Dosing regimens for NR2B-NMDA receptor NAMs for the treatment of depression

Abstract

The present invention relates to a dosing regimen 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 receptors, including, but not limited to, major depressive disorder, treatment-resistant depression, and suicidality. The present invention also relates to the use of Compound (I) or a pharmaceutically acceptable salt thereof in the treatment of major depressive disorder in patients with suicidal ideation.

Description

Technical Field

[0001] The present invention relates to a dosing regimen 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 receptors, including but not limited to major depressive disorder, treatment-resistant depression and suicidal tendencies. The present invention also relates to the use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment of major depressive disorder in patients with suicidal ideation with intent.

Background Art

[0002] Depression is a severe and life-threatening condition with a high incidence and chronic disease course. Depression is a common disease worldwide, affecting over 264 million people (WHO 2020). The prevalence varies by age, reaching a peak in the elderly (over 7.5% of women and over 5.5% of men aged 55-74 years (WHO 2017)). Depression can lead to a serious health condition if it persists for a long time and is moderate or severe. Depression causes great suffering to those affected, and may prevent them from working, maintaining relationships, and performing self-care. In the most severe cases, patients may be hospitalized or attempt or commit suicide.

[0003] Major depressive disorder (MDD) is the most commonly associated psychiatric diagnosis with suicide. Nearly 800,000 people die by suicide each year. Suicide is the second leading cause of death among those aged 15-29 (WHO 2020). Suicidal ideation is common among psychiatric patients with MDD and appears as a pre-state of suicide attempt (McAuliffe 2002; Sokero et al 2003; Coryell and Young 2005). The time between the onset of suicidal ideation and suicide attempt is often very short, ranging from minutes to days (Deisenhammer et al 2009; Otsuka et al 2015), which highlights the need for rapid intervention and the development of novel antidepressant therapies that can be initiated rapidly.

[0004] Coordinated efforts over the past 40 years have led to the introduction of safer, more tolerable, and easier-to-prescribe antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Nevertheless, approximately 30–40% of patients with MDD do not respond to first-line treatments, including all classes of oral antidepressants (SSRIs, SNRIs, tricyclic antidepressants (TCAs, etc.)) and psychotherapy (Rush et al 2006). In addition, the initiation of a treatment response often takes at least four weeks, even when effective, leading to greater suffering, expense, and suicide risk. For acute treatment of severe depression, electroconvulsive therapy (ECT) should be considered when a rapid response is needed or when other treatments have failed, however, the use of ECT is limited by significant adverse reactions and concerns about further intervention, such as the use of general anesthesia, seizure induction, cognitive impairment, and memory loss. Therefore, there remains a particular need for rapid-acting, more effective, or better-tolerated treatments that can prevent depressive episodes in an effective way, reduce suicidal tendencies, and potentially prevent future depressive episodes.

[0005] Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and has been shown to be effective for MDD in off-label studies. A clinical trial completed by Berman et al. in 2000 was the first double-blind, placebo-controlled crossover trial demonstrating the rapid antidepressant effect of ketamine with a single dose (0.5 mg / kg infusion over 40 minutes) in seven patients. Following this initial trial, further trials have shown similar effects in patients with unipolar and bipolar depression, including treatment-resistant depression (TRD) (Zarate et al. 2006; Zarate et al. 2012; Diazgranados et al. 2010; Lapidus et al. 2014; Murrough et al. 2013; Murrough et al. 2013). Ketamine has also been shown to reduce suicidal tendencies (Katalinic et al. 2013; Murrough et al. 2015). SPRAVATO® (esketamine), a non-competitive NMDA receptor antagonist, was the first drug in its class approved for the treatment of TRD and for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. While both ketamine and SPRAVATO® exhibit a certain level of efficacy and a rapid mode of action, their safety profiles are not without significant adverse events for both patients and clinicians, and neither drug is approved for the treatment of MDD in patients with intended suicidal ideation. In fact, the prescribing information for SPRAVATO® includes a black-bordered warning about the increased risk of suicidal ideation and behavior in pediatric and young adult patients taking antidepressants. Therefore, there is still a need for a drug with a rapid mode of action but reduced side effects for the treatment / reduction of suicidal tendencies in patients with MDD, as well as for the treatment of depressive symptoms of MDD. [Overview of the project]

[0006] The present invention relates to a drug regimen of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases or disorders mediated by negative allosteric modulation or inhibition of the NR2B-NMDA receptor, including but not limited to major depressive disorder, treatment-resistant depression, and suicidal ideation. The present invention also relates to the use of compound (I) or a pharmaceutically acceptable salt thereof in the treatment of major depressive disorder in patients with suicidal ideation. [Modes for carrying out the invention]

[0007] When used herein, compound (I) is given by the following formula:

[0008] [ka] The compound is 6-((1S)-2-((3aR,5R,6aS)-5-(2-fluorophenoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-1-hydroxyethyl)pyridine-3-ol, which is an NR2B-NMDA receptor non-allosteric modulator (NAM), and can be prepared as described in International Publication No. 2016 / 049165, which is incorporated herein by reference.

[0009] Evidence suggests that NR2B-negative allosteric modulators (NAMs) MK-0657 (also known as CERC-301) and CP-101,606 have a low frequency of dissociative adverse events (Garner et al 2015; Pagnozzi et al 1995; Preskorn et al 2008). The relative contribution of each individual NMDAR subtype to the adverse effects of pan-NMDAR inhibition is not well understood due to the lack of selective inhibitors for various subtypes. However, collectively, this suggests that it is feasible to achieve safe and rapidly onset antidepressant efficacy using compounds that selectively inhibit the NR2B receptor.

[0010] Compound (I) or its pharmaceutically acceptable salts are highly potent, selective, and reversible low molecular weight NR2B-NMDA receptor NAMs. Compound (I) is intended for the rapid reduction of depressive symptoms in patients with MDD, including treatment-resistant depression and suicidal tendencies. This treatment is intended to enable patients to rapidly achieve significant improvement in their depressive symptoms and suicidal tendencies. Furthermore, patients with MDD and suicidal tendencies often require 4-5 days of hospitalization. Compound (I), with its rapidly onset efficacy, can reduce the number of days patients are hospitalized, thus offering an advantage over other antidepressants that require at least 4 weeks for patients to respond to treatment.

[0011] Compound (I) or its pharmaceutically acceptable salts are intended to treat suicidal tendencies, including but not limited to suicidal ideation, suicidal behavior and self-injurious behavior, in association with mental disorders, including major depressive disorder, alone or otherwise. In particular, Compound (I) or its pharmaceutically acceptable salts are intended to treat major depressive disorder in patients with intended suicidal ideation.

[0012] As used herein, the terms “salt,” “salts,” or “salt form” refer to the acid-added or base-added salt of each compound, for example, the compounds specified herein (e.g., compound (I) or further pharmaceutically active ingredients as defined herein). “Salt” includes, in particular, “pharmaceutically acceptable salt.” The term “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of the compound and is typically not biologically or otherwise undesirable. Compounds such as those specified herein (e.g., compound (I) or further pharmaceutically active ingredients as defined herein) may be capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or similar groups. The compounds of the present invention are capable of forming acid-added salts, and therefore, as used herein, the term “pharmaceutically acceptable salt of compound (I)” means the pharmaceutically acceptable acid-added salt of compound (I).

[0013] Pharmacologically acceptable acid addition salts can be formed using inorganic and organic acids.

[0014] Inorganic acids that can be derived from salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0015] Examples of organic acids that can be derived from salts include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0016] Pharmacopoecitable base addition salts can be formed using inorganic and organic bases.

[0017] 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, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly suitable.

[0018] Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0019] Pharmaceutically acceptable salts can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of the compound with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, or bicarbonates of Na, Ca, Mg, or K) or by reacting the free base form of the compound with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, organic solvents, or mixtures thereof. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferable when feasible. For a further enumeration of suitable salts, see, for example, “Remington's Pharmaceutical Sciences”, 22 nd In the edition published by Mack Publishing Company (2013), and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2011). nd It can be found within the edition.

[0020] Compound (I) or a pharmaceutically acceptable salt thereof can be administered via conventional routes, such as orally, sublingually, or intravenously. Intravenous administration may take the form of a bolus, slow injection, solution as an infusion or drop, nanosuspension, or lipid-based formulation, which are known pharmaceutical technologies in the art (e.g., “Remington Essentials of Pharmaceutics, 2013, 1 st Edition, edited by Linda Felton, published by Pharmaceutical Press 2012, ISBN 978 0 8571 1 105 0; in particular Chapter 30) can be manufactured by means of, for example, “Handbook of Pharmaceutical Excipients, 2012, 7 th This is similar to what is described in "Edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5".

[0021] Compound (I) or its pharmaceutically acceptable salts are administered intravenously in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg. Compound (I) or its pharmaceutically acceptable salts may be administered twice weekly, once weekly, once every two weeks, once a month, or once every six weeks. Compound (I) may also be administered orally, sublingually, orally, intravenously, or intranasally. When administered via intravenous infusion, the infusion time is between 20 and 90 minutes, particularly 40 minutes. Compound (I) is administered in the doses listed above as a free base.

[0022] Compound (I) or a pharmaceutically acceptable salt thereof can also be administered as a single dose, for example, at 0.16 mg / kg and 0.048 mg / kg, to treat patients with major depressive disorder having suicidal thoughts with intent.

[0023] In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, once every other week, once a month or once every six weeks in an amount of about 0.32 mg / kg. In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every other week or once a month in an amount of about 0.32 mg / kg.

[0024] In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, once every other week, once a month or once every six weeks in an amount of about 0.16 mg / kg. In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every other week or once a month in an amount of about 0.16 mg / kg.

[0025] In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, once every other week, once a month or once every six weeks in an amount of about 0.048 mg / kg. In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once a week or once every other week in an amount of about 0.048 mg / kg.

[0026] In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, once every other week, once a month or once every six weeks in an amount of about 0.016 mg / kg.

[0027] In another embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered once every two weeks, once a week, once every other week, once a month or once every six weeks in an amount of about 0.0048 mg / kg.

[0028] In a proof-of-concept study conducted in patients with treatment-resistant depression, a dose of compound (I) at 0.16 mg / kg administered weekly or bi-weekly was found to be as effective as a dose of 0.32 mg / kg administered weekly or bi-weekly. This effect occurred within 24 hours and was maintained for 6 weeks after repeated administration.

[0029] Compound (I) or a pharmaceutically acceptable salt thereof may be administered in combination with another antidepressant. Examples of antidepressants include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine (Prozac®), paroxetine (Paxil®, Pexeva®), sertraline (Zoloft®), citalopram (Celexa®), and escitalopram (Lexapro®); and serotonin and norepinephrine reuptake inhibitors (SNRIs), e.g., duloxetine (Cymbalta®), venlafaxine (Effexor) Examples include XR®, desvenlafaxine (Pristiq®), and levomirunacipran (Fetzima®); atypical antidepressants, such as trazodone, mirtazapine (Remeron®), vortioxetine (Trintellix®), bilazodone (Viibryd®), and bupropion (Wellbutrin SR, Wellbutrin XL, etc.); tricyclic antidepressants, such as imipramine (Tofranil), nortriptyline (Pamelor®), amitriptyline, doxepin, and desipramine (Norpramin)®; and monoamine oxidase inhibitors (MAOIs), such as tranylcypromine (Parnate®), phenelzine (Nardil®), and isocarboxazide (Marplan®).

[0030] Compound (I) or a pharmaceutically acceptable salt thereof may be administered in combination with other antidepressants and antipsychotics or mood stabilizers (such as those listed above). Examples of antipsychotics or mood stabilizers include, but are not limited to, lithium carbonate, carbamazepine (Tegretol®), valproic acid (Depakote®, Depakene®), gabapentin (Neurontin®), topiramate (Topamax®), lamotrigine (Lomictal®), olanzapine (Zyprexa®), clozapine (Clozaril®), and risperidone (Risperdal®).

[0031] Embodiment Embodiment (a) 1a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0032] 2a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0033] 3a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0034] 4a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of suicidal tendencies in major depressive disorder, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0035] 5a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal ideation, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0036] 6a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal ideation and suicidal intent, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0037] 7a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal behavior, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0038] 8a. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of self-injurious behavior in major depressive disorder, comprising administering Compound (I) or a pharmaceutically acceptable salt thereof in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0039] 9a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 8a, in which use is in combination with one or more other antidepressants.

[0040] 10a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 8a, in which use is combined with psychotherapy.

[0041] 11a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 8a, in which use is in combination with another antidepressant and psychotherapy.

[0042] 12a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 8a, to be administered intravenously.

[0043] 13a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 8a, administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0044] 14a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 8a, administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0045] 15a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to Embodiment 14a, administered at a dose of approximately 0.16 mg / kg once every two weeks or once a month.

[0046] 16a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to Embodiment 14a, administered once weekly or every other week at a dose of approximately 0.048 mg / kg.

[0047] 17a. Compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 8a, in which use is in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

[0048] Embodiment (b) 1b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0049] 2b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of treatment-resistant depression, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0050] 3b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of depressive symptoms, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0051] 4b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of suicidal tendencies in major depressive disorder, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0052] 5b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal ideation, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0053] 6b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal ideation and suicidal intent, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0054] 7b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of major depressive disorder with suicidal behavior, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0055] 8b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of self-injurious behavior in major depressive disorder, comprising administering compound (I) or a pharmaceutically acceptable salt thereof in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0056] 9b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, wherein the use is in combination with one or more other antidepressants.

[0057] 10b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, wherein the use is in combination with psychotherapy.

[0058] 11b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, in combination with another antidepressant and psychotherapy.

[0059] 12b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, to be administered intravenously.

[0060] 13b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0061] 14b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0062] 15b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to Embodiment 14b, administered at a dose of approximately 0.16 mg / kg once every two weeks or once a month.

[0063] 16b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to Embodiment 14b, administered once weekly or every other week at an amount of approximately 0.048 mg / kg.

[0064] 17b. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1b to 8b, wherein use is in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

[0065] Embodiment (c) 1c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0066] 2c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of treatment-resistant depression, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0067] 3c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depressive symptoms, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0068] 4c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of suicidal tendencies in patients with major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0069] 5c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient having major depressive disorder with suicidal ideation, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0070] 6c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal ideation and suicidal intent, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0071] 7c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal behavior, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0072] 8c. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of self-injury in patients with major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0073] 9c. Use of compound (I) or a pharmaceutically acceptable salt thereof, in combination with one or more antidepressants, according to any one of embodiments 1c to 8c.

[0074] 10c. Use of compound (I) or a pharmaceutically acceptable salt thereof, in conjunction with psychotherapy, according to one of embodiments 1c to 8c.

[0075] 11c. Use of compound (I) or a pharmaceutically acceptable salt thereof, in combination with an antidepressant and psychotherapy, according to one of embodiments 1c to 8c.

[0076] 12c. Use of compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1c to 8c, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0077] 13c. Use of compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1c to 8c, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of about 40 minutes.

[0078] 14c. Use of compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1c to 8c, wherein the pharmaceutical composition is administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0079] 15c. Use of compound (I) or a pharmaceutically acceptable salt thereof according to Embodiment 14c, wherein the pharmaceutical composition is administered at an amount of about 0.16 mg / kg once every two weeks or once a month.

[0080] 16c. Use of compound (I) or a pharmaceutically acceptable salt thereof according to Embodiment 14c, wherein the pharmaceutical composition is administered once a week or once every two weeks in an amount of about 0.048 mg / kg.

[0081] 17c. Use of compound (I) or a pharmaceutically acceptable salt thereof, in combination with one or more other antidepressants and antipsychotics or mood stabilizers, according to any one of Embodiments 1c to 8c.

[0082] Embodiment (d) 1d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0083] 2d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of treatment-resistant depression, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0084] 3d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of depressive symptoms, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0085] 4d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of suicidal tendencies in patients with major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0086] 5d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient having major depressive disorder with suicidal ideation, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0087] 6d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal ideation and suicidal intent, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0088] 7d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal behavior, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of about 0.0048 mg / kg to about 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0089] 8d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of self-injury in patients with major depressive disorder, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0090] 9d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1d to 8d, in combination with one or more antidepressants.

[0091] 10d. Use of compound (I) or a pharmaceutically acceptable salt thereof, in conjunction with psychotherapy, according to one of embodiments 1d to 8d.

[0092] 11d. Use of compound (I) or a pharmaceutically acceptable salt thereof, in combination with an antidepressant and psychotherapy, according to any one of embodiments 1d to 8d.

[0093] 12d. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 8d, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0094] 13d. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 8d, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0095] 14d. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 8d, wherein the pharmaceutical composition is administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0096] 15d. Use of compound (I) or a pharmaceutically acceptable salt thereof according to Embodiment 14d, wherein the pharmaceutical composition is administered at an amount of about 0.16 mg / kg once every two weeks or once a month.

[0097] 16d. Use of compound (I) or a pharmaceutically acceptable salt thereof according to Embodiment 14d, wherein the pharmaceutical composition is administered once a week or once every two weeks in an amount of about 0.048 mg / kg.

[0098] 17d. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1d to 8d, in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

[0099] Embodiment (e) 1e. A method for treating major depressive disorder, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0100] 2e. A method for treating treatment-resistant depression, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0101] 3e. A method for treating depressive symptoms, comprising administering to a patient in need of such treatment a compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0102] 4e. A method for treating suicidal tendencies in patients with major depressive disorder, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0103] 5e. A method for treating major depressive disorder with suicidal ideation, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0104] 6e. A method for treating major depressive disorder with suicidal ideation and suicidal intent, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0105] 7e. A method for treating major depressive disorder with suicidal behavior, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0106] 8e. A method for treating self-injurious behavior in major depressive disorder, comprising administering to a patient in need of such treatment compound (I) or a pharmaceutically acceptable salt thereof in an amount of approximately 0.0048 mg / kg to approximately 0.32 mg / kg of the patient's body weight, particularly 0.0048 mg / 3 kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0107] 9e. A method according to any one of Embodiments 1e to 8e, wherein the treatment is combined with one or more other antidepressants.

[0108] 10e. A method according to one of the embodiments 1e to 8e, in which the treatment is combined with psychotherapy.

[0109] 11e. A method according to any one of Embodiments 1e to 8e, wherein the treatment is combined with another antidepressant and psychotherapy.

[0110] 12e. A method according to any one of Embodiments 1e to 8e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0111] 13e. A method according to any one of Embodiments 1a to 8e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0112] 14e. A method according to any one of Embodiments 1a to 8e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0113] 15e. The method according to Embodiment 14e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered at an amount of about 0.16 mg / kg once every two weeks or once a month.

[0114] 16e. The method according to Embodiment 14e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once a week or once every two weeks in an amount of about 0.048 mg / kg.

[0115] 17e. A method according to any one of Embodiments 1e to 8e, wherein the treatment is combined with one or more other antidepressants and antipsychotics or mood stabilizers.

[0116] Embodiment (f) 1f. A method for treating major depressive disorder, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0117] 2f. A method for treating treatment-resistant depression, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0118] 3f. A method for treating depressive symptoms, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0119] 4f. A method for treating suicidal tendencies in patients with major depressive disorder, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0120] 5f. A method for treating major depressive disorder with suicidal ideation, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0121] 6f. A method for treating major depressive disorder with suicidal ideation and suicidal intent, comprising administering to a patient in need of such treatment a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0122] 7f. A method for treating major depressive disorder with suicidal behavior, comprising administering to a patient in need thereof a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0123] 8f. A method for treating self-injurious behavior in a patient with major depressive disorder, comprising administering to the patient in need a pharmaceutical composition containing compound (I) or a pharmaceutically acceptable salt thereof in an amount of

[0124] 9f. A method according to any one of embodiments 1f to 8f, wherein the treatment is combined with one or more other antidepressants.

[0125] 10f. A method according to one of embodiments 1f to 8f, in which the treatment is combined with psychotherapy.

[0126] 11f. A method according to any one of embodiments 1f to 8f, wherein the treatment is combined with another antidepressant and psychotherapy.

[0127] 12f. A method according to any one of embodiments 1f to 8f, wherein the pharmaceutical composition is administered intravenously.

[0128] 13f. A method according to any one of Embodiments 1f to 8f, wherein the pharmaceutical composition is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0129] 14f. A method according to any one of Embodiments 1f to 8f, wherein the pharmaceutical composition is administered twice a week, once a week, once every other week, once a month, or once every six weeks.

[0130] 15f. A method according to Embodiment 13f, wherein the pharmaceutical composition is administered at an amount of approximately 0.16 mg / kg once every two weeks or once a month.

[0131] 16f. A method according to Embodiment 13f, wherein the pharmaceutical composition is administered once a week or once every two weeks in an amount of approximately 0.048 mg / kg.

[0132] 17f. A method according to any one of embodiments 1f to 8f, wherein the treatment is combined with one or more other antidepressants and antipsychotics or mood stabilizers.

[0133] Embodiment (g) 1 g. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of suicidal tendencies in patients with major depressive disorder.

[0134] 2g. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with major depressive disorder accompanied by suicidal ideation.

[0135] 3g. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with major depressive disorder with suicidal ideation and suicidal intent.

[0136] 4g. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of patients with major depressive disorder presenting with suicidal behavior.

[0137] 5g. Compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of self-injurious behavior in patients with major depressive disorder.

[0138] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 5 g, in which use is in combination with one or more antidepressants.

[0139] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 5 g, in which use is combined with psychotherapy.

[0140] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 5 g, in which use is in combination with one or more antidepressants and psychotherapy.

[0141] 9 g. Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 7 g, administered intravenously.

[0142] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments, from 1 g to 7 g, administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0143] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 7 g, administered intravenously in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg per patient's body weight, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg.

[0144] 12 g of compound (I) or a pharmaceutically acceptable salt thereof for use according to Embodiment 10a, administered once weekly or once every other week.

[0145] Compound (I) or a pharmaceutically acceptable salt thereof for use in any one of embodiments from 1 g to 5 g, in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

[0146] Embodiment (h) 1h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of suicidal tendencies in patients with major depressive disorder.

[0147] 2h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of patients with major depressive disorder with suicidal ideation.

[0148] 3h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of patients with major depressive disorder with suicidal ideation and suicidal intent.

[0149] 4h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of patients with major depressive disorder with suicidal behavior.

[0150] 5h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use in the treatment of self-injurious behavior in patients with major depressive disorder.

[0151] 6h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1h to 5h, and at least one pharmaceutically acceptable excipient, wherein use is in combination with one or more antidepressants.

[0152] 7h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to any one of embodiments 1h to 5h, wherein the use is in combination with one or more psychotherapies.

[0153] 8h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to any one of embodiments 1h to 5h, wherein use is in combination with one or more antidepressants and psychotherapy.

[0154] A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to any one of embodiments 1h to 8h, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0155] A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to any one of embodiments 1 to 8h, administered intravenously by infusion over a time frame of approximately 40 minutes.

[0156] A pharmaceutical composition for use according to any one of Embodiments 1h to 8h, comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, administered intravenously in amounts of compound (I) or a pharmaceutically acceptable salt thereof, particularly 0.0048 mg / kg to approximately 0.32 mg / kg per patient's body weight, especially 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg, for use according to any one of Embodiments 1h to 8h.

[0157] A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient for use according to Embodiment 11h, administered once weekly or once every other week.

[0158] 13h. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1h to 5h and at least one pharmaceutically acceptable excipient, wherein use is in combination with one or more antidepressants and antipsychotics or mood stabilizers.

[0159] Embodiment (i) 1i. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of suicidal tendencies in patients with major depressive disorder.

[0160] 2i. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of a patient with major depressive disorder with suicidal ideation.

[0161] 3i. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of patients with major depressive disorder with suicidal ideation and suicidal intent.

[0162] 4i. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of a patient with major depressive disorder with suicidal behavior.

[0163] 5i. Use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of self-injury in patients with major depressive disorder.

[0164] 6i. Use of compound (I) or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1i to 5i, in combination with one or more antidepressants.

[0165] 7i. Use of compound (I) or a pharmaceutically acceptable salt thereof, in conjunction with psychotherapy, according to one of embodiments 1i to 5i.

[0166] 8i. Use of compound (I) or a pharmaceutically acceptable salt thereof in combination with one or more antidepressants and psychotherapy, according to any one of Embodiments 1i to 5i.

[0167] 9i. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1i to 8i, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0168] 10i. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1i to 8i, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0169] 11i. Use of compound (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1i to 8i, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously in amounts of about 0.0048 mg / kg to about 0.32 mg / kg per body weight of the patient, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0170] 12i. Use of compound (I) or a pharmaceutically acceptable salt thereof according to Embodiment 11c, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once a week or once every two weeks.

[0171] 13i. Use of compound (I) or a pharmaceutically acceptable salt thereof, according to any one of Embodiments 1i to 5i, in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

[0172] Embodiment (j) 1j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of suicidal tendencies in patients with major depressive disorder.

[0173] 2j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal ideation.

[0174] 3j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal ideation and suicidal intent.

[0175] 4j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of a patient with major depressive disorder with suicidal behavior.

[0176] 5j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for the manufacture of a medicament for the treatment of self-injury in patients with major depressive disorder.

[0177] 6j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, according to any one of embodiments 1j to 5j, in combination with one or more antidepressants.

[0178] 7j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, in combination with psychotherapy, according to any one of embodiments 1j to 5j.

[0179] 8j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, according to any one of embodiments 1j to 5j, in combination with one or more antidepressants and psychotherapy.

[0180] 9j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient according to any one of embodiments 1j to 8j, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0181] 10j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient according to any one of embodiments 1j to 8j, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of about 40 minutes.

[0182] 11j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient according to any one of Embodiments 1j to 8j, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously in amounts of about 0.0048 mg / kg to about 0.32 mg / kg per body weight of the patient, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg.

[0183] 12j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient according to Embodiment 11j, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once a week or once every two weeks.

[0184] 13j. Use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, according to any one of embodiments 1j to 5j, in combination with one or more antidepressants and antipsychotics or mood stabilizers.

[0185] Embodiment (k) 1k. A method for treating suicidal tendencies in a patient with major depressive disorder, comprising administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0186] 2k. A method for treating major depressive disorder with suicidal ideation, comprising administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0187] 3k. A method for treating major depressive disorder with suicidal ideation and suicidal intent, comprising administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0188] 4k. A method for treating major depressive disorder with suicidal behavior, comprising administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0189] 5k. A method for treating self-injury in a patient with major depressive disorder, comprising administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need.

[0190] 6k. A method according to any one of embodiments 1k to 5k, wherein the treatment is combined with one or more antidepressants.

[0191] 7k. A method according to one of embodiments 1k to 5k, in which the treatment is combined with psychotherapy.

[0192] 8k. A method according to any one of embodiments 1k to 5k, wherein the treatment is combined with one or more antidepressants and psychotherapy.

[0193] 9k. A method according to any one of Embodiments 1k to 8k, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously.

[0194] 10k. A method according to any one of Embodiments 1k to 8k, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0195] 11k. A method according to any one of Embodiments 1e to 8e, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered intravenously in amounts of approximately 0.0048 mg / kg to approximately 0.32 mg / kg per body weight of the patient, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg.

[0196] 12k. A method according to Embodiment 11k, wherein compound (I) or a pharmaceutically acceptable salt thereof is administered once a week or once every two weeks.

[0197] 13k. A method according to any one of Embodiments 1e to 5e, wherein the treatment is combined with one or more antidepressants and antipsychotics or mood stabilizers.

[0198] Embodiment (l) 1. A method for treating suicidal tendencies in a patient with major depressive disorder, comprising administering to the patient in need a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0199] 2l. A method for treating major depressive disorder with suicidal ideation, comprising administering to a patient in need a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0200] 3l. A method for treating major depressive disorder with suicidal ideation and suicidal intent, comprising administering to a patient in need a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0201] 4l. A method for treating major depressive disorder with suicidal behavior, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0202] 51. A method for treating self-injurious behavior in a patient with major depressive disorder, comprising administering to the patient in need a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0203] 6. A method according to any one of embodiments 1 to 5, wherein the treatment is combined with one or more antidepressants.

[0204] 7l. A method according to one of embodiments 1l to 5l, in which the treatment is combined with psychotherapy.

[0205] 8. A method according to any one of Embodiments 1l to 5l, wherein the treatment is combined with one or more antidepressants and psychotherapy.

[0206] 9. A method according to any one of Embodiments 1 to 8, wherein the pharmaceutical composition is administered intravenously.

[0207] A method according to any one of Embodiments 1 to 8, wherein the pharmaceutical composition is administered intravenously by drip infusion over a time frame of approximately 40 minutes.

[0208] 11. A method according to any one of Embodiments 1 to 8, wherein the pharmaceutical composition is administered intravenously in amounts of compound (I) or a pharmaceutically acceptable salt thereof, particularly 0.0048 mg / kg to about 0.32 mg / kg per the patient's body weight, in particular 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg, and 0.32 mg / kg.

[0209] 12l. A method according to Embodiment 11l, wherein the pharmaceutical composition is administered once a week or once every two weeks.

[0210] 13l. A method according to any one of Embodiments 1l to 5l, wherein the treatment is combined with one or more antidepressants and antipsychotics or mood stabilizers.

[0211] As used herein, the term “depressive symptoms” refers to one or more of the following symptoms associated with major depressive disorder: • Feeling sad or depressed • Loss of interest or pleasure in activities that were once enjoyed. • Changes in appetite - weight loss or gain unrelated to dieting • Do you have trouble sleeping, or do you have excessive sleepiness? • Energy loss or increased fatigue • Increased aimless physical activity (e.g., inability to sit still, pacing, handwringing), or slower movement or speech (these activities must be severe enough to be observable by others). • Feelings of worthlessness or guilt Difficulty thinking, concentrating, or making decisions. • Thoughts of death or suicide

[0212] As used herein, the term “preparatory behavior” means any action or preparation for attempting suicide, but before the possibility of injury begins. This may include anything beyond verbalization or thought, such as concretizing a method (e.g., purchasing a gun, gathering drugs) or preparing for death by suicide (e.g., writing a suicide note, disposing of belongings).

[0213] As used herein, the term "psychotherapy" refers to the deliberate application, with knowledge, of clinical methods and interpersonal stances derived from established psychological principles, with the aim of helping people modify their behavior, cognition, affect and / or other personal characteristics in a direction that the participants deem desirable.

[0214] As used herein, the term “self-injury” means intentionally inflicting upon oneself any act that causes pain, destructiveness, or harm, without the intent to cause death.

[0215] As used herein, the term "suicide" means death caused by an action that is harmful to oneself, with the intention of dying as a result of that action.

[0216] As used herein, the term “suicidal ideation” refers to suicidal thoughts, suicide, suicide attempts, and preparatory actions.

[0217] As used herein, the term “suicidal attempt” means a potentially harmful action that does not result in death but is intended to result in death. Suicidal attempts may or may not result in injury.

[0218] As used herein, the term “suicidal behavior” includes suicide, suicide attempts, and acts of preparing for suicide.

[0219] As used herein, the term “suicidal ideation” refers to a negative thought of wanting to die or a positive thought of wanting to commit suicide, without any preparatory action. Suicidal ideation refers to thinking about or planning suicide. Thoughts can range from detailed planning to a fleeting thought, but do not include the final act of suicide. Negative suicidal ideation is when there is a thought of suicide or self-injury, but no plan to carry it out. Positive suicidal ideation is when there is a thought of suicide or self-injury, and a plan to carry it out.

[0220] The terms “suicidal ideation with intent” or “suicidal ideation with suicidal intent,” as used herein, refer to a negative thought of wanting to die or a positive thought of wanting to commit suicide, which is accompanied by a desire, aspiration, purpose or goal of an act of self-destruction that leads to death.

[0221] The term "unintentional suicidal ideation," as used herein, refers to the presence of a negative thought of wanting to die or a positive thought of wanting to commit suicide, but without the intention to do so.

[0222] As used herein, the term “treatment-resistant depression (TRD)” refers to a type of major depressive disorder in which a patient does not respond to two different antidepressants administered in sufficient doses over a full period of typically six weeks.

[0223] The terms “to treat,” “to treat,” “treatment,” or “therapy,” as used herein, mean to obtain a beneficial or desired outcome, such as a clinical outcome. Beneficial or desired outcomes include, but are not limited to, the alleviation of one or more symptoms of suicide, particularly in patients with major depressive disorder as defined herein, such as suicide attempts, suicidal ideation, suicidal intent, and suicidal behavior. One aspect of treatment is, for example, that the treatment should have minimal adverse effects on the patient, and that, for example, the drugs used should have a high level of safety without causing the side effects of, for example, previously known treatment regimens. The term “alleviation,” as used herein, in reference to symptoms of a condition, means reducing at least one of the frequency or intensity of symptoms of the condition in the patient.

[0224] As used herein, the term “subject” refers to a mammalian organism, preferably a human being (male or female).

[0225] As used herein, the term “patient” refers to a person who has a disease and would benefit from treatment.

[0226] As used herein, a subject "needs" a treatment if such subject (patient) would benefit from such treatment biologically, medically, or in terms of quality of life.

[0227] The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject for treating a particular condition affecting the subject (i.e., at least one of a disease, disorder or condition, or its clinical manifestations).

[0228] When used herein, the term "pharmaceutically acceptable excipients" refers to those that are publicly known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 22 nd (See Ed. Mack Printing Company, 2013, pp. 1049–1070) This includes all solvents, dispersions, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobials, antifungals), isotonic agents, absorption retarders, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, fragrances, dyes, etc., and combinations thereof. Its use in therapeutic or pharmaceutical compositions is intended, provided that no conventional carrier is incompatible with the active ingredient.

[0229] The terms “drug,” “active substance,” “active ingredient,” “pharmaceutical activator,” “activator,” or “therapeutic agent” are understood to mean compounds in free form or in the form of pharmaceutically acceptable salts, in particular compounds of the types specified herein.

[0230] The term "intravenous" refers to a pharmaceutical composition designed to be administered intravenously.

[0231] As used herein, the term "mg / kg" refers to the amount of a compound or drug, such as compound (I) or a pharmaceutically acceptable salt thereof, per kilogram of the patient's or subject's body weight.

[0232] The term “pharmaceutical combination” refers to either a fixed combination in a single dosage form (e.g., capsule, tablet, caplet, or particle), an unfixed combination, or a kit of parts for combination administration, wherein compound (I) and one or more combination partners (e.g., another drug as identified herein, also referred to as a further “pharmaceutical activator,” “therapeutic agent,” or “co-agent”) may be administered simultaneously and independently, or separately within a time interval that allows the combination partners to exert a cooperative, for example, synergistic effect. Terms such as “co-administration” or “combination administration,” as used herein, mean the administration of selected combination partners to a single subject (e.g., a patient) requiring it, and are intended to include treatment regimens in which the drugs are not necessarily administered via the same route or simultaneously. The term “fixed combination” means that the active ingredient, e.g., the compound of the present invention, and one or more combination partners are both administered simultaneously to the patient in the form of a single entity or dosage. The term "non-fixed combination" means that both the active ingredient, for example, the compound of the present invention, and one or more combination partners are administered as separate entities, simultaneously or sequentially without any specific time limit, and such administration delivers therapeutically effective levels of the two compounds into the patient's body.

[0233] The compounds of the present invention may be administered separately or together in the same pharmaceutical composition as other agents, either by the same or different routes of administration. In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and other therapeutic agents may be combined in a combination therapy by (i) before the transfer of the combination product to the physician (for example, in the case of a kit containing the compounds of the present invention and other therapeutic agents), (ii) immediately before administration by the physician himself (or under the guidance of the physician), or (iii) by the patient himself, for example, between sequential administrations of the compounds of the present invention and other therapeutic agents.

[0234] Where used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present invention (particularly in the context of the claims) are to be interpreted as encompassing both singular and plural, unless otherwise specified herein or unless the context clearly contradicts this interpretation.

[0235] Any use of examples or illustrative language (e.g., "like") provided herein is intended solely to clarify the invention and, unless otherwise asserted, does not limit the scope of the invention.

[0236] experiment [Example 1] Clinical evaluation Phase Ila A multicenter, randomized, subject- and investigator-blinded, placebo-controlled, active-comparator, parallel-group proof-of-concept trial to evaluate the efficacy, safety, tolerability, and pharmacokinetics of compound (I) in patients with treatment-resistant depression (TRD). The trial included two different doses of active compound (I) at 0.16 mg / kg and 0.32 mg / kg, administered in two different regimens: once weekly and every two weeks (bi-weekly). The trial also included a ketamine group.

[0237] Adults with major depressive disorder who had not previously responded to two or more standard antidepressants at adequate doses for a period of more than 8 weeks during a major depressive episode (according to DSM-5 criteria), and who had a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥24 were eligible. Patients were randomized for 36 days to one of six treatment groups: low-dose (0.16 mg / kg) compound (I) once weekly (N=11) or every other week (q2w [N=10]); high-dose (0.32 mg / kg) compound (I) once weekly (N=10) or q2w (N=9); placebo (N=20); or ketamine 0.5 mg / kg once weekly (N=10) (3:3:3:3:6:4). The change in total MADRS score from baseline at 24 hours (h) (primary endpoint) was analyzed using analysis of covariance. Secondary endpoints included changes in MADRS scores at 48 hours and 6 weeks, as well as changes in clinical global impression-improvement (CGI-I) scores at 24 hours, 48 ​​hours, and 6 weeks. Safety and tolerability were also evaluated.

[0238] At 24 hours, the mean reduction in MADRS score was 15.51 points in the pooled compound (I) 0.16 mg / kg group, 12.98 points in the pooled compound (I) 0.32 mg / kg group, 12.94 in the ketamine group, and 7.27 in the placebo group. The adjusted mean difference (ΔAM) compared to placebo was -8.25 (p=0.001), -5.71 (p=0.019), and -5.67 (p=0.046) at 24 hours for the pooled compound (I) 0.16 mg / kg, pooled compound (I) 0.32 mg / kg, and ketamine groups, respectively, and -7.06 (p=0.013), -7.37 (p=0.013), and -11.02 (p=0.019) at 48 hours. Compared to placebo, greater improvement in MADRS scores was observed at week 6 in the compound (I) 0.32 mg / kg once weekly (ΔAM [80% CI]: -5.42 [-10.8, -0.02], p=0.099) and the ketamine group (-5.24 [-10.4, -0.06], p=0.097), but the greatest benefit was observed with compound (I) 0.16 mg / kg q2w dose (-6.46 vs placebo [-11.8, -1.15], p=0.059). The results for compound (I) vs placebo also suggested benefits for CGI-I scores at 24 hours, 48 ​​hours, and 6 weeks. Adverse events (AEs) occurred in 29%, 63%, 50%, and 10% of patients in the pooled compound (I) 0.16 mg / kg, compound (I) 0.32 mg / kg, ketamine, and placebo groups, respectively. The most common AEs in all treatment groups were amnesia, dissociation, sedation, and vomiting. Dissociative AEs occurred in 24%, 26%, 50%, and 10% of patients in the pooled compound (I) 0.16 mg / kg, compound (I) 0.32 mg / kg, ketamine, and placebo groups, respectively, with corresponding sedation rates of 14%, 21%, 10%, and 0%, respectively. On average, the time to onset and recovery from both dissociative AEs and sedation was longer in compound (I) than in ketamine.

[0239] In this proof-of-concept trial, compound (I) was associated with a significant improvement in MADRS scores compared to placebo in patients with TRD. No novel safety signals were identified.

[0240] [Example 2] Clinical evaluation Phase IIb A double-blind, placebo-controlled, randomized dose-determining study to investigate the efficacy and safety of intravenous infusion of compound (I) in addition to pharmacological antidepressant treatment for rapid reduction of symptoms of major depressive disorder in subjects with suicidal ideation.

[0241] The primary objective of this study is to assist in dose selection for future Phase 3 clinical trials by evaluating the efficacy and safety of four compound (I) doses (0.0048, 0.016, 0.048, and 0.16 mg / kg) administered by bi-weekly intravenous infusion in addition to pharmacological antidepressant treatment for rapid reduction of MDD symptoms in participants with intentional suicidal ideation. In addition, the study will explore the efficacy of single doses of 0.16 and 0.048 mg / kg for treating MDD in participants with intentional suicidal ideation.

[0242] The trial will also have a 12-month extension period to explore the persistence of the effect of the treatment in the trial, the possibility that compound (I) may prevent recurrence, and the safety of repeated administration of compound (I).

[0243] Goals and endpoints

[0244] [Table 1-1]

[0245] [Table 1-2]

[0246] [Table 1-3]

[0247] [Table 1-4]

[0248] Main Estimates The primary clinical challenge of this study is to determine the effect of compound (I) compared to placebo on the change from baseline in the MADRS total score 24 hours after the initial dose in combination with standard care (SoC) in patients with MDD with intentional suicidal ideation, taking into account potential confounding intermediate events (IEs) and IEs that could lead to trial discontinuation before the 24-hour evaluation.

[0249] This Phase 2b, double-blind, placebo-controlled, randomized, parallel-group dose-determining trial investigates the efficacy and safety of four doses of compound (I) administered via 40-minute intravenous infusion for rapid reduction of MDD symptoms in participants with intentional suicidal ideation. Comprehensive standard care includes initial hospitalization and pharmacological antidepressant therapy (antidepressant monotherapy or antidepressant with augmentation). In addition, the trial will explore the effects of single doses of 0.16 mg / kg and 0.048 mg / kg administered once to treat MDD in participants with intentional suicidal ideation.

[0250] Participants who meet the eligibility criteria will be randomized in a ratio of 2:1:2:2:2:2:2 to receive the following treatments in addition to their ongoing pharmacological antidepressant SoC treatment: • Bi-weekly placebo • Compound (I) 0.0048 mg / kg every other week • Compound (I) 0.016 mg / kg every other week • Compound (I) 0.048 mg / kg every other week • Compound (I) 0.16 mg / kg every other week A single intravenous infusion of 0.048 mg / kg, followed by two placebo doses administered every other week. A single intravenous infusion of 0.16 mg / kg, followed by two placebo doses administered every other week. In all treatment groups, the treatment under investigation was administered intravenously every other week for a total of three infusions during a 6-week placebo-controlled, double-blind core study period.

[0251] The trial consists of three periods: a screening period (up to 48 hours), a double-blind core period (6 weeks), and an extension period (up to 12 months).

[0252] Screening period The screening period begins when participants sign the informed consent form. Participant eligibility is determined based on screening visits (-2 to -1, up to -48 hours) and assessments also conducted on day 1 before randomization.

[0253] All participants must require hospitalization for MDD with intended suicidal ideation. Participants may already be hospitalized prior to screening and must agree to be hospitalized for treatment during the trial and between screenings.

[0254] All participants must be receiving pharmacological antidepressant status of care (SOC), which must be initiated before trial enrollment or during the screening period.

[0255] Double-blind core period The double-blind core period will begin on day 1. All baseline assessments (including the primary efficacy scale MADRS) must be performed on day 1, prior to randomization. The drug under investigation will be administered on days 1, 15, and 29 in the form of a 40-minute intravenous infusion in a double-blind manner. A designated open-label staff member is required to prepare the infusion before administration.

[0256] Hospitalization and discharge. The first intravenous infusion on day 1 must be administered while the participant is hospitalized, and the participant should remain hospitalized for the recommended 72-hour observation period (shorter or longer hospital stays are possible if clinically required by local standard practice), and thereafter for as long as required by the clinical judgment of the principal investigator and local practice guidelines / recommendations. The shortest possible hospital stay is 24 hours after the infusion on day 1.

[0257] If hospitalization is no longer required based on the clinical judgment of the principal investigator and local practice, and the patient meets the minimum protocol discharge criteria (as defined below), the principal investigator should ensure that the participant continues to visit the study site according to the visit schedule (on an outpatient basis) for the procedures being investigated and for the study evaluation. During the second and third intravenous infusions (days 15 and 29), the patient must be observed on an outpatient basis for at least 4 hours after the initiation of the infusion. During the 4-hour observation period, any relevant safety events (e.g., sedation, dissociation, memory loss, elevated blood pressure, or clinically relevant ECG results) must be monitored at the site until the safety risk is resolved or eliminated as assessed by the principal investigator.

[0258] All patients who are ready for discharge based on the clinical judgment of the principal investigator must meet at least the following discharge criteria: Participants should be confirmed to have no intentional suicidal ideation at the time of discharge by responding "no" to questions 3, 9, and 10 of the SSTS. Participants should be confirmed to have no intentional suicidal ideation for at least 24 hours prior to discharge, as confirmed by the SSTS scale at the time of assessment. • Elimination of all safety risks, as assessed by the principal investigator based on clinical evaluation and judgment.

[0259] Standard treatment / psychotherapy Dose escalation and adjustment of antidepressant pharmacological settings of care (SoC) treatment are permitted only as needed during the first two weeks of the double-blind treatment, and the SoC dosage is maintained thereafter throughout the core period.

[0260] Psychotherapy is possible if it is a stable regimen, at least 6 weeks prior to screening and during the core test treatment period.

[0261] Double-blind extension period After completing the double-blind core period, all participants will enter an extension period of at least two months.

[0262] Participants who were neither responders nor reducers at the end of the core will be observed for two months solely to obtain safety data and assess for withdrawal or rebound of the effect. These participants will not receive retreatment in this initial phase, as they did not adequately respond to the treatment. These participants may have their standard treatment modified during the two-month extension period if necessary.

[0263] Test treatment Participants classified as responders or militants at the end of the core period are eligible for retreatment if they relapse during the extension period and should be followed up for 12 months or until a second relapse, whichever comes first. These participants cannot have their standard treatment changed until a relapse occurs.

[0264] If relapse occurs, participants will receive one course of the study treatment (three IV infusions) in a dose-blinded manner. All participants will be pre-randomized for retreatment of any relapses that have occurred on day 1 of the core, as described below. • Participants who received compound (I) during the core period will be assigned to the same dose and regimen for treatment of relapse (if any occurs during the extension period). • Participants who were randomized to placebo during the core period will be randomized again during the extension period to one of the active treatment groups in a dose-blinded manner for any recurrence treatment (if any during the extension period) (in a ratio of 1:2:2:2:2:2).

[0265] Based on the results of the core period trial, if an optimal dose and regimen is established before participants receive retreatment during the extension period, participants who were initially randomized to a dose and / or regimen of a suboptimal compound (I) will receive the optimal dose and regimen in a dose-blinded manner for treatment of relapse. Participants will be assigned to the optimal dose and regimen in a blinded manner through the IRT.

[0266] Standard treatment / psychotherapy During the extension period, pharmacological antidepressant therapy may be modified only for participants who are not eligible for retreatment (neither responders nor those who have achieved remission). Participants classified as responders or reducers at the end of the core period should remain stable with respect to SoC (if any) and, as feasible, stable with respect to psychotherapy until the time of relapse during the extension period. If a relapse occurs, SoC pharmacological treatment may be adjusted during the first two weeks of relapse treatment, if necessary. Participants may or may not be hospitalized for relapse treatment (according to clinical judgment and local practice).

[0267] Similarly, if a patient is classified as a responder or mitigator at the end of a relapse-retreatment visit, similar measures should be continued with regard to standard treatment. In the case of a second relapse, the patient should discontinue the trial.

[0268] Duration of the extension period The termination of the examination / extension period for participants (those who have completed the examination) will be announced if any of the following conditions are met: All participants must complete the initial two-month extension (follow-up). For participants who did not achieve remission and were not responders at the end of the core period (day 43, visit 170), these trial participants should complete a 2-month follow-up. Participants who are classified as responders or reducers at the end of the core period (day 43, visit 170) and who do not experience any relapses will be extended for 12 months (52 weeks). · At the end of the core period (day 43, visit 170), for participants classified as responders or remitters who relapse within 12 months (52 weeks) of the extension period, they receive a re-treatment with one course of compound (I) (as described above). If they are re-classified as responders or remitters again after re-treatment (the score should be compared with the MADRS score at the time of relapse confirmation), the extension period should be continued until either 12 months or the time to the second relapse, whichever is earlier. For these patients, a follow-up observation of at least 2 months must be conducted. If the patient is not classified as either a responder or a remitter at the end of the relapse re-treatment visit, this patient should be observed for 2 months after the end of their relapse treatment and then the extension should be discontinued.

[0269] Study population The study population consists of male and female participants, 18 years of age or older and 65 years of age or younger, with MDD having suicidal ideation with intent. The goal is to randomize a total of approximately 195 participants at approximately 50 - 60 sites worldwide. Randomized patients who discontinue early will not be replaced.

[0270] Inclusion criteria Participants eligible for inclusion in this study must meet all of the following criteria.

[0271] 1. Signed informed consent must be obtained prior to study participation

[0272] 2. Male and female participants, 18 - 65 years of age (inclusive) at screening

[0273] 3. A major depressive episode (MDE) defined by DSM-5 without psychotic features at screening, confirmed by the Mini International Psychiatric Interview (MINI) based on clinical evaluation

[0274] 4. Participants must have suicidal ideation with present intent, as confirmed by a "yes" response to either question B10 or question B11, and by answering question B3 from the MINI Suicidal Tendency Assessment.

[0275] 5. Suicidal ideation with present intent, as confirmed by a "yes" response to either question 9 or question 10, obtained from baseline SSTS.

[0276] 6. Suicidal ideation with persistent intent, confirmed by a "yes" response to the further eligibility question for the SSTS at baseline: "Have you experienced suicidal thoughts, impulses, or actions for at least 15 minutes per day on most days (4 / 7) during the 7 days prior to your baseline visit today, and on at least one day after screening?"

[0277] 7. Pre-screening and pre-randomization Montgomery-Asberg Depression Rating Scale (MADRS) score > 28

[0278] 8. Participants must agree to receive standard pharmacological treatment to treat their MDD during the trial period (as determined by the treating physician based on clinical judgment and local treatment guidelines).

[0279] 9. In the physician's opinion, emergency psychiatric hospitalization is clinically necessary to address the patient's condition, and the patient is already hospitalized or has voluntarily agreed to hospitalization during the required protocol period.

[0280] Exclusion criteria Participants who meet any of the following criteria are not eligible for inclusion in this study.

[0281] 1. Previous or current diagnosis of bipolar disorder, MDD with psychotic features, schizophrenia, or schizoaffective disorder at the time of screening.

[0282] 2. Patients with acute alcohol or substance use disorder or withdrawal symptoms requiring detoxification, or patients who have undergone detoxification treatment within one month prior to screening (inpatient or outpatient).

[0283] 3. Participants have a current clinical diagnosis of autism, dementia, or intellectual disability.

[0284] 4. History of seizures. Note: Single episodes of febrile seizures in childhood are not excluded.

[0285] 5. Participants with borderline personality disorder

[0286] 6. Participants who exhibit suicidal ideation or behavior, primarily triggered by another non-MDD condition, as obtained from the MINI Suicidal Disorders Classification Interview.

[0287] 7. Previous suicidal tendencies due to the lack of response from ketamine or esketamine.

[0288] 8. Medical history and / or available medical records indicating active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or active COVID infection.

[0289] 9. History of hypersensitivity to the test drug, its excipients, or a similar class of chemicals.

[0290] 10. Participants receiving medication prohibited by the protocol.

[0291] 11. You are receiving the following medical / psychotherapy: • Esketamine or ketamine two months prior to screening • Monoamine oxidase inhibitors (MAOIs) 14 days prior to screening • Instability in psychotherapy regimens and / or initiation less than 6 weeks prior to screening

[0292] Abnormalities of the heart or cardiac repolarization, including any of the following · History of myocardial infarction (MI), angina pectoris or coronary artery bypass graft (CABG) within 6 months prior to starting the test treatment. · Clinically significant arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, advanced AV block (e.g., bifascicular block, Mobitz type II and third-degree AV block)

[0293] 13. QTcF ≥ 450 msec (male) or ≥ 460 msec (female) at rest at the time of screening or before the first dose on Day 1, or inability to determine the QTcF interval

[0294] 14. Uncorrected hypokalemia or hypomagnesemia, history of heart failure or clinically significant / symptomatic bradycardia, or risk factors for polymorphic ventricular tachycardia (TdP), including any of the following. · QT prolongation syndrome, family history of sudden unexplained death or congenital QT prolongation syndrome · Concomitant medications with a "known risk of polymorphic ventricular tachycardia" that cannot be discontinued or replaced with an alternative medication that is also safe to discontinue, during the 7 days prior to screening and between cores

[0295] 15. Participants have poorly controlled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) at the time of screening and before the first dose on Day 1, despite diet, exercise or stable doses of permitted antihypertensive treatments, or have a past history of any hypertensive crisis.

[0296] 16. Any other condition (e.g., known liver disease / liver dysfunction, active malignancy, etc.) that, in the opinion of the principal investigator of the clinical trial, would place the safety of the participant at risk, interfere with medication compliance, or impede the completion of the trial.

[0297] 17. Evidence of significant renal insufficiency as indicated by an estimated glomerular filtration rate (eGFR) < 40 mL / min / 1.73m 2 at the time of screening

[0298] 18. Use of other drugs being investigated within 30 days of screening.

[0299] 19. Pregnant or breastfeeding women

[0300] 20. Sexually active men who are unwilling to use condoms during sexual intercourse while undergoing the test treatment (in the core and extensions, in the case of retreatment) and for one week after discontinuing the test treatment. Condoms are required for all sexually active male participants to prevent them from becoming fathers of children and to prevent the delivery of the test treatment to their partners via semen. In addition, male participants must not donate sperm for the period specified above.

[0301] 21. A woman of childbearing age is defined as any woman who is physiologically capable of becoming pregnant, unless she is using a highly effective method of contraception during the trial treatment and for one week after discontinuing the medication (applicable to the core and extension).

[0302] The following are some highly effective methods of contraception: • Complete abstinence (if it is in line with the participant's preferred and normal lifestyle). Periodic abstinence (calendar method, ovulation method, symptomatic body temperature method, post-ovulation method) and withdrawal are not acceptable methods of contraception. • Sterilization (including surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to administration of the drug being investigated. In the case of oophorectomy only, only when the woman's reproductive status is confirmed by follow-up hormone level assessment. • Male sterilization (at least 6 months prior to screening). For female participants in the trial, a male partner who has undergone vasectomy should be her sole partner. • Use of an intrauterine device (IUD) or intrauterine contraceptive system (IUS)

[0303] Oral contraceptives or systemic hormonal contraceptives (e.g., transdermal or implantable hormonal methods) are not permitted for contraceptive purposes.

[0304] Women are considered postmenopausal and unable to bear children if they have a suitable clinical profile (e.g., age-appropriate history of vasomotor symptoms) along with 12 months of spontaneous amenorrhea, or if they have undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior. In cases of oophorectomy alone, women are considered unable to bear children only if their reproductive status is confirmed by follow-up hormone level assessments.

[0305] Patients eligible to receive compound (I) treatment for relapse during the extended period should not be pregnant before the start of treatment.

[0306] Response and remission criteria Response is defined as a reduction of ≥50% from the baseline MADRS score at any point in the trial. Remission is defined as a MADRS total score of ≤12 points at any point in the trial.

[0307] Participants who complete the core period of the study treatment and meet one of the above response or remission criteria at the end of the core period (day 43, 170 visits) will be eligible for re-treatment during the extension period.

[0308] Worsening of depression or suicidal symptoms during the core period should not be considered a relapse, and if clinically significant, should be reported as an adverse event (AE) during the core period (worsening of depression, increased suicidal ideation, etc.).

[0309] Recurrence criteria (extension period) Participants who complete the core period of the study treatment and meet one of the above response or remission criteria at the end of the core period (day 43, 170 visits) will be eligible for re-treatment during the extension period.

[0310] Relapse manifests as the appearance of new depressive symptoms or an exacerbation of previously stable or improved MDD symptoms. Participants experiencing exacerbations during the extension period must be evaluated by the treating physician, and relapses must be confirmed by MADRS assessment. A relapse is considered to occur if any of the following criteria are met: • All participants must independently have a total MADRS score of ≥22 over two consecutive visits 5–14 days apart and meet the DSM-5 criteria for MDD in order to be eligible for relapse retreatment if they achieve remission (MADRS ≤12) or ≥50% improvement at the end of the core period. In addition, participants who showed a treatment response (≥50% improvement) at the end of the core period but did not achieve remission (MADRS ≤12) must show a ≥50% deterioration from the total MADRS score reported at the end of the core period (end of core visits). Recurrence must be confirmed by two consecutive evaluations 5 to 14 days apart, with the date of the first MADRS evaluation being considered the date of recurrence. Recurrence can be confirmed either during a pre-treatment visit or before the first infusion for retreatment. This can then be done at any point after the course of retreatment to confirm a second recurrence (two MADRS evaluations 5 to 14 days apart are still required). or • Hospitalization for worsening depression or any other clinically relevant event suggesting a relapse (i.e., suicide attempt or hospitalization for suicide prevention). Such patients should meet the DSM-5 criteria for MDD (regardless of MADRS score) to be considered in a relapsed state. If a participant is hospitalized for any of these events, the date of commencement of hospitalization should be used as the date of relapse. Otherwise, if the participant is not hospitalized, the date of the event should be used.

[0311] If certain relapse criteria are met, the earlier date will be defined as the date of onset of the relapse for this participant.

[0312] evaluation: Montgomery Asberg Depression Rating Scale (MADRS), SIGMA version The Montgomery Asberg Depression Rating Scale (MADRS, SIGMA version) is a clinician rating scale designed to measure the severity of depression and detect changes in response to antidepressant treatment. The scale consists of 10 items, each scored from 0 (item absent or normal) to 6 (severe or persistent symptoms), with a possible total score of 60. Higher scores indicate a more severe condition. The MADRS assesses outward sadness, reported sadness, internal tension, sleep, appetite, concentration, fatigue, level of interest, pessimistic thoughts, and suicidal ideation (Khan et al 2000). The scale exhibits high inter-rater reliability.

[0313] A guideline for structured interviews using MADRS (SIGMA) will be used for each implementation. MADRS will be administered electronically by a qualified person.

[0314] This trial uses two recall periods: "the last 7 days" and "since the last visit / evaluation." At the 4-hour mark, sleep and appetite items are not evaluated (pre-treatment scores for these items obtained on the same day are carried over).

[0315] Clinical outcome assessment (COA) To assess suicidal tendencies among participants, the following assessments will be conducted. Sheehan Suicidal Tendency Tracking Scale (S-STS) Clinician Version • Clinical Global Impression of Severity of Suicidality Scale (CGI-SS) • Clinical Global Impression of Change in Suicidality Scale (CGIC-S) • Clinical Global Impression-Severity Scale (CGI-S) • Clinical Global Impression Improvement Scale (CGI-I)

[0316] All secondary suicidal tendency scales are psychometrically validated and reliable as measures of subtypes or symptom features of depressive states. They are used to explore the potential effects of subtypes and associated symptom changes in order to determine which forms of depression may be improved to some extent by the interventions performed.

[0317] Sheehan Suicidal Tendency Tracking Scale (S-STS) Standard Version, Clinician Assessment The Sheehan Suicidal Tendency Tracking Scale (S-STS) is a scale designed to assess and monitor suicidal tendency over time. The standard clinician-rated version of the scale will be used in this study. The standard version of the scale was designed for use in clinical research trials as a safety assessment measure for detecting suicidal tendency occurring under treatment and as a highly sensitive measure of treatment outcome. The standard version of the S-STS is a 16-item scale that assesses the severity of suicidal tendency phenomena on a Likert scale (0-4) ranging from “never” (0) to “very” (4). It also assesses the frequency of significant phenomena and the total time spent on suicidal tendencies. Sheehan et al 2014.

[0318] The S-STS is administered electronically by qualified facility staff. This test uses different recall periods: "last 24 hours," "last 7 days," and "since last visit / evaluation."

[0319] Clinical Global Impression Scale for Suicidal Tendency Severity (CGI-SS) The Clinical Global Impression Scale for Suicidal Tendency (CGI-SS) is a 5-point scale that measures a patient's level of suicidal tendency over time. This test uses three different recall periods: "last 24 hours," "last 7 days," and "since last visit / assessment." The CGI-SS is administered electronically by a qualified administrator.

[0320] Clinical Global Impression Scale for Changes in Suicidal Tendency (CGIC-S) The Clinical Global Impression Scale for Change in Suicidal Tendency (CGIS-S) is a 7-point scale that provides investigators' assessments of participants' suicidal tendencies compared to baseline. The CGIS-S is administered electronically by a qualified person.

[0321] Clinical Global Impression Scale for Depressed Mood - Severity (CGI-S) The Clinical Global Impression (CGI) is an observer-rated scale that measures the severity of symptoms, treatment response, and treatment efficacy in patients with mental disorders. The CGI-Severity (CGI-S) is a measure designed to assess the overall severity of the illness at any given time. The CGI-S for depressed mood will be used in this study.

[0322] The CGI-S assessment is conducted electronically by a qualified person. This test uses three different recall periods: "last 24 hours," "last 7 days," and "since the last visit / assessment."

[0323] Clinical Global Impression Scale for Depressed Mood - Improvement (CGI-I) The Clinical Global Impression (CGI) is an observer-rated scale that measures the severity of symptoms, treatment response, and treatment efficacy in patients with mental disorders. The CGI-I (CGI-I) (Guy, 1976) assesses the degree of change (improvement or worsening) of the disease compared to baseline.

[0324] CGI-I is performed electronically by qualified personnel.

Claims

1. 1. A pharmaceutical composition for the treatment of major depressive disorder, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 1】

2. A pharmaceutical composition for the treatment of treatment-resistant depression, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 2】

3. 1. A pharmaceutical composition for the treatment of depressive symptoms, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 3】

4. 1. A pharmaceutical composition for the treatment of suicidality in a patient with major depressive disorder, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of the patient's body weight. 【Chemistry 4】

5. A pharmaceutical composition for the treatment of major depressive disorder with suicidal ideation comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 5】

6. A pharmaceutical composition for the treatment of major depressive disorder with suicidal ideation and intent, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 6】

7. 1. A pharmaceutical composition for the treatment of major depressive disorder with suicidal behavior, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 7】

8. 1. A pharmaceutical composition for the treatment of self-injury in major depressive disorder, comprising Compound (I) or a pharma- ceutical acceptable salt thereof in an amount of about 0.0048 mg / kg to about 0.32 mg / kg, particularly 0.0048 mg / kg, 0.016 mg / kg, 0.048 mg / kg, 0.16 mg / kg and 0.32 mg / kg of a patient's body weight. 【Chemistry 8】

9. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the treatment is in combination with one or more other antidepressants.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the treatment is in conjunction with psychotherapy.

11. 9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the treatment is in combination with another antidepressant and psychotherapy.

12. The pharmaceutical composition of any one of claims 1 to 8, wherein the compound or a pharma- ceutically acceptable salt thereof is administered intravenously.

13. The pharmaceutical composition of any one of claims 1 to 8, wherein the compound or a pharma- ceutically acceptable salt thereof is administered intravenously by infusion over a time frame of about 40 minutes.

14. The pharmaceutical composition of any one of claims 1 to 8, wherein the compound or a pharma- ceutically acceptable salt thereof is administered twice weekly, once weekly, once every other week, once a month, or once every six weeks.

15. The pharmaceutical composition of claim 14, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once every two weeks or once a month in an amount of about 0.16 mg / kg.

16. The pharmaceutical composition of claim 14, wherein the compound or a pharma- ceutically acceptable salt thereof is administered once a week or once every other week in an amount of about 0.048 mg / kg.

17. 9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the treatment is in combination with one or more other antidepressants and antipsychotics or mood stabilizers.

18. A pharmaceutical composition for the treatment of suicidality in a patient with major depressive disorder comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 9】 19. A pharmaceutical composition for the treatment of major depressive disorder with suicidal ideation comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】 20. A pharmaceutical composition for the treatment of major depressive disorder with suicidal ideation and intent, comprising an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】

Images