b to 99b, wherein the antidepressant has been administered for at least four weeks duration, e.g., for at least six weeks duration.

Embodiment 101b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g. , patient, who is male or female. Embodiment 102b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., patient, who does not have an acute depressive episode lasting longer than two years continuously.

Embodiment 103b. The 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., patient, who is not receiving electroconvulsive therapy in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 104b. The 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, patient, who is not receiving transcranial magnetic stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 105b. The 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., patient, who is not receiving vagus nerve stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 106b. The 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, patient, who is not receiving deep brain stimulation in the current depressive episode or within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 107b. The 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., patient, who does not have a prior or current diagnosis of major depressive disorder with psychotic features, bipolar disorder, schizophrenia, or schizoaffective disorder, e.g, as determined by SCID-5.

Embodiment 108b. The 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. , patient, who does not have acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification.

Embodiment 109b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., patient, who has not had detoxification treatment within one month prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 110b. The 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., patient, who does not have borderline personality disorder or antisocial personality disorder, e.g., based on DSM-5 criteria.

Embodiment 11 lb. The 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., patient, who does not have a clinical diagnosis of autism, dementia, or intellectual disability.

Embodiment 112b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g, patient, who does not have a history of suicidal attempt or suicidal behavior within one year prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 113b. The 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., patient, who does not present suicidal ideation with intent, e.g., as determined by CSSRS by Yes response to Q4 or Q5 at baseline.

Embodiment 114b. The 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., patient, who does not show evidence of significant renal insufficiency, indicated by an estimated glomerular filtration rate (eGFR) of <40 mL/min/1.73 m ² at baseline.

Embodiment 115b. The 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., patient, who 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 the NMD A receptor.

Embodiment 116b. The 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, patient, who does not have Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or active CO VID-19 infection.

Embodiment 117b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g, patient, who does not have a history of seizures with the exception of childhood febrile seizures.

Embodiment 118b. The 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, patient, who does not have cardiac or cardiac repolarization abnormality, including any of the following: a) history of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof. b) history of clinically significant cardiac arrhythmias (e.g. , ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block) within 6 months prior to treatment with Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 119b. The 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., patient, who does not have a resting QTcF >450 msec (male) or >460 msec (female) at baseline.

Embodiment 120b. The 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., patient, who does not present risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, histoiy of cardiac failure, or history of clinically significant/symptomatic bradycardia or any of the following: a) long QT syndrome, family history of idiopathic sudden death or congenital long QT Syndrome. b) concomitant medication(s) with a “Known Risk of TdP” that cannot be discontinued or replaced by safe alternative medication.

Embodiment 121b. The 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, patient, who does not have a mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg at baseline; or past history of hypertensive crisis.

Embodiment 122b. The 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., patient, who does not have a history of hemorrhagic stroke or known cerebrovascular disorders (e.g., aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other location (e.g., aorta).

Embodiment 123b. The use according to any one of the preceding Embodiments, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to a subject, e.g., patient, who is not a pregnant or nursing (lactating) woman.

Embodiment 124b. The 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. , patient, who is not a woman of child-bearing potential who is not using highly effective contraception.

Embodiment 125b. The 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., patient, who is not a sexually active male not willing to use a condom during intercourse while taking Compound I, or a pharmaceutically acceptable salt, thereof, and for 1 week after stopping medication with Compound I, or a pharmaceutically acceptable salt thereof.

Embodiment 126b. The 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., patient, who is not taking any one 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 a psychiatric disorder, e.g., depression disorder, e.g., major depressive disorder, e.g., treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and 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 128b. The therapeutic agent for use according to Embodiment 127b, wherein the therapeutic agent is selected from the group consisting of an antidepressant, an antipsychotic, a mood stabilizer, a benzodiazepine, and combinations thereof.

Embodiment 129b. The therapeutic agent for use according to any one of Embodiments 127b and 128b, wherein the therapeutic agent is an antidepressant, e.g., an oral antidepressant. Embodiment 130b. The therapeutic agent for use according to any one of Embodiments 127b to 129b, wherein the therapeutic agent is administered for a period of about at least 4 weeks, e.g. , about at least 6 weeks, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 131b. The 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. The therapeutic agent for use according to any one of Embodiments 128b to 131b, wherein the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants.

Embodiment 133b. The 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. The 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 a lithium member, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

Embodiment 135b. The 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 lb 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, wherein treatment is in conjunction with at least one oral antidepressant.

Embodiment 137b. The 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.

Embodiments c

Embodiment 1c. A method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously to the subject, e.g, patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 2c. A method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising administering subcutaneously to the subject, e g., 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 of reducing at least one depressive symptom in a subject, e.g., patient, suffering from depression disorder, the method comprising administering subcutaneously to the subject, e.g., patient, a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 4c. A method for the long-term treatment of depression disorder in a subject, e.g. , patient, in need thereof, the method comprising administering subcutaneously Compound (I), or a pharmaceutically acceptable salt thereof, to the subject, e.g. , patient, in need thereof.

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

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

Embodiment 7c. A method of treating depression disorder, in a subject, e.g., patient, in need thereof, the method comprising the steps of: a. determining or having determined the baseline MAD RS score of the subject, e.g., patient; and b. administering subcutaneously to said subject, e.g, 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 about at least by at least about 30%, e.g., by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60%, by at least about 65%, relative to the measured baseline MADRS score, wherein baseline is the MADRS total score for the subject, e.g., 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., patient, is evaluated at regular intervals following step (b) to determine the relative effectiveness, wherein the evaluation comprises measuring the MADRS score of the subject, e.g., patient.

Embodiment 9c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having depression disorder.

Embodiment 10c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having major depressive disorder.

Embodiment 11c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has been diagnosed or is diagnosed as having treatment resistant depression (TRD).

Embodiment 12c. The method according to any one of the preceding Embodiments, wherein a score is improved in one of more depression assessment instruments selected from the group consisting of Montgomery-Asberg Depression Rating Scale (MADRS), Mini International Neuropsychiatric Interview (M.I.N.I.), e.g., Version 7.0.2, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ), Columbia Suicide Severity Rating Scale (C-SSRS), and Clinical Global Impression (CGI).

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

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

Embodiment 15c. The method according to any one of the preceding Embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is subcutaneously administered at a dose of about 1 mg, about

4 mg, or about 10 mg, wherein the dosing amount refers to the free base of Compound (I).

Embodiment 16c. The method according to any one of the preceding Embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is administered once a week to the subject, e.g., patient.

Embodiment 17c. The method according to any one of the preceding Embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is administered twice a week to the subject, e.g., patient.

Embodiment 18c. The method according to any one of the preceding Embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is administered once every two weeks to the subject, e.g., patient.

Embodiment 19c. The method according to any one of the preceding Embodiments, wherein Compound (I) or a pharmaceutically acceptable salt thereof, is administered once every three weeks to the subject, e.g., patient.

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

Embodiment 21c. The 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 week, 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. The method according to any one of the preceding Embodiments, wherein the depression disorder is selected from major depressive disorder, treatment resistant depression, suicidality in major depressive disorder, major depressive disorder with suicidal ideation, major depressive disorder with suicidal ideation and suicidal intent, major depressive disorder with suicidal behavior, and self-harm in major depressive disorder. Embodiment 23 c. The method according to any one of the preceding Embodiments, wherein the depression disorder is major depressive disorder.

Embodiment 24c. The method according to any one of the preceding Embodiments, wherein the depression disorder is treatment resistant depression.

Embodiment 25c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., 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. The method according to Embodiment 25c, wherein the antidepressant treatment is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine dopamine reuptake inhibitors (e.g., bupropion), norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs) (including reversible inhibitors of monoamine oxidase (RIMAs)), and multimodal antidepressants.

Embodiment 27c. The 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. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, is undergoing a major depressive episode.

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

Embodiment 30c. The method according to Embodiment 29c, wherein the subject, e.g., patient, has not responded to the at least one antidepressant in the current major depressive episode.

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

Embodiment 32c. The method according to Embodiment 29c, wherein the subject, e.g., patient, has not responded to at least two antidepressants in the current major depressive episode.

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

Embodiment 34c. The 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. The method according to any one of Embodiments 28c to 34c, wherein the current major depressive episode is of about at least 4 weeks, e.g., at least 6 weeks, about 8 weeks, in duration.

Embodiment 36c. The method according to any one of the preceding Embodiments, wherein treatment is in combination with at least one additional therapeutic agent. Embodiment 37c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, receives treatment with Compound (I), or a pharmaceutically acceptable salt thereof, in addition to treatment with one or more standard of care medicaments prescribed for a psychiatric disorder, e.g., depression disorder.

Embodiment 38c. The method according to any one of Embodiments 36c and 37c, wherein treatment is in combination with at least one additional antidepressant, antipsychotic, mood stabilizer, or combinations thereof.

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

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

Embodiment 41c. The method according to any one of Embodiments 38c to 40c, wherein the 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 (RIMAs)), and multimodal antidepressants.

Embodiment 42c. The method according to Embodiment 41c, wherein the 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. The method according to any one of Embodiments 38c to 42c, wherein the antipsychotic or mood stabilizer is selected from lithium, e.g., lithium carbonate, valproic acid, lamotrigine, olanzapine, aripiprazole, and risperidone.

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

Embodiment 45 c. The method according to any one of the preceding Embodiments, further comprising the step of determining or having determined the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, e.g, at about 24 hours, about 7 days, about 14 days, about 21 days and/or about 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment to thereby assess efficacy of treatment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof. Embodiment 46c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has a reduced MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has a reduced MADRS total score at about 24 hours, about 7 days, about 14 days, about 21 days and/or about 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e g., patient, prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof.

Embodiment 47c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has more than about 30%, e.g, more than about 35%, more than about 40%, more than about 45%, more than about 50%, improvement in the MADRS total score after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g. , the subject, e.g., patient, has more than 30 about %, e.g., more than about 35%, more than about 40%, more than about 45%, more than about 50%, improvement in the MADRS total score at about 24 hours, about 7, about 14, about 21 and/or about 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e.g., patient, prior to subcutaneous administration of Compound (I) or a pharmaceutically acceptable salt thereof. Embodiment 48c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, has a MADRS total score less than 12 after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, e.g., the subject, e.g., patient, has a MADRS total score less than 12 at about 24 hours, about 7 days, about 14 days, about 21 days and/or about 28 days after subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof, compared to baseline assessment, wherein baseline is the MADRS total score for the subject, e g., patient, prior to subcutaneous administration of Compound (I), or a pharmaceutically acceptable salt thereof.

Embodiment 49c. The method according to any one of the preceding Embodiments, wherein the subject, e.g., patient, is not concomitantly, e.g., simultaneously, treated with a treatment, e.g., antidepressive treatment, selected from ketamine, Compound (I), or a pharmaceutically acceptable salt thereof, electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, amantadine, monoamine oxidase inhibitors, citalopram, escitalopram, medications with a known risk of Torsades de Pointes, e.g., according to www.qtdrug.org, amitryptyline, nortryptyline, quetiapine, benztropine, diphenhydramine, trazodone, cannabis, medical marijuana, psychostimulants, e.g., amphetamines, methylphenidate, modafanil, armodafinil, and opioids.

Embodiment 50c. The method according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered subcutaneously, in the upper arm or abdominal area. Embodiment 51c. The 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. The method according to any one of the preceding Embodiments, wherein Compound (I), or a pharmaceutically acceptable salt thereof, is administered as the free base.

Embodiment 53c. A composition comprising Compound (I) in combination with a carrier, wherein the composition is 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. The composition of Embodiment 53c or 54c, wherein the composition comprises a tonicity agent and/or is isotonic.

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

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

Embodiment 58c. The device of Embodiment 57c wherein the actuator is a button or a plunger.

Embodiment 59c. The device of any one of Embodiments 56c to 58c, wherein the piercing element is a needle.

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

Embodiment 61c. The kit of Embodiment 60c, further comprising instructions for use.

Certain features that are described in this disclosure in the context of separate implementations can also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation also can be implemented in multiple implementations separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations, one or more features from a claimed combination can in some cases be excised from the combination, and the combination may be claimed as a subcombination or variation of a subcombination.

Examples

Abbreviations

AE Adverse Event

ALP Alkaline Phosphatase

ALT Alanine Aminotransferase

ANCOVA Analysis of covariance APA American Psychiatric Association

AST Aspartate Aminotransferase

AUC Area Under the Curve

AUClast Area under the curve from time zero to time of last measurable concentration

AV Atrioventricular

BP Blood Pressure

C-SSRS Columbia Suicide Severity Rating Scale

CADSS Clinical-Administered Dissociative States Scale

CGI Clinical Global Impression Scale

CGI-I Clinical Global Impression of Improvement

CGI-S Clinical Global Impression of Severity

ClinRO Clinician Reported Outcomes cm Centimeters

Cm ax Maximum plasma drug concentration

CNS Central Nervous System

COA Clinical Outcome Assessment

COVID-19 Coronavirus Disease

CR Concentration-response

CRF Case Report/Record Form (paper or electronic)

CYP2D6 Cytochrome P450 2D6

DBP Diastolic Blood Pressure

DBS Deep brain stimulation

DDI Drug-drug interaction

DNA Deoxyribonucleic Acid

DR Dose Response

DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

DSST Digit Symbol Substitution Task

EBT Emotional Bias Task

ECG Electrocardiogram

ECT Electroconvulsive therapy

EMA European Medicines Agency

EOS End-of-study

FDA Food and Drug Administration

FIH First in Human

G-GT Gamma-glutamyl transferase HBV Hepatitis B Virus

HCV Hepatitis C Virus

HIV Human immunodeficiency virus

HV Healthy volunteer

I.E. Intercurrent event

Intravenous

ICF Informed Consent Form

IN Investigator Notification

IRT Interactive Response Technology

IUD Intrauterine device

IUS Intrauterine system kg Kilogram(s)

M.I.N.I. Mini International Neuropsychiatric Interview

MADRS Montgomery Asberg Depression Scale

MAOI Monoamine oxidase inhibitors

MCP Multiple Comparison Procedures

MCP-Mod Multiple Comparison Procedure - Modeling

MDD Major Depressive Disorder mg Milligram (s)

MGH-ATRQ Massachusetts General Hospital Antidepressant Treatment Response Questionnaire mL Milliliter(s) mmHg Millimetre of mercury

MOAA/S Modified Observer's Assessment of Alertness and Sedation msec Millisecond

NAM Negative allosteric modulator ng Nanogram(s)

NMDA N-methyl-D-aspartate

NMDAR N-methyl-D-aspartate receptor

PD Pharmacodynamic(s)

PE Physical examination

PGIC Patient Global Impression of Change

PK Pharmacokinetic(s)

PoC Proof of Concept

PRO Patient reported outcome

PT Prothrombin time PT/INR Prothrombin time/Intemational normalized ratio

QTcF QT interval corrected by Fridericia’s formula

RO Receptor occupancy

S-STS Sheehan-Suicidality Tracking Scale s.c. Subcutaneous

SAD Single Ascending Dose

SAE Serious Adverse Event

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2

SBP Systolic Blood Pressure

SIGMA Structured Interview Guide for MADRS

SNRI Selective Norepinephrine Reuptake Inhibitors

SPRAVATO Esketamine

SSRI Selective Serotonin Reuptake Inhibitors

Tl/2 Elimination half-life

TBIL Total Bilirubin

TdP Torsades de Pointes

TEAE Treatment-emergent adverse event

Tmax Time to reach maximum plasma concentration

TMS Transcranial magnetic stimulation

TRD Treatment-Resistant Depression

VNS Vagus nerve stimulation

WHO World Health Organization

LLM Micromolar

Example 1 Absorption, bioavailability and pharmacokinetics

Compound (I) demonstrated low oral bioavailability in animals (<10% in mice, rats, or dogs).

Following subcutaneous administration, the bioavailability was surprisingly higher (61% in mice, and 70% in rats). The subcutaneous route of administration has surprisingly shown higher bioavailability compared to oral gavage dosing.

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

Example 2 Preclinical study with s.c. Compound (I) NMDA receptor blockers like ketamine and MK-801, also known as Dizocilpine, are known to reverse haloperidol-induced catalepsy in rats. The pharmacodynamic effect of Compound (I) was measured by quantifying the degree of reversal of haloperidol-induced catalepsy in this model. Locomotor activity in rats was measured as a surrogate model for the potential to induce psychotomimetic effects. Rat haloperidol-induced catalepsy (The BAR test):

The bar test was used to assess catalepsy whereby the front paws of a rat are placed on a horizontal metal bar raised 6” above a Plexiglas platform and the time spent holding the bar is recorded for up to 60s per trial. The test ends when the animal’s front paws return to the platform or after 60s.

In this test, rats were treated by subcutaneous injection either with vehicle (negative control) or Compound (I) (at 0.1, 0.3, 1, 3, and 10 mg/kg). CP-101,606 (Traxoprodil), an NMDA receptor antagonist specific to the NR2B subunit, served as a positive control at 10 mg/kg (subcutaneous injection). The test started 30 min post dose.

Compound (I) dose-dependently reduced bar holding time at all doses tested (Figure 2), with a minimal efficacious dose of 0.1 mg/kg and was found to reverse haloperidol-induced catalepsy.

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

Locomotor Test

Locomotor activity is a measure that can detect alterations across multiple activity measures in addition to basic exploratory drive. It is frequently used as a preclinical surrogate of psychotomimetic effects. In this test, rats are placed in a locomotor activity chamber and distance traveled is measured from horizontal photocell beam breaks automatically recorded by a computer system.

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

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

Rat Quantitative Electroencephalography (qEEG)

Quantitative EEG (qEEG) experiments provide real-time assessment of the EEG frequency when the animal is at rest or upon drug administration, thus translating 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 decreases in mid-low frequency bands, most notably in alpha, beta, and the beta sub-bands (Keavy et al, 2016; Nagy et al, 2016).

In this test, rats were treated by subcutaneous injection either with vehicle (negative control) or Compound (I) (at 0.1, 0.3, and 1 mg/kg). EEG recording began 60 min pre-dose (habituation phase) and continued up to 2h post dose. Results (Figure 4) demonstrate that Compound (I) preferentially modulates mid-frequency spectral powers, specifically within the beta (primarily driven by the betal sub-band) and alpha frequency bands while having no significant effect above vehicle on relative gamma power, confirming its selectivity as NR2B NAM in vivo.

Data are presented as mean ± SEM (N=10). Data were analyzed by One-Way AN OVA.

Taken together, these nonclmical data show that Compound (I) administered subcutaneously to rats was active and selective to the NR2B subunit and reversed haloperidol-induced catalepsy, a model of target engagement and pharmacodynamic activity.

In summary, the preclinical data are considered supportive of the subcutaneous administration of Compound (I) in patients in clinical studies.

Example 3 Clinical study with subcutaneous dosage of Compound (I)

Phase 1 study in HVs with subcutaneous dosage of Compound (I)

This is a SAD (single ascending dose) study with randomized, participant and investigator blinded, placebo-controlled design to investigate the safety, tolerability and PK of subcutaneous administered Compound (I) in healthy participants. The study is ongoing and will include approximately 32 non-Japanese and 12 Japanese participants. Study participants (non-Japanese) have already been enrolled into three sequential cohorts and received a single subcutaneous dose of 1, 4 or 12 mg Compound (I) or placebo. Eight participants completed treatment in each cohort with a randomization ratio 3:1 for Compound (I) to placebo. Subsequently, 12 Japanese participants will be enrolled into a single cohort and receive a dose of subcutaneous 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) cohorts (1, 4 and 12 mg subcutaneous Compound (I) or placebo) indicate that the safety and tolerability of Compound (I) was acceptable across the dose ranges tested in the study.

Purpose

The main purpose of this non-confirmatory study is to evaluate the safety and immediate efficacy of a single subcutaneous injection of Compound (I) in addition to standard pharmacological antidepressant (SoC) treatment in participants suffering from TRD assessed by the MAD RS (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 employed scale in depression disorder trials, evaluated approximately 24 h after study drug administration. Objectives, endpoints and estimands

Table 3-1 _ Objectives and related endpoints

Objective(s) Endpoint(s)

Primary objective(s) Endpoint(s) for primary objective(s) • To assess efficacy of Compound • (MADRS total score at 24 hours after s.c. injection compared to

(I) (versus placebo) in treatment baseline assessment resistant depression after single s.c.

(subcutaneous) injection

Secondary objective(s) Endpoint(s) for secondary objective(s)

• To assess safety and tolerability of • Incidence and severity of treatment-emergent adverse events Compound (I) after single s.c. (TEAEs), including AEs of special interest; standard safety injection assessments such as vital signs, ECG, hematology, blood chemistry, urinalysis; Clinician-Administered Dissociative States Scale (CADSS) score, Modified Observer's Assessment of Alertness/Sedation (MOAA/S), C-SSRS (Columbia Suicide Severity Rating Scale), memory assessment using orientation questions, results of local tolerability assessments

• To assess Compound (I) PK in • PK properties of Compound (I) in plasma described by Area plasma after single s.c. injection under the curve from time zero to time of last measurable concentration (AUClast), maximum plasma drug concentration (Cmax), time to reach maximum plasma concentration (Tmax) (parameters not limited).

• To assess the duration of • MADRS total score at Day 8, 15, 22 and 29 visits compared to antidepressant effect of Compound baseline

(I)

• To characterize the dose-response • Dose-response relationship of Compound (I) with respect to and exposure-response relationship change from baseline in MADRS total score at 24 hours after of Compound (I) single s.c. injection

• Exposure-response relationship of Compound (I) with respect to change from baseline in MADRS total score at 24 hours (Day 2)

Exploratory objective(s) Endpoint(s) for exploratory objective(s)

• To assess the participant's • Proportion of participants achieving improvement evaluated by impression of change in the severity Patient Global Impression of Change (PGIC) score by visit of their disease

• To assess the efficacy of • Percent (%) treatment response (>50% improvement in MADRS

Compound (I) on measures of from baseline) at Day 2, 8, and 29 visits response and remission Percent (%) treatment remission (MADRS<12) at Day 2, 8, and 29 visits • To assess the effect of Compound • MADRS total score at Day 8, 15, 22 and 29 visits compared to (I) on depressive symptoms and baseline mood • Clinical Global Impression of Severity (CGI-S) score at Day 8,

15, 22 and 29 visits compared to baseline

• Proportion of patients achieving improvement evaluated by Clinical Global Impression of Improvement (CGI-I) at Day 8, 15, 22 and 29 visits

• To assess the effect of treatment • Digital Symbol Substitution Task (DSST) score at Day 2, 8, 15, on cognition and emotional bias 22 and 29 visits compared to baseline

• Emotional Bias Task (EBT) at Day 2, 8, 15, 22 and 29 visits compared to baseline

• To characterize Compound (I) • CADSS (Clinical-Administered Dissociative States Scale) score effect on dissociation, sedation and at each visit and time point compared to baseline amnesia • MOAA/S (Modified Observer's Assessment of Alertness and

Sedation) scale score at each visit and time point compared to baseline

• Memory assessment using orientation questions

• To assess CYP2D6 genotype • Classification of participants into CYP2D6 metabolizer status of each participant (optional) phenotypes and the correlation between PK • PK parameters of primary interest for the correlation (if data parameters and the CYP2D6 allows): Cmax, AUClast (parameters not limited) genotype, if data allows

• To perform optional genetic • DNA sampling. Due to the exploratory nature of this objective, research to investigate drug related endpoints are not predefined. response mechanisms, to better understand the disease and/or the safety and efficacy of Compound (I)

The clinical study aims to establish the effect of s.c. Compound (I) (versus placebo) given in addition to standard of care pharmacological antidepressant (SoC) treatment 24 hours after the injection of Compound (I) on change in depressive symptoms in participants with TRD, who have already failed to adequately respond to at least two conventional antidepressants.

Rationale

The justification for the primary estimand is that it will allow estimating the rapid effect of Compound (I) in a population of depressed participants, who are considered treatment resistant, based on the definition above. A rapid response is clinically valuable, as conventional antidepressants might need several weeks to achieve reduction of depressive symptoms.

The primary estimand is described by the following attributes:

1. Population: participants with treatment resistant depression, who have failed to show adequate treatment response to at least 2 antidepressants previously.

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

3. Treatment of interest: the randomized treatment (Compound (I) or the placebo treatment) administered as a single s.c. injection on Day 1. The dose of the allowed concomitant medication (i.e. SoC) for depression must remain stable during the trial.

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

• New intake or change in concomitant medications/therapies that have a potential confounding effect: hypothetical strategy

• Intake of prohibited medications: hypothetical strategy

• Intake of rescue medications: hypothetical strategy

• lEs related to pandemic: hypothetical strategy

• lEs leading to study discontinuation due to adverse events (AEs), lack of efficacy or other reasons: treatment policy

Participants who took prohibited medications, rescue medications, or took new or change concomitant therapy that have potential confounding effect, will continue in the study and be assessed as scheduled.

The summary measure: difference in variable means between study drug and placebo.

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

Studv design

As shown 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 single subcutaneous Compound (I) administration in addition to pharmacological antidepressant standard of care (“SoC”) treatment. Approximately 56 participants will be randomized in a total of 20-25 centers worldwide.

Participants will be randomly allocated to one of the following four treatment arms in a 1 : 1 : 1 : 1 ratio:

• Single administration of Compound (I) s.c. 1 mg

• Single administration of Compound (I) s.c. 4 mg

• Single administration of Compound (I) s.c. 10 mg

• Single administration of Placebo s.c. The screening period starts when the participant signs the informed consent form and can last up to 28 days. The eligibility of participants is determined based on the assessments performed during the screening period and also on Day 1, prior to randomization. With the exception of lab results, all other baseline evaluations including the primary efficacy scale (MADRS) must be performed on Day 1, prior to randomization, and reviewed against the eligibility criteria before dosing. On Day 1/pre-dose, eligible participants will be randomized to one of the above treatment arms.

Treatment is administered as a single s.c. injection on Day 1, followed by a safety observation at the clinical site for a minimum of 4 hours after administration. Study participants will be continuously observed by site personnel during the first 30 minutes after administration for emergence of adverse events, particularly CNS (Central Nervous System) or cardiovascular AEs. Safety assessments will include physical examinations (PEs), ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and urinalysis), administration of the CADSS, MOAA/S, C-SSRS, and memory assessment using orientation questions. Local tolerability will be evaluated by visual inspection of the injection area. Injection site abnormalities reaching the threshold of mild changes will also be assessed quantitatively.

Participants will be allowed to leave the clinical site at the earliest 4 hours after dosing, if all of the following criteria are fulfilled:

• The participant does neither report nor present with any CNS adverse events (dissociation, amnesia, sedation)

• There is no increase in suicidal intensity or new occurrence of suicidal ideation as assessed by C-SSRS

• No clinically relevant QTcF prolongation (QTcF>500 msec or increase in QTcF from baseline>60 msec)

• No clinically relevant abnormalities in blood pressure (BP) (90<Sysotlic BP (SBP) >180 mmHg or 50<Diastolic BP (DBP) >105 mmHg or increase or decrease in SBP of at least 20 mmHg or increase or decrease in DBP of at least 1 mmHg from baseline) or any increase in BP that is accompanied by symptoms, such as headache, dizziness, nausea, visual disturbances or other neurological symptoms

• The investigator does not identify any other AEs that require continued monitoring

If the participant cannot be released from the clinical site 4 hours after dosing, extended safety monitoring will be performed as described below.

The post-dose follow-up period will continue for 4 weeks (28 days) after treatment. On-site visits to assess efficacy and safety are scheduled on Day 2 (24 hours post-dose) and subsequently every week (i.e. on Days 8, 15, 22 and 29) during the follow-up period. The assessment to address the primary objective will be performed at Day 2 (24 hours post-dose). Phone calls will be conducted 3 days after each on-site visit. End-of-study (EOS) visit will be completed on site on Day 29 and the safety follow-up call will be conducted over the phone on Day 31 (30 days after dosing). The total duration of the study is approximately 8 weeks (56 days), including screening. Extended safety monitoring, in case of AEs on Day 1

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

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

• If there are any dissociative AEs, amnesia or somnolence/sedation present, the participant should be monitored at the clinical site until these AEs are fully resolved. If the dissociative AEs or cognitive symptoms do not resolve within 6 hours after onset, the participant will be required to stay at the clinical site for overnight monitoring and can be discharged after the assessments are completed on Day 2 and the AEs have resolved. The onset and resolution time of dissociative and cognitive AEs should be captured as accurately as possible. The following assessments are recommended to follow CNS AEs, whenever possible (e.g., participant is awake):

• If dissociative AEs are present, it is recommended to administer the CADSS every hour until the total score returns to baseline or normal level (i.e. , total score not higher than 4)

• If memory gaps/amnesia is present, it should be assessed with orientation questions at least once per hour until the amnesia is resolved

• Sedation/somnolence should be assessed by questionning or the administration of the MOAA/S every hour until the AE is resolved

• Monitoring of suicidal ideation or behavior:

• If moderate to severe suicidal ideation or any suicidal behavior is present, either based on rating scales or investigator judgment, the investigator must hospitalize the participant at least overnight

• If suicidal ideation is mild, either based on rating scales or investigator judgment, the investigator's judgment can be used to allow the participant to leave the clinical setting, but in that case arrangements should be made such that family members or friends are present with the participant for at least 24 hours. If such arrangements cannot be made, it is recommended that the participant is hospitalized at least overnight

• Monitoring of QTcF prolongation:

• If the initial QTcF prolongation is confirmed by repeated ECG at least 10 minutes later, close observation of the participant should be initiated at the investigator’s discretion

• ECG should be performed eveiy 30 minutes until QTcF is below 500 msec and the increase from baseline is less than 60 msec

• Serum electrolyte levels should be determined and corrected, if needed (in particular hypokalemia, hypomagnesemia)

• Consultation with a cardiologist can be performed at the investigator's discretion Monitoring of increased blood pressure:

• Increase in blood pressure should be monitored but initial treatment is not recommended unless clinically indicated. Blood pressure increase associated with Compound (I) treatment is usually transient and the blood pressure typically returns to pre-dose values within 3-4 hours

• At 1.5 hours post-dose, if SBP is >160 mmHg and/or the DBP >100 mmHg, assessments should continue every 30 minutes until:

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

2. As per investigator’s clinical judgment, the participant is clinically stable, or

3. The participant is referred for appropriate medical care, if clinically indicated

4. If the blood pressure remains > 160 mmHg SBP and/or / >100 mmHg DBP after 4 hours post-dose, the participant should be referred for immediate medical treatment

Rationale for study design and overall study desi n

The main purpose of the study is to investigate the efficacy of Compound (I) after s.c. administration in participants with treatment resistant depression. The design of this study has been selected to adequately assess the primary objective and follows the treatment guidelines of American Psychiatric Association (APA) treatment for depression 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 effect of expectation bias and measurement bias. A parallel design was selected as it ensures unbiased comparison between the treatment arms. This design also avoids any potential carry over effect that might arise in a different design, such as cross-over.

Three Compound (I) arms with different doses are included in the study to allow estimation of the dose-response and exposure-response relationship of the antidepressive effect 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 pivotal Phase 3 studies.

The study includes a frequent visit schedule, with weekly on-site visits at the clinical sites and phone calls in between, for safety and efficacy assessments.

In a previously completed PoC study in treatment resistant depression participants, the efficacy of Compound (I) has been evaluated after i.v. administration. Results of the current study with s.c. Compound (I) will be compared to those of the completed PoC study in a similar population with i.v. Compound (I) to explore if there are any major differences in safety and efficacy of Compound (I) when administered via s.c. or i.v. route. It is therefore important to ensure that the two studies utilize essentially the same design, same primary endpoint and recruit the same participant population. Rationale for choice and timing, of efficacy assessments

For the primary objective, the efficacy will be determined using the MADRS Montgomery and Asberg 1979 which is a standard for the evaluation of a major depressive episode. The 24-hour post-dose time point was chosen for the primary analysis to collect information about Compound (I). Achieving a rapid antidepressant effect is clinically meaningful, as participants with major depression are at risk of suicide or self-harm, while conventional antidepressant drugs might take several weeks to reach efficacy. The primary endpoint and its timing are also the same as in the completed PoC study to ensure that the results of the two studies can be compared.

Rationale for safety assessments

The safety assessments and their frequency were selected based on the completed FIH and PoC studies and the ongoing SAD study with s.c. Compound (I) in healthy volunteers.

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

Other potential risks associated with Compound (I) are QTc prolongation and increase in blood pressure. These events are associated with Cmax of Compound (I) and tend to decline during the first 4 hours after administration. Therefore, frequent ECG and BP measurements will be performed during the first 4 hours after injection to identify any potential effect on QTc and BP.

Additional safety assessments include standard lab tests (hematology, blood chemistiy, and urinalysis), physical examination and monitoring of AEs and SAEs. As participants with major depressive disorder or treatment resistant depression are at risk of suicide, the Columbia Suicide Severity Rating Scale (C-SSRS) will be used at every visit to monitor suicidal thoughts and behavior.

Selection of patient population

The study intends to investigate Compound (I) in participants with treatment resistant depression, where a potentially rapid acting antidepressant drug can be beneficial. Treatment resistance will be defined based on retrospective assessment of previous treatment regimens and their outcome by the investigator and supported by medical records. The same approach was used in the completed PoC study and is adapted here to ensure participants enrolled into the two studies represent the same participant population.

Other eligibility criteria are defined to ensure a homogenous study population and minimize the risk associated with study participation.

Rationale of treatment duration

A rapid response is meaningful in treatment resistant depression, a population that failed to respond to conventional antidepressants used for adequate duration of time and at adequate dose. Depression disorder often leads to suicidal thoughts or behavior, putting patients at risk. However, conventional antidepressant treatment might take a few weeks to achieve treatment benefit. There is thus a need for rapid acting, safe antidepressant treatments. To assess, whether Compound (I) can rapidly improve symptoms of treatment resistant depression after s.c. administration, a single dose treatment is sufficient.

Another purpose of the study is to assess the duration of efficacy of s.c. Compound (I). To assess the duration of efficacy, single dose treatment is the most suitable method, as it provides direct information about the efficacy of a single injection without any confounding effect of repeated dosing.

In the completed PoC study, Compound (I) was superior to placebo in reducing depressive symptoms measured by the MADRS total score at 24 hours after the first administration. Compound (I) also was significantly better than placebo after repeated dosing for 6 weeks when administered at 0.16 mg/kg dose biweekly or at 0.32 mg/kg dose weekly. The other two dose groups (0.16 mg/kg weekly and 0.32 mg/kg biweekly) also showed numerical improvement on MADRS score. Nevertheless, the PoC results demonstrate that the early response (24-hour post first dose) to Compound (I) and the results of repeated administration (6 week results) were similar, suggesting that the early response might be indicative of longer term results. In the PoC study, the maximum improvement of the MADRS score in the active treatment groups was already observed after the first drug administration. There was no further accumulation of the effect after later drug administrations. This suggests, surprisingly, that a single drug administration is sufficient to estimate the maximum drug effect.

Rationale for choice of control drugs (comparator/ylacebo) or combination drugs

The use of a double-blind placebo arm against the Compound (I) arms is to provide a comparison group for an unbiased collection of efficacy, safety, and tolerability data. Based on the high degree of placebo response in depression disorder trial, placebo is necessary to assess the efficacy of an investigational drug (Kirsch I (2019) Placebo Effect in the Treatment of Depression and Anxiety. Front Psychiatry; 10:407). Purpose and timing of interim analyses

An interim analysis, for internal modelling purposes will be performed after approximately 28 participants have completed the study at Day 29 (or discontinued prior to Day 29). The purpose of this interim analysis will be outside of study goals. This interim analysis for internal modelling purposes will be conducted by unblinded pharmacometric members. The unblinded results of the interim analysis for internal modelling purposes will not be communicated to the blinded study team.

Further interim analysis might be performed at any time during the study to support decision making concerning the current clinical study, the sponsor’s clinical development plan or in case of any new safety concerns.

Study Population

Approximately 56 participants with TRD will be randomized to receive either Compound (I): 1 mg, 4 mg, or lOmg or placebo, in addition to standard pharmacological antidepressant SoC treatment, in a 1 : 1: 1 : 1 ratio in a total of 20-25 centers worldwide.

TRD is defined based on retrospective assessment of antidepressant treatment failure as per treatment history, as specified in the Inclusion criteria below. The investigator must ensure that all participants being considered for the study meet the following eligibility criteria. No additional criteria should be applied by the investigator, in order that the study population will be representative of all eligible participants.

Participants selection is to be established by checking through all eligibility criteria at screening and the relevant eligibility criteria at baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source documentation at the study site.

Deviation from any entry criterion excludes a participant from enrollment into the study.

Inclusion criteria

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

1. Signed informed consent must be obtained prior to participation in the study.

2. Male and female participants, 18 to 65 years of age (inclusive) at screening.

3. Participant has a diagnosis of recurrent MDD and a current major depressive episode of at least 8 weeks in duration as defined by DSM-5 criteria and confirmed by both the MINI and an adequate clinical psychiatric evaluation at screening.

4. MADRS > 24 at screening and before randomization on Day 1.

5. Failure to respond to 2 or more antidepressant treatments but no more then 5, where the two failed treatments are two different antidepressants and at least one of which was used in the current depressive episode, with adequate dose and duration (> 6 weeks duration, doses defined per agent), as identified by the MGH-Antidepressant Treatment Response Questionnaire, based on the patient's report and prior psychiatric history, assessed by the investigator, and further documented by medical records. Patients with historical treatment failure to esketamine, ketamine or arketamine are excluded.

6. Participant must agree to receive pharmacological standard of care treatment to treat their MDD (as determined by the treating physician(s) based on clinical judgement and local treatment guidelines) during the trial duration.

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

8. The antidepressant should be at a stable dose for at least 4 weeks before baseline. No new antidepressant initiated 6 weeks or less before baseline. No psychotherapy initiated 4 weeks or less before baseline.

9. Able to communicate well, and to understand and comply with study requirements.

Exclusion criteria

Participants meeting any of the following criteria are not eligible for inclusion in this study:

1. Current acute depressive episode lasting longer than two years continuously, or participants receiving electroconvulsive therapy (ECT), vagal brain stimulation (VNS) or deep brain stimulation (DBS) within last year prior to screening. 2. Any prior or current diagnosis of MDD with psychotic features, bipolar disorder, schizophrenia, or shizoaffective disorder as obtained from M.I.N.I, Module C (Manic and Hypomanic Episodes) and Module K (Psychotic Disorders and Mood Disorders with Psychotic Features) assessed at screening.

3. Participants with acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, or participants who went through detoxification treatment (inpatient or outpatient) within 1 month before Screening, as obtained from SCID-5 at 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 suicidal attempt or suicidal behaviour within last year prior to screening and participants presenting suicidal ideation with intent documented by C-SSRS by Yes response to Q4 or Q5 at screening or baseline.

7. Participants with evidence of significant renal insufficiency, indicated by an estimated glomerular filtration rate (eGFR) of < 40 mL/min/1.73 m2 at screening.

8. Use of other investigational drugs at the time of screening, or within 30 days or 5 half-lives of screening, whichever is longer.

9. History of hypersensitivity to any of the study treatments or excipients or to drugs of similar mechanism of action (i.e. drugs that affect the NMDA receptor).

10. Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or active COVID-19 infection as per medical history and/or available medical records.

11. History of seizures. Note: childhood febrile seizures are not exclusionary.

12. Cardiac or cardiac repolarization abnormality, including any of the following:

• History of myocardial infarction, angina pectoris, or coronary artery bypass graft within 6 months prior to starting study treatment

• History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g. , bifascicular block, Mobitz type II and third degree AV block) within 6 months prior to starting study treatment

13. Resting QTcF >450 msec (male) or >460 msec (female) at screening or baseline.

14. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia or any of the following:

• Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome

• Concomitant medication(s) with a “Known Risk of TdP” that cannot be discontinued or replaced by safe alternative medication 15. Participant has mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg at Screening or pre first dose on Day 1 ; or past history of hypertensive crisis.

16. History of hemorrhagic stroke or known cerebrovascular disorders (e.g. aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other location (e.g. aorta).

17. Pregnancy (including a positive human chorionic gonadotropin [hCG] test) or lactation at screening or baseline.

18. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. Highly effective contraception methods include:

• Total abstinence from heterosexual intercourse (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to screening). For female participants on the study the vasectomized male partner should be the sole partner for that participant.

• Use of intrauterine device (IUD) or intrauterine system (IUS). In case of use of an IUD or IUS, the device or system should have been placed and well tolerated by the patient for a minimum of 3 months before taking the study treatment.

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception other forms of hormonal contraception are not allowed for the purpose of contraception.

If local regulations deviate from the contraception methods listed above and require more extensive measures to prevent pregnancy, local regulations apply and will be described in the ICF.

Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

19. Sexually active males unwilling to use a condom during intercourse while taking investigational drug and for 1 week after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child and to prevent delivery of the investigational drug via seminal Ill fluid to their partner. In addition, male participants should not donate sperm for the time period specified above.

20. Participants taking medications prohibited by the protocol (see Table 3-4)

21. Any other condition (e.g. known liver disease/liver dysfunction, active malignancy etc.) which in the opinion of the investigator would put the safety of the participant at risk, affect compliance or make the patient an unsuitable candidate for the study.

General Note: In the case where a safety laboratory assessment at screening and/or baseline is outside of the range specified above, the assessment may be repeated once prior to randomization. If the repeat value remains outside of the specified ranges, the participant is excluded from the study.

Study treatment

Study treatment consists of Compound (I) or placebo. Compound (I) 20 mg will be supplied centrally as lyophilized powder in vials (pharmaceutical form).

Compound (I) 20 mg will be reconstituted with water for injection to obtain the solution for injection 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 at site.

Details on the requirements for storage and management of study treatment, and instructions to be followed for participant numbering, prescribing/dispensing, and administration of study treatment are outlined in the Pharmacy Manual.

Investigational and control drugs

Table 3-2 Investigational and control drug

Investigational/ Pharmaceutical D Route of Supply Type Sponsor (global

Control osage Form Administration or local)

Drug

Compound (I) 20 Powder for Injection use (after Open label supply, Sponsor (global) mg solution for reconstitution) vials (one vial per

Lyophilisate in vial injection kit)

Placebo 0.9% Injection use Open label; Locally by site sodium chloride infusion bag/bottle solution

The investigational treatment for this study is Compound (I). Due to the difference in preparation between Compound (I) and placebo, unblinded qualified site personnel, independent from the investigational staff, are required to maintain the blind.

Additional study treatments No other treatment beyond investigational drug, control drug (placebo), and antidepressant pharmacological standard of care are included in this trial.

Standard of care pharmacological treatment in the study consists of antidepressants or combinations of antidepressant with other drugs used for depression disorder augmentation. It is recommended that antidepressants used as background therapy during the study are FDA approved for MDD indication (see

Table 3-3 below).

Table 3-3 Antidepressants recommended to be used as background therapy during the study

* Table adapted from FDA-Approved Drugs to Treat Major Depressive Disorder (MDD). 2021

Treatment arms/group Participants will be randomly allocated to one of the following four treatment arms in a 1 : 1 : 1 : 1 ratio, on Day 1:

• Single administration of Compound (I) 1 mg, one s.c. injection

• Single administration of Compound (I) 4 mg, one s.c. injection • Single administration of Compound (I) 10 mg, one s.c. injection

• Single administration of placebo, one s.c. injection

Treatment duration

Participants will receive a single s.c. injection on Day 1.

Concomitant therapy

All medications, procedures and significant non-drug therapies (including physical therapy and blood transfusions, SARS-CoV-2 vaccine) administered after the participant was enrolled into the study must be recorded in the concomitant medications/significant non-drug therapies CRF.

The investigator should instruct the participant to notify the study site about any new medications he/she takes after the participant is enrolled in the study. All medications, procedures and significant non-drug therapies administered after the participant is enrolled into the study must be recorded. The start and stop date and time of each medication use should be recorded as precisely as possible.

Each concomitant drug must be individually assessed against all exclusion criteria/prohibited medication.

All allowed concomitant baseline psychotropic medications used for treatment of depression must be documented as Standard of Care (SoC) and remain unchanged throughout the study. Any change in SoC after randomization (dose changing or starting new drugs) should be documented in medical records and reported in the eCRF.

Certain benzodiazepines, specifically lorazepam or alprazolam (as authorized by country), will be allowed for episodic or chronic use. These should not be taken within 12 hours before and within 4 hours after dosing unless it is used as rescue medication not to exceed 2 mg in a 24-hour period. Such lorazepam or alprazolam use will be documented as concomitant medication(s) and administration time should be documented in medical records and reported in the eCRF.

Any vaccinations 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 time period after s.c. administration should be monitored with extra caution. All safety observations should be carefully observed for increased or unexpected frequency and severity.

Based on nonclinical information, Compound (I) is predicted to be eliminated predominately by oxidative metabolism via CYP2D6 (64% of elimination). Inhibition of the elimination pathways may lead to an increase of Compound (I) exposure. The following investigations have been executed to assess the potential drug -drug interaction on the major elimination pathway via CYP2D6:

• The impact of strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine and bupropion) on the exposure of i.v. infused Compound (I) has been investigated in drug-drug interaction (DDI) simulations by means of the SimCYP® software. The simulated Cmax values were in maximum 1.3-fold higher in the presence of fluoxetine or paroxetine and the AUC values in maximum 2-fold for all CYP2D6 genotypes (poor, extensive, or ultra-metabolizers). The resulting mean exposure values in the presence of strong CYP2D6 inhibitors are within the exposure range investigated in the FIH study after i.v. 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 estimated. Following s.c. administration of the highest dose (12 mg) in the s.c. SAD study with HVs, the exploratory mean AUClast and Cmax values are 257 h*ng/mL and 77.4 ng/mL, respectively, being comparable to the exposure values after i.v. infusion of 0.16 mg/kg Compound (I) in the FIH study. As discussed above, the mean exposure values after s .c. administration of the highest dose in this study (10 mg) are within the exposure range investigated in the FIH study in the presence of strong CYP2D6 inhibitors.

• Furthermore, in the PoC study, Compound (I) doses: 0.16 and 0.32 mg/kg), approximately 70% of participants received at least one CYP2D6 inhibitor (weak to strong CYP2D6 inhibitor or combinations of them). The Cmax values at both doses and the AUC values at 0.16 mg/kg do not exceed the exposure range determined in the FIH study.

Based on overall clinical experience, the totality of the safety data suggest that Compound (I) is generally safe and well tolerated and observed adverse events were transient. The risk of an overdose or unexpected AEs due to an exposure increase by CYP2D6 inhibition is considered to be low for the proposed Compound (I) doses being less or equal to 10 mg. In conclusion, CYP2D6 inhibitors are allowed as co-medications. Nevertheless, caution has to be taken when strong CYP2D6 inhibitors are administered.

Based on nonclinical information, Compound (I) may affect the elimination of compounds eliminated predominantly via CYP3A4 and CYP2D6. The impact of Compound (I) on the exposure of midazolam (CYP3A4 substrate) and desipramine (CYP2D6 substrate) has been investigated in drug-drug interaction (DDI) simulations by means of SimCYP® software. No exposure increase of both probe substrates has been estimated at the highest tested Compound (I) dose of 0.48 mg/kg after i.v. infusion. Therefore, the risk of an overdose or unexpected adverse events of co-administered sensitive CYP3A4 and CYP2D6 substrates is considered to be not significant at s.c. doses of < 10 mg Compound (I).

Prohibited medication

Use of the treatments displayed in the below table are not allowed 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 impact on memory and cognitive functions. Medications with a potential impact should be avoided for at least one half-life of the medication before each study visit and one half-life after each study drug administration.

Table 3-4 _ Prohibited Medications or Treatment

Rescue medication

Rescue medications will not be supplied by the sponsor.

The following rescue medications may be considered and the use of these should be documented in the medical records and in the eCRF.

For agitation and anxiety or aggressive behavior (per investigator's judgment or local clinical practice): as required, midazolam (maximum dose 2.5 mg orally or intramuscular), any short-acting benzodiazepine (e.g., lorazepam), or antipsychotics (e.g., quetiapin, olanzapine, promethazin, or dipiperon).

Prohibited medication (see Table 3-4) can be administered as rescue medication at any time if clinically warranted.

Handling of study treatment and other treatment

Instruction for prescribing and taking study 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 abdominal area, above (i.e. cranial to) the line of the umbilicus, but not within 5 cm from the umbilicus. The injection must not be administered in an area with scars, inflammation, proliferative skin disease (including nevus), tattoo, bum or other abnormalities of the skin. The injection must be administered by trained staff with appropriate technique and by considering the participant’s body shape (e.g. , thickness of local subcutaneous tissue). For thin participants, using the skin-fold technique is recommended. The injection will be administered slowly (over 15-30 sec). Care must be taken not to administer the study treatment as intramuscular injection, as that might change 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 will be recorded in the IRT system.

Each study site will be supplied with investigational treatment (Compound (I)) kits.

Efficacy Assessments

Handling of Efficacy Assessments by Independent Site Raters

The primary efficacy endpoint of Compound (I) compared with 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 gaps/amnesia and cardiovascular events. To minimize the risk of introducing bias, trained and qualified site personnel will perform efficacy and safety assessments. Independent site raters who perform the MADRS, CGI -I and CGI-C will be different from those who evaluate vital signs, adverse events, ECG results, MOAA/S, CADSS and C-SSRS. Independent site raters for the MADRS, CGI-I and CGI-C are not allowed to access or review participants safety records and, therefore, must not provide clinical care for participants. Clinical care of participants will be performed by the investigator or delegate at the study site who are not MADRS, CGI-I and CGI-C raters.

Whenever possible, all efforts should be made to use the same independent raters for the MADRS, CGI-S and CGI-I at each site to assess the same participant throughout the study. If this is not possible, review of the appropriate prior assessments and communication with prior raters should be conducted, as needed. Any clinically relevant safety findings from the scales or the interviews must be communicated to the investigator.

During the study, the roles of the investigator and the independent site rater, including their backups, are not interchangeable at the participating sites.

Montgomery Asberg Depression disorder Rating Scale (MADRS), SIGMA version

The Montgomery Asberg Depression disorder Rating Scale (MADRS, SIGMA version) is a clinicianrated scale designed to measure depression disorder severity and detects changes due to antidepressant treatment: the test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts and suicidal thoughts (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 exhibits high inter-rater reliability. In this study, the following recall periods will be used: “Last 7 days with euthymic baseline”, “over the past 4 hours”, "Last 7 days", and "Since last evaluation" for the primary endpoint. Whenever possible, the MADRS should be administered by the same rater to assess the same participant throughout the study.

The MADRS is a standard scale used for registration studies of depression disorder. It is relatively quick to administer, does not focus predominately on the somatic symptoms of depression disorder, but rather addresses core mood symptoms such as sadness, tension, lassitude, pessimistic thoughts, and suicidal thoughts. The MADRS is sensitive to change from treatment effects over time and is considered a gold standard registration scale for depression.

Additional assessments

Clinical Outcome Assessments (COAs)

During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, COA data may be collected remotely. Clinician Reported Outcomes (ClinRO)

ClinROs will be used to establish the diagnosis of depression and to assess and record the patient's treatment history at Screening. They will also be used to measure the impact 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 CGLI)

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 DSM-5 and ICD- 10. It is divided into diagnostic modules including screening questions corresponding to the criteria for each disorder that allow the physician to assess whether the diagnostic criteria have been met.

The full M.I.N.I. version will be provided to the sites. M.I.N.I. will be administered on paper by qualified personnel at 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 Disorder), Module J (Substance Use Disorder, 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 must be added to the source records to confirm the 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 who are familiar with the DSM-5 classification and diagnostic criteria. The version used for this trial is the SCID-5 -Clinical Trials version (SCID-5-CT). It guides the clinician step-by-step, through the DSM-5 diagnostic process, and allows to assess whether the diagnostic criteria have been met. Interview questions are provided along each corresponding DSM-5 criterion, which aids in rating each criterion as either present or absent. The SCID-5 - CT covers the DSM-5 diagnoses most commonly seen in clinical settings.

The SCID-5 -CT will be administered at screening only.

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

The MGH-ATRQ examines the adequacy of duration and dose of prior and current antidepressant treatments in a step-by-step procedure (Chandler 2010). When assessing the duration and dose of antidepressants, the examiner must always inquire about adherence to each treatment. In addition, the MGH- ATRQ assesses the degree of improvement on a scale from 0% (not improved at all) to 100% (completely improved).

The MGH-ATRQ will be administered at screening. Treatments with a response of “less than 25% improved” will be considered failed treatments. All treatments (failed and successful) used in the current and previous episodes for each participant should be listed on the MGH-ATRQ and entered in the corresponding CRF page. All treatments listed on the MGH-ATRQ and on-going at the time of screening should also be entered in the Concomitant Medication CRF page.

Columbia Suicide Severity Rating Scale (C-SSRS)

The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal behavior. In this study, the following recall periods will be used: "one month/one year" and "since last evaluation".

Clinical Global Impression (CGI)

The CGI is a three-item observer-rated scale which measures the severity of symptoms, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders (Guy (1976) ECDEU assessment manual for psychopharmacology (Internet)). CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. CGI is rated by an experienced clinician who is familiar with the disease under study and the likely progression of treatment. The CGI is rated without regard to the clinician's belief that any clinical changes are or are not due to medication and without consideration of the etiology of the symptoms.

For the study purpose two items will be used: the CGI-S, which rates illness severity, and the CGI-I, which rates change from the initiation of treatment. The following recall periods will be used for the CGI-S: “past 4 hours”, "Last 7 days" and "Since Last Evaluation". The CGI-S and the CGI-I will be administered electronically/on paper by qualified site personnel.

Patient reported outcomes (PRO) The participants impression of the impact of Compound (I) on their disease severity will be assessed by the PGIC.

Participant’s refusal to complete all or any part of a PRO measure should be documented in the study data capture system and should not be captured as a protocol deviation. Participant questionnaires should be completed in the language most familiar to the participant. The participant should be given sufficient space and time to complete the PRO measure(s). The participant should be made aware that completed measure(s) are not reviewed by the investigator/study personnel.

Patient Global Impression of Change (PGIC)

PGIC scale aims to quantify disease activity relative to baseline. Participants are asked to calculate the difference between their current and previous health state based on a Likert scale. The PGIC comprises a number of points that show optimal patient preference, discriminative ability and test-retest ability, tailored to specific conditions and disease parameters.

Digital Health Technology (selected countries)

Cambridge Automated Neuropsychological Test Battery (CANTAB) assessments (i.e. cognitive testing and emotional bias task) will be performed at site, on a tablet provided by the vendor with the application pre-installed. The testing will be performed at sites, where the equipment and trained personnel are available. The assessments will be performed during the following study visits: screening (training only), Day 1 pre-dose, Day 2 (24h post dose), Day 8, Day 15, Day 22 and Day 29. Site personnel will need to complete the training provided by the vendor before administering the tests to the participants. Refer to training material provided by the vendor for more information. The tablet will be returned at the end of the study.

The test battery will consist of the Digit Symbol Substitution Task (DSST) and the Emotional Bias Task (EBT) and will take approximately 6-7 minutes to complete.

The DSST is a global measure of cognitive ability, requiring multiple cognitive domains to complete effectively. It measures attention and processing speed. The task presents participants with an array of abstract symbols associated with numbers. When a particular number is highlighted on screen, the participant must draw the corresponding abstract symbol using their index finger on the touchscreen. The participant is instructed to complete as many symbols as possible within 90 seconds. Outcome measures include total correct, errors and latency (movement latency and response latency).

The EBT is an assessment that measures whether people can perceive facial emotions in others. Participants are required to view images of faces that are morphed between happy and sad emotions of varied intensities. They then indicate whether they perceive the face shown on the screen to be happy or sad. Many of the faces may appear ambiguous, meaning participants should select the emotion they think was shown on screen. The task takes around four minutes to complete and will follow a consistent format throughout; presenting a face on screen very briefly, followed by a screen with the buttons ‘Sad’ or ‘Happy’ which can be used for response selection. Feedback will not be provided on response decisions. The key outcome measure for the EBT is the bias point - the proportion of trials selected as happy compared to the alternative emotion, adjusted to a scale of 0 to 15. This is used to determine the extent and direction of the participant’s perceptual bias in facial emotion perception (happy or sad). Additionally, latency measures and measures of how many times each emotion was selected are also available.

Pharm acokin e tics

Pharmacokinetic (PK) samples will be collected at the -Ih, Oh (treatment), 0.17h, 0.33h, 0.5h, 0.75h, Ih, 1.5h, 2h, 4h, and 24h time points. The concentration in plasma of Compound (I) will be determined by 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 "zero" 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 PK parameters of Compound (I) will be determined using the actual recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 8 or higher): primary PK parameters: AUClast, Tmax, and Cmax; secondary PK parameters: if data permit, additional PK parameters will be estimated e.g. Tl/2, Area Under the Curve from time zero to infinity (AUCinf), AUCO-t (if needed, time range to be defined during PK analysis), CL/F, Vz/F (data not limited). The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal elimination phase for the potential determination of Tl/2 will include at least 3 data points after Cmax. If the R ² value of the regression analysis of the terminal phase will be less than 0.75, no values will be reported of PK parameters depending on the estimation of the terminal elimination phase (e.g. CL/F, Vz/F, AUCinf).

Biomarkers

The purpose of genetic research may be to better understand the safety and efficacy of Compound (I), or to learn more about human diseases, or to help develop ways to detect, monitor and treat diseases. Non- clinical information suggests that Compound (I) is predominantly eliminated by oxidative metabolism via the polymorph enzyme CY2D6. The CYP2D6 genotype status supports the understanding that PK and its potential variability at a given dose. Knowledge of the CYP2D6 genotype may be used to better understand the exposureresponse analysis. In the future, patients may be selected or excluded based on CYP2D6 genotype status. A blood sample will be collected from consenting patients to evaluate CYP2D6 and other polymorphisms. Other Assessments

Local tolerability of the injection site will be assessed by clinical evaluation by the investigator or delegate of the following parameters: Erythema/redness, Induration/swelling, Ecchymosis/bruising, Pain. The presence of erythema, induration and ecchymosis will be evaluated visually. If the size of any of these abnormalities is above 2.5 cm, the exact size of the lesion must also be measured. The lesion size will be estimated and recorded as the largest diameter of the best fitted ellipsoidal form. Lesions will be graded as described below and recorded in the eCRF: Mild lesion: 2.5-5 cm, Moderate lesion: 5.1-10 cm, Severe lesion: >10 cm.

Adverse events An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.

AEs must be recorded under the signs, symptoms, or diagnosis associated with them, accompanied by the following information (as far as possible). The severity grade is as follows: mild: usually transient in nature and generally not interfering with normal activities; moderate: sufficiently discomforting to interfere with normal activities; severe: prevents normal activities.

Conditions that were already present at the time of informed consent should be recorded in medical history of the participant. Adverse events (including lab abnormalities that constitute AEs) should be described using a diagnosis whenever possible, rather than individual underlying signs and symptoms. Adverse event monitoring should be continued for at least 30 days following the last dose of study treatment. Once an adverse event is detected, it must be followed until its resolution or until it is judged to be permanent (e.g. continuing at the end of the study), and assessment must be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the interventions required to treat it, and the outcome.

Abnormal laboratory values or test results constitute adverse events only if they fulfill at least one of the following criteria: they induce clinical signs or symptoms, they are considered clinically significant, they require therapy. Clinically significant abnormal laboratory values or test results must be identified through a review of values outside of normal ranges/clinically notable ranges, significant changes from baseline or the previous visit, or values which are considered to be non-typical in participant with the underlying disease. Alert ranges for laboratoiy and other test abnormalities are included in Table 3-5.

Table 3-5 Clinically notable values for vital signs

Variable Criterion value Change relative to baseline

Heart rate/pulse >120 bpm; <50 bpm increase of > 15 bpm decrease of > 15 bpm

Systolic blood pressure >180 mm Hg; <90 mm Hg increase of > 20 mm Hg decrease of > 20 mm Hg

Diastolic blood pressure >105 mm Hg; <50 mm Hg increase of > 15 mm Hg decrease of > 15 mm Hg bpm= beats per minute

Dissociation means a lack of connection within or between oneself and one’s environment. It is not the same thing as “psychosis” which means fixed false beliefs (delusions) or false sensory experiences (hallucinations) but can be compared to the normal cognitive process of dreaming, where one is disconnected from one’s body and the real world. Deja vu and deja entendu are classic dissociative experiences. The two main forms of dissociation are depersonalization and derealization. In depersonalization one feels disconnected from oneself, whereas in derealization one feels disconnected from the world. This experience often is described as a sense of unreality, as if there was a film between oneself and one’s experience of the world. Dissociation is not the same as a hallucination, as there is no false sensory experience (e.g. , hearing voices that do not exist). Rather normal sensory experiences occur as if they are not fully normal, as if there is some disconnection between the observer and the objects experienced. Depersonalization in extreme cases may involve a feeling that one’s self is not one’s self, or that perhaps multiple selves can be identified in oneself. Dissociation can affect cognitive processes. One’s memories are not false, but they are remembered as if they are somehow not completely real. In severe cases, actual events may be forgotten.

Amnesia means loss of memory. Dissociative amnesia means that things are not remembered because of dissociation, i. e. , because of a sense of lack of connection between the self and the world. All other types of amnesia occur in settings where there is no dissociation. In assessing dissociative AEs or cognitive AEs of interest (such as amnesia or sedation), these AEs of special interest will be described in detail by participants and Investigators in writing in the source documents. The reported term should be as specific to the participant’s experience as possible. Investigators will record carefully the onset and resolution time of such AEs. Safety scales should be more frequently administrated every hour for the first 4 hours since the start of the event.

To ensure participant safety and enhance reliability in determining the hepatotoxic potential of an investigational drug, a standardized process for identification, monitoring and evaluation of liver events has to be followed. Liver chemistry tests (z.e. ALT, AST, TBL, PT/INR, ALP and G-GT) are used to confirm hepatotoxic potential.

Once a participant is exposed to study treatment, the following two categories of abnormal renal laboratory alert values should be assessed during the study period: Serum creatinine increase > 25% compared to baseline during normal hydration status; Any one of the following: Urine protein-creatinine ratio (PCR) >lg/g or >100 mg/mmol, OR New onset dipstick proteinuria > 3+, OR New onset dipstick hematuria > 3+ (after excluding menstruation, Urinary Tract Infection (UTI), extreme exercise, or trauma). Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment.