Methods of treatment using mtorc1 modulator

Abstract

To provide methods, compositions, and unit dosage forms useful for selectively modulating mTORC1 activity.SOLUTION: The present invention provides, inter alia, methods of treating depression comprising administering to a patient in need thereof a therapeutically effective amount of ((S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid), or a pharmaceutically acceptable salt or composition thereof. In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, the depression is treatment-resistant depression (TRD).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 929,449, filed November 1, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Technical field of the invention The present invention relates to methods useful for modulating mTORC1 activity.The present invention relates to methods useful for selectively modulating mTORC1 activity.The present invention relates to methods useful for activating mTORC1. [Background technology]

[0003] Background of the Invention The target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that senses diverse environmental cues, such as growth factors, cellular stress, and nutrient and energy levels. Upon activation, mTORC1 phosphorylates substrates that enhance anabolic processes such as mRNA translation and lipid synthesis, and restricts catabolic processes such as autophagy. Dysregulation of mTORC1 occurs in a wide range of diseases, including diabetes, epilepsy, neurodegeneration, immune responses, suppressed skeletal muscle growth, and cancer, among others (Howell et al., (2013) Biochemical Society transactions). 41,906-912; Kim et al., (2013) Molecules and cells 35,463-473; Laplante and Sabatini, (2012) Cell 149,274-293). There is an urgent and compelling unmet medical need for more effective treatments for diseases, disorders, or conditions associated with mTORC1. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Howell et al. (2013) Biochemical Society transactions 41,906-912 [Non-patent document 2] Kim et al., (2013) Molecules and cells 35,463-473; Laplante and Sabatini, (2012) Cell 149,274-293 Summary of the Invention [Means for solving the problem]

[0005] The present invention particularly relates to a therapeutically effective amount of ((S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid), i.e., Compound A: [ka] The present invention provides a method for treating depression, comprising administering to a patient in need thereof or its pharmaceutically acceptable salt or composition.In some embodiments, the depression is major depressive disorder (MDD).In some embodiments, the depression is treatment-resistant depression (TRD).

[0006] In some embodiments, the present invention further provides a composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present invention further provides a unit dosage form comprising Compound A, or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 depicts the dose escalation scheme for Part A of the clinical trial study described in Example 1.

[0009] [Figure 2] FIG. 2 shows the HAM-D6 scores indicating rapid and sustained efficacy with a single dose of Compound A.

[0010] [Figure 3] FIG. 3 shows the response rate of Compound A at 2 hours after administration, as measured by HAM-D6.

[0011] [Figure 4] FIG. 4 shows the response rate of Compound A 12 hours after administration, as measured by HAM-D6.

[0012] [Figure 5] FIG. 5 shows the response rate of Compound A 24 hours after administration, as measured by HAM-D6.

[0013] [Figure 6] Figure 6 presents the correlation between the HAM-D6 and MADRS scales in measuring core symptoms of depression.

[0014] [Figure 7] FIG. 7 depicts a clinical trial study flow chart for the trial described in Example 2.

[0015] [Figure 8] FIG. 8 shows that human CSF levels match those of rodents at effective doses of Compound A.

[0016] [Figure 9] FIG. 9 shows CSF BDNF levels after a single dose of Compound A.

[0017] [Figure 10] FIG. 10 shows BDNF receptor (NTRK2) fragment levels after a single dose of Compound A.

[0018] [Figure 11]Figure 11 depicts a chart showing changes in qEEG band amplitude following administration of a single dose of Compound A. Symbols indicate either no significant change (-), a slight to large increase (↑, ↑↑, ↑↑↑), a slight to large decrease (↓, ↓↓, ↓↓↓) or a mixed decrease and increase (↓↑) in the mean difference. Changes identified as significant treatment effects in a formal ANOVA model are indicated with a double asterisk (**).

[0019] [Figure 12] Figure 12 presents a chart showing the change in coherence of qEEG bands after administration of a single dose of Compound A. Symbols indicate either no significant change (-), a slight to large increase (↑, ↑↑, ↑↑↑), a slight to large decrease (↓, ↓↓, ↓↓↓) or a mixed decrease and increase (↓↑) in the mean difference. Changes identified as significant treatment effects in a formal ANOVA model are indicated with a double asterisk (**).

[0020] [Figure 13] FIG. 13 depicts a graph showing mean (±SD) plasma Compound A concentrations (y-axis) versus time (x-axis) overlaid with days of dosing (linear scale). DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention General Description of Specific Embodiments of the Invention Major depressive disorder (MDD) is a common mental disorder with a lifetime prevalence of approximately 13–17% in the United States. Although pharmacological treatment options have expanded significantly over the past 25 years, one-third to two-thirds of patients fail to respond to their first prescribed antidepressant, and up to 33% fail to respond to multiple interventions. Novel antidepressants that alleviate MDD symptoms in patients who have not adequately responded to one or more treatments, without significant side effects, would be an important advance in the treatment of treatment-resistant depression (TRD).

[0022] mTORC1, also known as target of rapamycin complex 1, is a multiprotein complex that functions as a cellular nutrient / energy / redox sensor and regulates global metabolic homeostasis through multiple anabolic and catabolic processes, including protein, lipid, and nucleic acid synthesis. Recent data support important roles for mTORC1 activity in neurons, including regulating spine expansion, axonal outgrowth, dendritic branching, and mTORC1 involvement in cognition, mood, learning, and memory. Two compounds that require mTORC1 activation for antidepressant activity in animal models, ketamine and rapastinel (also known as GLYX-13), have demonstrated efficacy in placebo-controlled studies in subjects with TRD.

[0023] Compound A [(S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid] is a novel, orally bioavailable, specific small molecule that activates mTORC1 pathway signaling in the brain, including centers involved in mood. In preclinical rodent models of stress-induced depressive behavior, Compound A demonstrated rapid antidepressant activity comparable to that of ketamine without producing significant adverse effects when compared head-to-head. Compound A's pharmacological activity was also found to be comparable to that of ketamine in non-human primate models of anxiolytic / depressive behavioral responses. Finally, similar to ketamine, the antidepressant effect of Compound A was shown to depend on postsynaptic activation of mTORC1 and was associated with increased downstream signaling of mTORC1, synaptic protein expression (e.g., GluR1 and synapsin), and synaptic branching in layer V pyramidal neurons of the rat medial prefrontal cortex. However, unlike ketamine, the pharmacological efficacy of Compound A was not related to modulation of N-methyl-D-aspartate (NMDA) receptors. Taken together, these data demonstrate the antidepressant potential of Compound A for the treatment of TRD.

[0024] Nonclinical toxicity studies were conducted in rats and cynomolgus monkeys with Compound A. No adverse effects were observed following single oral doses of up to 500 mg / kg in rats and up to 2000 mg / kg in cynomolgus monkeys. Ataxia was observed in rats following a single oral dose of 2000 mg / kg. This ataxia resolved by 24 hours after administration.

[0025] In rats administered 160, 500, or 1000 mg / kg PO every 3 days (Q3D) for 14 days (5 doses total), the no-observed-adverse-effect level (NOAEL) was 160 mg / kg. At 500 mg / kg, findings included lymphocytic atrophy in the paracortex of mesenteric nodes (but not in other lymphoid tissues) and decreased eosinophil counts. At 1000 mg / kg, adverse effects included regenerative anemia, possibly a possible episode of gastrointestinal (GI) bleeding, in one male, and hepatocellular injury without associated histopathological findings in one male. Other findings not considered adverse included slight decreases in lymphocyte, monocyte, and neutrophil counts.

[0026] In cynomolgus monkeys given 160, 500, or 2000 mg / kg PO Q3D for 14 days (5 doses total), the NOAEL was 160 mg / kg. At 500 mg / kg and above, adverse effects included decreased heart rate and vomiting. At 2000 mg / kg, adverse effects included dehydration possibly secondary to vomiting in one animal and an increase in aspartate aminotransferase (AST) in one animal.

[0027] The nonclinical safety evaluation from these studies supports the clinical evaluation of Compound A in humans. The initial planned dose of Compound A in this study was 150 mg once daily (QD) based on an evaluation of the nonclinical safety data of Compound A.

[0028] Accordingly, in some embodiments, the present invention provides a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the depression is major depressive disorder (“MDD”).

[0030] In some embodiments, the depression is treatment-resistant depression (“TRD”).

[0031] In some embodiments, the depression is refractory to first-line treatments.

[0032] In some embodiments, the depression is refractory to second line treatments.

[0033] In some embodiments, the present invention provides a composition described herein comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the present invention provides a unit dosage form described herein comprising Compound A or a pharmaceutically acceptable salt thereof. definition

[0035] As used herein, the term "compound A" refers to ((S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid), i.e.: [ka] or a pharmaceutically acceptable salt thereof. U.S. Patent No. 10,100,066 ("the '066 patent"), filed on October 21, 2016 as U.S. Patent Application Serial No. 15 / 331,362, and published as U.S. Patent Application Publication No. 2017 / 0114080 ("the '080 publication") (each of which is incorporated herein by reference in its entirety), describes certain mTORC1 modulating compounds, including Compound A. Compound A is designated Compound I-90 in the '066 patent, and the synthesis of Compound A is described in detail in Example 90 of the '066 patent.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is consistent with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0037] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0038] As used herein, the terms "about" or "approximately" shall mean within 20% of a given value or range. In some embodiments, the term "about" refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0039] Description of Exemplary Methods and Applications The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0040] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease, disorder, or condition, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other susceptibility factors). Treatment may be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0041] As used herein, the phrase "mTORC1-mediated disease, disorder, or condition" refers to a disease or other deleterious condition in which mTORC1 is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which mTORC1 is known to play a role.

[0042] Unless otherwise indicated, when the methods of the invention described above and herein refer to the administration of Compound A, or a pharmaceutically acceptable salt thereof, it will be understood that said methods also contemplate the administration of a pharmaceutically acceptable composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0043] As described above and herein, in some embodiments, the present invention provides a method of modulating mTORC1 activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the present invention provides a method for activating mTORC1 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the present invention provides a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the present invention provides a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutically acceptable composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the patient has been diagnosed with major depressive disorder ("MDD"). In some such embodiments, the patient has been diagnosed with major depressive disorder (MDD) without psychotic features, as described in DSM-5 criteria. In some embodiments, the patient does not have a history of a psychotic disorder, e.g., a psychotic disorder as described and defined in the Examples included herein.

[0048] In some embodiments, the depression is treatment-resistant depression (“TRD”).

[0049] In some embodiments, the depression is refractory to first-line treatments.

[0050] In some embodiments, the treatment-resistant depression is resistant to second-line treatments.

[0051] In some embodiments, the patient has experienced a depressive episode and has had at least one inadequate response to at least one antidepressant during the depressive episode, hi some embodiments, the patient has experienced a depressive episode and has had an inadequate response to two, three, or four different antidepressants during the depressive episode.

[0052] In some embodiments, the patient has been assessed to have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 21 or greater prior to treatment with Compound A.

[0053] In some embodiments, the patient has been assessed as having a score of 9 or greater on the Ruskin Depression Rating Scale prior to treatment with Compound A.

[0054] In some embodiments, the patient has not been using an antidepressant for at least 1, 2, 3, or 4 weeks prior to treatment with Compound A or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the patient is 18 years of age or older.

[0056] In some embodiments, the patient does not have a seizure disorder.

[0057] In some embodiments, the patient has no clinically significant abnormalities on the electroencephalogram (EEG).

[0058] In some embodiments, the patient does not have one or more exclusion criteria such as those described in the Examples contained herein.

[0059] In some embodiments, the patient has one or more selection criteria as described in the Examples contained herein.

[0060] In some embodiments, the present invention provides a method for treating depression in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to the patient, wherein the patient's depression scale score is reduced by at least 50%. In some embodiments, the patient's depression scale score is reduced by at least 50% within less than six weeks of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's depression scale score is reduced by at least 50% within less than four weeks of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's depression scale score is reduced by at least 50% within two weeks of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's depression scale score is reduced by at least 50% within less than two weeks of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's depression scale score is reduced by at least 50% within one week of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's depression scale score is reduced by at least 50% within seven days of administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, within 6 days of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 5 days of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 4 days of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 3 days of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 2 days of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 1 day of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%.In some embodiments, within 24 hours of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 50%. In some embodiments, within 24 hours of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 10%, 20%, 30%, or 40%. In some embodiments, within 12 hours of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 10%, 20%, 30%, or 40%. In some embodiments, within 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 hours of administering Compound A or a pharmaceutically acceptable salt thereof, the patient's depression scale score is reduced by at least 10%, 20%, 30%, or 40%. In some embodiments, the depression scale score is selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD-6), the Inventory of Depression Symptomatology Self-Rated Scale (IDS-SR), and the Clinical Global Impression Severity Scale (CGI-S). In some embodiments, the depression scale score is selected from any of the depression rating scales described above and herein.

[0061] In some embodiments, the methods of the present invention are characterized by achieving a clinically significant antidepressant effect as measured using standardized effect size statistics, with an effect size of 0.40 or greater being considered to indicate a clinically significant effect. By way of example, in some embodiments, the effect size is measured according to any of the depression valence scales described above and herein, and the effect size at a particular time interval is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 or greater. In some embodiments, the effect size is measured according to any of the depression valence scales described above and herein, and the effect size at 2-4 hours is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 or greater. In some embodiments, the effect size is measured according to any of the depression valence scales described above and herein, and the effect size at 4-8 hours is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 or greater. In some embodiments, the effect size is measured according to any of the depression valence scales described above and herein, and the effect size at 8-12 hours is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 or greater. In some embodiments, the effect size is measured according to any of the depression valence scales described above and herein, and the effect size at 12, 24, 36, 48, or 72 hours is 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, or 1.0 or greater. In some such embodiments, the size effect is 0.40 or greater. In some such embodiments, the size effect is 0.50 or greater.

[0062] In some embodiments, the present invention provides a method for treating depression in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to the patient, wherein the patient experiences a decrease in depression valence scale score comparable to that of ketamine administered via intraperitoneal injection. In some embodiments, the decrease in depression valence scale score results from a single administration. In some such embodiments, the administration is oral administration. In some embodiments, the decrease in depression valence scale score results from at least two administrations. In some such embodiments, the administration is oral administration. In some embodiments, the decrease in depression valence scale score results from multiple oral administrations. In some such embodiments, the administration is oral administration.

[0063] In some embodiments, the present invention provides a method for inducing rapid onset of antidepressant activity in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to the patient. In some such embodiments, the patient is suffering from TRD. In some embodiments, the rapid onset of antidepressant activity occurs within two weeks of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within one week of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within seven days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within six days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within five days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within four days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within 3 days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within 2 days of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within 1 day of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within less than 24 hours of administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the rapid onset of antidepressant activity occurs within less than 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 hours of administration of Compound A or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the present invention provides a method for inducing long-lasting antidepressant activity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient in need thereof is suffering from TRD. In some embodiments, the long-lasting antidepressant activity persists for at least 24 hours after a single administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the long-lasting antidepressant activity persists for at least two days. In some embodiments, the long-lasting antidepressant activity persists for at least three days. In some embodiments, the long-lasting antidepressant activity persists for at least four days. In some embodiments, the long-lasting antidepressant activity persists for at least five days. In some embodiments, the long-lasting antidepressant activity persists for at least six days. In some embodiments, the long-lasting antidepressant activity persists for at least seven days.

[0065] In some embodiments, the present invention provides methods for eliciting rapid onset and long-lasting antidepressant activity.

[0066] In some embodiments, the present invention provides a method for eliciting a positive behavioral response in a patient in need thereof, comprising administering to the patient a composition comprising Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is suffering from TRD. In some embodiments, the positive behavioral response is correlated with improved mood. In some embodiments, the positive behavioral response is correlated with reduced anxiety. In some embodiments, the positive behavioral response is correlated with improved ability to cope with stress. In some embodiments, the positive behavioral response is correlated with reduced outward sadness. In some embodiments, the positive behavioral response is correlated with reduced verbalized sadness. In some embodiments, the positive behavioral response is correlated with improved sleep. In some embodiments, the positive behavioral response is correlated with improved appetite. In some embodiments, the positive behavioral response is correlated with improved concentration. In some embodiments, the positive behavioral response is correlated with improved self-esteem. In some embodiments, the positive behavioral response is correlated with improved fatigue levels. In some embodiments, the positive behavioral response is correlated with reduced pessimistic and suicidal thoughts. In some embodiments, the positive behavioral response is correlated with an increased interest in work or other activities. In some embodiments, the positive behavioral response is correlated with a decrease in physical symptoms. In some embodiments, the positive behavioral response is correlated with a decrease in symptoms of psychomotor developmental delay.

[0067] In some embodiments, the present invention provides a method for inducing the rapid onset of a positive behavioral response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is suffering from TRD. In some embodiments, the positive behavioral response occurs within less than 24 hours of administration. In some embodiments, the positive behavioral response occurs within one day of administration. In some embodiments, the positive behavioral response occurs within two days of administration. In some embodiments, the positive behavioral response occurs within three days of administration. In some embodiments, the positive behavioral response occurs within four days of administration. In some embodiments, the positive behavioral response occurs within five days of administration. In some embodiments, the positive behavioral response occurs within six days of administration. In some embodiments, the positive behavioral response occurs within seven days of administration. In some embodiments, the positive behavioral response occurs within one week of administration.

[0068] In some embodiments, the present invention provides a method for inducing a long-lasting positive behavioral response in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is suffering from TRD. In some embodiments, the long-lasting positive behavioral response lasts for more than one day. In some embodiments, the long-lasting positive behavioral response lasts for at least two days. In some embodiments, the long-lasting positive behavioral response lasts for at least three days. In some embodiments, the long-lasting positive behavioral response lasts for at least four days. In some embodiments, the long-lasting positive behavioral response lasts for at least five days. In some embodiments, the long-lasting positive behavioral response lasts for at least six days. In some embodiments, the long-lasting positive behavioral response lasts for at least seven days.

[0069] In some embodiments, the present invention provides methods for eliciting a positive behavioral response that is rapid in onset and long-lasting.

[0070] Administration In some embodiments, the methods of the present invention comprise administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is from about 10 mg to about 5000 mg, or from about 20 mg to about 4000 mg, or from about 40 mg to about 4000 mg, or from about 60 mg to about 4000 mg, or from about 80 mg to about 4000 mg, or from about 100 mg to about 4000 mg, or from about 120 mg to about 4000 mg, or from about 130 mg to about 4000 mg, or from about 140 mg to about 4000 mg, or from about 100 mg to about 3000 mg, or about 1 50 mg to about 3000 mg, or about 160 mg to about 3000 mg, or about 170 mg to about 3000 mg, or about 180 mg to about 3000 mg, or about 190 mg to about 3000 mg, or about 200 mg to about 3000 mg, or about 210 mg to about 3000 mg, or about 220 mg to about 3000 mg, or about 230 mg to about 3000 mg, or about 240 mg to about 3000 mg, or about 250 mg to about 3000 mg, or about 260 mg to about 3000 mg, or about 270 mg to about 3000 mg, or about 280 mg to about 3000 mg, or about 290 mg to about 3000 mg, or about 300 mg to about 3000 mg, or about 310 mg to about 3000 mg, or about 320 mg to about 3000 mg, or about 330 mg to about 3000 mg, or about 340 mg to about 3000 mg, or about 350 mg to about 3000 mg, or about 360 mg to about 3000 mg, or about 370 mg to about 3000 mg, or about 380 mg to about 3000 mg, or about 390 mg to about 3000 mg, or about 400 mg to about 3000 mg, or about 410 mg to about 3000 mg, or about 420 mg to about 3000 mg, or or about 430 mg to about 3000 mg, or about 440 mg to about 3000 mg, or about 450 mg to about 3000 mg, or about 460 mg to about 3000 mg, or about 470 mg to about 3000 mg, or about 480 mg to about 3000 mg, or about 490 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 510 mg to about 3000 mg, or about 520 mg to about 3000 mg, or about 530 mg to about 3000 mg, or about 540 mg to about 3000 mg, or about 550 mg to about 3000 mg, or about 560 mg to about 3000 mg,or about 570 mg to about 3000 mg, or about 580 mg to about 3000 mg, or about 590 mg to about 3000 mg, or about 600 mg to about 3000 mg, or about 610 mg to about 3000 mg, or about 620 mg to about 3000 mg, or about 630 mg to about 3000 mg, or about 640 mg to about 3000 mg, or about 650 mg to about 3000 mg, or about 660 mg to about 3000 mg, or about 670 mg to about 3000 mg, or about 680 mg to about 3000 mg, or about 690 mg to about 3 000mg, or about 700mg to about 3000mg, or about 710mg to about 3000mg, or about 720mg to about 3000mg, or about 730mg to about 3000mg, or about 740mg to about 3000mg, or about 750mg to about 3000mg, or about 760mg to about 3000mg, or about 770mg to about 3000mg, or about 780mg to about 3000mg, or about 790mg to about 3000mg, or about 800mg to about 3000mg, or about 810mg to about 3000mg, or about 82 0 mg to about 3000 mg, or about 830 mg to about 3000 mg, or about 840 mg to about 3000 mg, or about 850 mg to about 3000 mg, or about 860 mg to about 3000 mg, or about 870 mg to about 3000 mg, or about 880 mg to about 3000 mg, or about 890 mg to about 3000 mg, or about 900 mg to about 3000 mg, or about 910 mg to about 3000 mg, or about 920 mg to about 3000 mg, or about 930 mg to about 3000 mg, or about 940 mg to about 3000 mg, Or a total daily dose of about 950 mg to about 3000 mg, or about 960 mg to about 3000 mg, or about 970 mg to about 3000 mg, or about 980 mg to about 3000 mg, or about 990 mg to about 3000 mg, or about 1000 mg to about 3000 mg, or about 1000 mg to about 2500 mg, or about 1000 mg to about 2000 mg, or about 400 mg to about 2400 mg, or about 800 mg to about 2400 mg, or about 800 mg to about 1600 mg, or about 1600 mg to about 2400 mg.

[0071] In some embodiments, the methods of the present invention comprise administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is from about 50 mg to about 1600 mg, or from about 50 mg to about 1500 mg, or from about 50 mg to about 1400 mg, or from about 50 mg to about 1300 mg, or from about 50 mg to about 1200 mg, or from about 50 mg to about 1100 mg, or from about 50 mg to about 1000 mg, or from about 50 mg to about 900 mg, or from about 50 mg to about 800 mg, or from about 50 mg to about 700 mg, or from about 50 mg to about 4 00mg, or about 50mg to about 300mg, or about 50mg to about 200mg, or about 50mg to about 100mg, or about 100mg to about 500mg, or about 100mg to about 400mg, or about 100mg to about 300mg, or about 100mg to about 200mg, or about 200mg to about 1000mg, or about 200mg to about 900mg, or about 200mg to about 800mg, or about 200mg to about 700mg, or about 200mg to about 600mg, or about 200mg to about 500mg, or about 200mg to about 400mg.

[0072] In some embodiments, the methods of the present invention comprise administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the therapeutically effective amount is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 200 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg total daily dose. In some such embodiments, the total daily dose is about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400, or about 3000 mg.

[0073] In some embodiments, the methods of the present invention comprise administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is between about 1 and about 100 mg / kg, or between about 1 and about 90 mg / kg, or between about 1 and about 80 mg / kg, or between about 1 and about 70 mg / kg, or between about 1 and about 60 mg / kg, or between about 1 and about 50 mg / kg, or between about 1 and about 40 mg / kg, or between about 1 and about 35 mg / kg, or between about 1 and about 30 mg / kg, or between about 1 and about 25 mg / kg, or between about 1 and about 20 mg / kg, or between about 1 and about 19 mg / kg. or a total daily dose of between about 1 and about 18 mg / kg, or between about 1 and about 17 mg / kg, or between about 1 and about 16 mg / kg, or between about 1 and about 15 mg / kg, or between about 1 and about 14 mg / kg, or between about 1 and about 13 mg / kg, or between about 1 and about 12 mg / kg, or between about 1 and about 11 mg / kg, or between about 1 and about 10 mg / kg, or between about 1 and about 9 mg / kg, or between about 1 and about 8 mg / kg, or between about 1 and about 7 mg / kg, or between about 1 and about 6 mg / kg, or between about 1 and about 5 mg / kg, or between about 1 and about 4 mg / kg, or between about 1 and about 3 mg / kg. In some embodiments, the total daily dose is between about 2 mg / kg and about 40 mg / kg, or between about 5 mg / kg and about 40 mg / kg, or between about 10 mg / kg and about 40 mg / kg, or between about 15 mg / kg and about 40 mg / kg, or between about 20 mg / kg and about 40 mg / kg, or between about 25 mg / kg and about 40 mg / kg, or between about 30 mg / kg and about 40 mg / kg, or between about 35 mg / kg and about 40 mg / kg of the patient's body weight per day.

[0074] In some embodiments, the total daily dose of Compound A or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some such embodiments, the total daily dose is any of those described above and herein. In some such embodiments, the total daily dose is about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400, or about 3000 mg.

[0075] In some embodiments, the total daily dose is administered two, three, or four times daily. In some such embodiments, each dose is the same. In some such embodiments, at least one dose is different from another dose. In some such embodiments, the total daily dose is any of those described above and herein, and the doses are administered "BID." In some such embodiments, the total daily dose is any of those described above and herein, and the doses are administered "TID." In some such embodiments, the total daily dose is any of those described above and herein, and the doses are administered "QID."

[0076] In some embodiments, the total daily dose is administered to a patient under fed conditions. In some such embodiments, the total daily dose is any of those described above and herein. In some such embodiments, the total daily dose is administered QD. In some such embodiments, the total daily dose is administered orally. In some embodiments, the total daily dose is administered every day for at least 1, 2, 3, 4, 5, 6, or 7 consecutive days.

[0077] In some embodiments, the total daily dose is administered to the patient under fasting conditions. In some such embodiments, the total daily dose is any of those described above and herein. In some such embodiments, the total daily dose is administered QD. In some such embodiments, the total daily dose is administered orally. In some such embodiments, the patient fasts for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours prior to administration. In some such embodiments, the patient fasts for at least about 2-8 hours prior to administration. In some such embodiments, the patient fasts for about 2 hours, about 4 hours, or about 8 hours prior to administration.

[0078] In some embodiments, the patient fasts for a certain period of time after administration. For example, in some embodiments, the patient fasts for about 1, 2, 3, 4, 5, 6, 7, or 8 hours after administration. In some embodiments, the patient fasts for about 2 hours after administration.

[0079] In some embodiments, a total daily dose of about 150 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasting conditions. In some embodiments, a total daily dose of about 150 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasting conditions. In some embodiments, a total daily dose of about 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasting conditions. In some embodiments, a total daily dose of about 400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasting conditions. In some embodiments, a total daily dose of about 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 800 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasted conditions. In some embodiments, a total daily dose of about 800 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 1000 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasted conditions. In some embodiments, a total daily dose of about 1000 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 1600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasted conditions. In some embodiments, a total daily dose of about 1600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of about 2400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasting conditions.In some embodiments, a total daily dose of about 2400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions. In some embodiments, a total daily dose of greater than about 2400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fasted conditions. In some embodiments, a total daily dose of greater than about 2400 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to a patient once daily under fed conditions.

[0080] In some embodiments, provided methods include administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof, including administering a single dose. In some embodiments, provided methods include administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof, including administering at least two doses. In some such embodiments, the at least two doses include administering a first dose about 24 hours before administering a second dose. In some such embodiments, the at least two doses include administering a first dose about 48 hours before administering a second dose. In some embodiments, provided methods include administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof, including administering multiple doses. In some embodiments, provided methods include administering a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof to a patient in need thereof, including administering Compound A daily, weekly, or monthly. In some embodiments, provided methods include administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein Compound A is administered at the same time every day. For example, in some embodiments, Compound A is administered at the same time every morning. In some embodiments, Compound A is administered at the same time every evening.

[0081] Unit dosage form In some embodiments, the methods of the present invention comprise administering to a patient in need thereof a pharmaceutical composition comprising one or more unit doses of Compound A, or a pharmaceutically acceptable salt thereof. In some such embodiments, the unit dose is from about 10 mg to about 5000 mg, or from about 20 mg to about 4000 mg, or from about 40 mg to about 4000 mg, or from about 60 mg to about 4000 mg, or from about 80 mg to about 4000 mg, or from about 100 mg to about 4000 mg, or from about 120 mg to about 4000 mg, or from about 130 mg to about 4000 mg, or from about 140 mg to about 4000 mg, or from about 150 mg to about 3000 mg, or from about 160 mg to about 3000 mg, or from about 170 mg to about 3000 mg. , or about 180 mg to about 3000 mg, or about 190 mg to about 3000 mg, or about 200 mg to about 3000 mg, or about 210 mg to about 3000 mg, or about 220 mg to about 3000 mg, or about 230 mg to about 3000 mg, or about 240 mg to about 3000 mg, or about 250 mg to about 3000 mg, or about 260 mg to about 3000 mg, or about 270 mg to about 3000 mg, or about 280 mg to about 3000 mg, or about 290 mg to about 3000 mg, or about 300 mg to about 3000 mg, or about 310 mg to about 3000 mg, or about 320 mg to about 3000 mg, or about 330 mg to about 3000 mg, or about 340 mg to about 3000 mg, or about 350 mg to about 3000 mg, or about 360 mg to about 3000 mg, or about 370 mg to about 3000 mg, or about 380 mg to about 3000 mg, or about 390 mg to about 3000 mg, or about 400 mg to about 3000 mg, or about 410 mg to about 3000 mg, or about 420 mg to about 3000 mg, or about 4 30 mg to about 3000 mg, or about 440 mg to about 3000 mg, or about 450 mg to about 3000 mg, or about 460 mg to about 3000 mg, or about 470 mg to about 3000 mg, or about 480 mg to about 3000 mg, or about 490 mg to about 3000 mg, or about 500 mg to about 3000 mg, or about 510 mg to about 3000 mg, or about 520 mg to about 3000 mg, or about 530 mg to about 3000 mg, or about 540 mg to about 3000 mg, or about 550 mg to about 3000 mg,or about 560 mg to about 3000 mg, or about 570 mg to about 3000 mg, or about 580 mg to about 3000 mg, or about 590 mg to about 3000 mg, or about 600 mg to about 3000 mg, or about 610 mg to about 3000 mg, or about 620 mg to about 3000 mg, or about 630 mg to about 3000 mg, or about 640 mg to about 3000 mg, or about 650 mg to about 3000 mg, or about 660 mg to about 3000 mg, or about 670 mg to about 3000 mg, or about 680 mg to about 3000 mg, or about 690 mg to about 3000 mg, or about 700 mg to about 3000 mg, or about 710 mg to about 3000 mg, or about 720 mg to about 3000 mg, or about 730 mg to about 3000 mg, or about 740 mg to about 3000 mg, or about 750 mg to about 3000 mg, or about 760 mg to about 3000 mg, or about 770 mg to about 3000 mg, or about 780 mg to about 3000 mg, or about 790 mg to about 3000 mg, or about 800 mg to about 3000 mg, or about 810 mg to about 3 000mg, or about 820mg to about 3000mg, or about 830mg to about 3000mg, or about 840mg to about 3000mg, or about 850mg to about 3000mg, or about 860mg to about 3000mg, or about 870mg to about 3000mg, or about 880mg to about 3000mg, or about 890mg to about 3000mg, or about 900mg to about 3000mg, or about 910mg to about 3000mg, or about 920mg to about 3000mg, or about 930mg to about 3000mg, or about 940mg to about 3000 mg, or about 950 mg to about 3000 mg, or about 960 mg to about 3000 mg, or about 970 mg to about 3000 mg, or about 980 mg to about 3000 mg, or about 990 mg to about 3000 mg, or about 1000 mg to about 3000 mg, or about 1000 mg to about 2500 mg, or about 1000 mg to about 2000 mg, or about 400 mg to about 2400 mg, or about 800 mg to about 2400 mg, or about 800 mg to about 1600 mg, or about 1600 mg to about 2400 mg.

[0082] In some such embodiments, the unit dose is from 50 mg to about 1600 mg, or from about 50 mg to about 1500 mg, or from about 50 mg to about 1400 mg, or from about 50 mg to about 1300 mg, or from about 50 mg to about 1200 mg, or from about 50 mg to about 1100 mg, or from about 50 mg to about 1000 mg, or from about 50 mg to about 900 mg, or from about 50 mg to about 800 mg, or from about 50 mg to about 700 mg, or from about 50 mg to about 400 mg, or from about 50 mg to about 3 00mg, or about 50mg to about 200mg, or about 50mg to about 100mg, or about 100mg to about 400mg, or about 100mg to about 300mg, or about 100mg to about 200mg, or about 200mg to about 1000mg, or about 200mg to about 900mg, or about 200mg to about 800mg, or about 200mg to about 700mg, or about 200mg to about 600mg, or about 200mg to about 500mg, or about 200mg to about 400mg.

[0083] In some embodiments, the unit dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, or about 3000 mg. In some such embodiments, the unit dose of Compound A or a pharmaceutically acceptable salt thereof comprises about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400 mg, or about 3000 mg.

[0084] In some embodiments, a unit dose of Compound A or a pharmaceutically acceptable salt thereof is administered as a single dose (QD). In some such embodiments, the unit dose is about 150, about 300, about 400, about 600, about 800, about 1000, about 1600, about 2400 mg, or about 3000 mg. In some such embodiments, the unit dose is any of those described above and herein. In some embodiments, the unit dosage form is administered as a liquid. For example, in some embodiments, the unit dosage form comprises Compound A or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable liquids for dissolving or suspending Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more pharmaceutically acceptable liquids for dissolving or suspending Compound A or a pharmaceutically acceptable salt thereof comprise water. In some embodiments, the one or more pharmaceutically acceptable liquids for dissolving or suspending Compound A or a pharmaceutically acceptable salt thereof comprise a flavoring. In some such embodiments, the unit dosage form contains between about 10 mg and about 100 mg, or between about 10 mg and about 90 mg, or between about 10 mg and about 80 mg, or between about 10 mg and about 70 mg, or between about 15 mg and about 60 mg, or between about 15 mg and about 55 mg, or between about 15 mg and about 50 mg, or between about 20 and about 50 mg of Compound A per gram of total solution weight. In some such embodiments, the unit dosage form contains about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of Compound A per gram of total solution weight.

[0085] In some embodiments, the unit dose of Compound A is a liquid formulation for oral administration, and Compound A is present in the total solution at a concentration of about 10 mg / mL, or about 15 mg / mL, or about 20 mg / mL, or about 25 mg / mL, or about 30 mg / mL, or about 35 mg / mL, or about 40 mg / mL, or about 45 mg / mL, or about 50 mg / mL, or about 55 mg / mL, or about 60 mg / mL. In certain embodiments, the unit dose is a liquid formulation for oral administration, and Compound A is present in the total solution at a concentration of about 40 mg / mL.

[0086] Pharmaceutically acceptable compositions In some embodiments, the method of the present invention comprises administering a composition comprising a therapeutically effective amount of Compound A or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, adjuvant, or vehicle.In certain embodiments, the composition for use in the method provided herein is formulated for administration to a patient in need of such a composition, for example, a patient suffering from depression.In some embodiments, such a composition is formulated for oral administration to a patient.

[0087] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0088] The compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0089] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injections, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0090] The pharmaceutically acceptable compositions for use in the provided methods can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavors or coloring agents can also be added.

[0091] In some embodiments, the pharmaceutically acceptable compositions for use in the provided methods are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions for use in the provided methods are administered without food. In some embodiments, the pharmaceutically acceptable compositions for use in the provided methods are administered with food.

[0092] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0093] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0094] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. These can optionally contain opacifying agents and can be composed to release one or more active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0095] The compound may be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. These may optionally contain opacifying agents, and may be of a composition that releases one or more active ingredients only, or preferentially, in a specific part of the intestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0096] Alternatively, the pharmaceutically acceptable compositions for use in the provided methods may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0097] Pharmaceutically acceptable compositions for use in the provided methods may be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0098] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. A topical-transdermal patch may also be used.

[0099] For topical application, the pharmaceutically acceptable composition for use in the provided method can be formulated into a suitable ointment, containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, the pharmaceutically acceptable composition can be formulated into a suitable lotion or cream, containing the active compound suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0100] Pharmaceutically acceptable compositions for use in the provided methods may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0101] The amount of Compound A that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, compositions for use in the provided methods should be formulated so that a patient receiving these compositions can receive a dosage of the inhibitor of 0.01 to 100 mg / kg body weight / day.

[0102] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

[0103] As described above and herein, pharmaceutically acceptable compositions for use in the provided methods can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), buccally as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, Compound A may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times daily to achieve the desired therapeutic effect.

[0104] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0105] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0106] To prolong the effect of a compound, it may be desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the compound to polymer ratio and the properties of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0107] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by distributing the compound in a polymer matrix or gel.

[0108] All features of each aspect of the invention apply mutatis mutandis to all other aspects.

[0109] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any way. [Example]

[0110] Example Example 1: A randomized, double-blind, placebo-controlled study of the safety, tolerability, pharmacokinetics, and preliminary efficacy of a single dose of Compound A in healthy volunteers and subjects with treatment-resistant depression Compound A [(S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid] is a novel, orally bioavailable, specific small molecule that activates mTORC1 pathway signaling in the brain, including centers involved in mood. In preclinical rodent models of stress-induced depressive behavior, Compound A demonstrated rapid antidepressant activity comparable to that of ketamine without producing significant adverse effects when compared head-to-head. Compound A's pharmacological activity was also found to be comparable to that of ketamine in non-human primate models of anxiolytic / depressive behavioral responses. Finally, similar to ketamine, the antidepressant effects of Compound A were shown to depend on postsynaptic activation of mTORC1 and were associated with increased downstream signaling of mTORC1, synaptic protein expression (e.g., GluR1 and synapsin), and synaptic branching in layer V pyramidal neurons of the rat medial prefrontal cortex. However, unlike ketamine, the pharmacological efficacy of Compound A was not related to modulation of N-methyl-D-aspartate (NMDA) receptors. Taken together, these data demonstrate the antidepressant potential of Compound A for the treatment of TRD.

[0111] Research purpose: Primary Objective: The primary objective of this study was to evaluate the safety and tolerability of single ascending dose levels of Compound A versus placebo in healthy volunteers and a single dose of Compound A versus placebo in subjects with TRD.

[0112] Secondary Objectives: Secondary objectives were to evaluate the pharmacokinetics of Compound A in healthy volunteers and subjects with TRD, and to evaluate the preliminary efficacy of Compound A in subjects with TRD.

[0113] Study endpoints: Safety Endpoints: - Evaluated the safety and tolerability of single ascending dose levels of Compound A versus placebo in healthy volunteers - Evaluate the safety and tolerability of a single dose of Compound A versus placebo in subjects with TRD

[0114] Preliminary Efficacy Endpoints: Primary Efficacy Endpoint: The primary efficacy endpoint was the difference between the Compound A and placebo groups in the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score on Day 2 (24 hours after dosing).

[0115] Secondary Efficacy Endpoints: The secondary exploratory efficacy endpoints were the differences between the Compound A group and the placebo group in the following: - Change from baseline in MADRS total score at each time point - Change from baseline in Hamilton Depression Rating Scale-6 items (HAM-D6) total score at each time point - Change from baseline in IDS-SR30 total and domain scores at each time point - Change from baseline in Clinical Global Impression-Severity (CGI-S) score at each time point

[0116] Pharmacokinetic endpoints: - Evaluated the pharmacokinetics of Compound A in healthy volunteers - To evaluate the pharmacokinetics of Compound A in subjects with TRD

[0117] Pharmacodynamic Endpoints (Part B subjects only): - To evaluate the potential association between plasma concentrations of Compound A and efficacy parameters

[0118] Pharmacogenetic Endpoints (Part B subjects only): -Evaluated potential associations between a single nucleotide polymorphism in the BDNF gene (a substitution of valine [Val] by methionine [Met] at codon 66; Val66Met) and efficacy parameters. Overall study design:

[0119] This was a randomized, two-part, double-blind, placebo-controlled study of single ascending dose levels of Compound A in healthy volunteers (Part A) and a single administration of Compound A in subjects with TRD (Part B). Subjects, including 48 healthy subjects and 32 subjects with TRD, were randomized at different study sites. Each subject's participation period was a maximum of 39 days, including screening / washout and follow-up. The total duration of the study is expected to be approximately 12 months.

[0120] Overall design of Part A (single ascending dose [SAD] portion of this study in healthy volunteers): Part A was a randomized, two-part, double-blind, placebo-controlled, single-center trial of single ascending dose levels of Compound A in healthy volunteers. The study included a screening period of up to 28 days, an in-hospital period during which Compound A or placebo was administered, and a follow-up period of 3 to 7 days after discharge. Up to approximately 48 healthy volunteers were randomly assigned to double-blind treatment. Eight subjects were randomized to each of six dose-level cohorts (150, 300, 600, 1000, 1600, or 2400 mg of Compound A, or placebo, administered as an oral solution). Within each cohort, six subjects were randomized to receive Compound A and two subjects were randomized to receive placebo. Each subject received only one dose of either Compound A or placebo on Day 1. Within each cohort, one subject initially received Compound A and one subject received placebo. Because no clinically significant safety issues were observed within 24 hours of dosing in the first two subjects in the cohort, the remaining six subjects in the cohort were dosed. The in-hospital period was 6 days / 5 nights. Each subject's participation period, including screening / washout and follow-up, was a maximum of 39 days.

[0121] The chart for Part A of the study is shown in Table 1, and the dose escalation scheme for Part A is shown in Figure 1. [Table 1]

[0122] Overall design of Part B of this study (single-dose portion of subjects with TRD): Part B was a randomized, two-part, double-blind, placebo-controlled, multicenter, single-dose study of Compound A in subjects with TRD. The study included a screening period of up to 28 days, an in-hospital period during which Compound A or placebo was administered, and a follow-up period of 3 to 7 days after discharge. The dose level for this cohort (2400 mg) was based on preliminary safety, tolerability, and PK data from Part A of the study. Within this cohort, potential eligibility was confirmed through a site-independent review process. The site-independent review process consisted of a telephone interview with potential subjects (conducted after subjects passed the initial screening and before admission to the clinical unit) and a symptom stability review (conducted on day -2).

[0123] In Part B of the study, approximately 32 subjects were randomly assigned to double-blind treatment within one cohort. Within this cohort, 16 subjects were randomized to receive Compound A and 16 subjects were randomized to receive placebo. Each subject received a single-blind placebo once daily (QD) from Day -3 to Day -1, and a single dose of either Compound A or placebo (double-blind) on Day 1. The single-blind placebo run-in was intended to facilitate selection of placebo responders.

[0124] For Part B of the study, after signing informed consent, potential subjects discontinued antidepressant use for at least 14 days before dose administration (Day 1). For fluoxetine, a washout period of at least 3 weeks was required for doses of 20 mg / day or less, and at least 4 weeks for doses greater than 20 mg / day. Subjects were instructed to contact the site if they experienced any adverse events, including worsening depression, during the screening period.

[0125] The in-hospital period was 8 days / 7 nights. The participation period for each subject was a maximum of 39 days, including screening / washout and follow-up. A chart of Part B of this study is shown in Table 2 below. [Table 2]

[0126] Study design rationale: This study was designed to evaluate the safety, tolerability, PK, and preliminary efficacy of Compound A. Because this was the first clinical trial of Compound A, healthy volunteers were enrolled in Part A of the study. After the safety, tolerability, and PK of Compound A were evaluated in healthy volunteers in Part A of the study, the safety, tolerability, PK, and preliminary efficacy of Compound A were evaluated in subjects with TRD in Part B of the study.

[0127] Initially, single ascending doses were administered and evaluated in Part A of the study. To ensure subject safety, a Safety Review Committee (SRC) evaluated safety, tolerability, and plasma PK data before moving from one dose level cohort to the next higher dose level cohort and before moving from Part A of the study to Part B of the study.

[0128] The study included standard safety and tolerability assessments, such as physical, neurological, and psychiatric examinations, vital signs, oral temperature, respiratory rate, weight, 12-lead electrocardiogram (pECG), dECG, clinical laboratory tests, monitoring of adverse events (AEs), and concomitant medications, and, in Part A of the study, cardiovascular (CV) telemetry and safety EEG. The study also included drug-specific safety and tolerability assessments that may have psychiatric effects, such as the Columbia-Suicide Severity Rating Scale (C-SSRS; Part B only), the Brief Psychiatric Rating Scale-Positive Symptoms subscale [BPRS(+)], and the Clinician-Administered Dissociative States Scale (CADSS).

[0129] Frequent PK sampling was included in the study to evaluate single-dose PK. Part B of the study included assessments designed to evaluate preliminary efficacy.

[0130] Rationale for dose selection: The selection of the human dose for Compound A was based on Compound A nonclinical safety pharmacology, toxicology, and Compound A PK findings, along with predicted human Compound A exposure.

[0131] Factors affecting the starting and stopping doses of Compound A: The proposed starting dose of Compound A (150 mg) was based on the NOAEL dose of Compound A in the most sensitive species (160 mg / kg administered Q3D for 14 days in rats), determining the human equivalent dose (HED) (approximately 26 mg / kg, or approximately 1560 mg for a 60 kg human) based on the difference in body surface area between the two species, and then applying a safety factor of 10 to obtain the maximum recommended starting dose (MRSD). Based on the above considerations, the starting dose of Compound A in this study was 150 mg. Based on an integrated evaluation of nonclinical findings with Compound A, the planned maximum dose of Compound A in the first-time-in-human (FTIH) study was 2400 mg. Extrapolating based on body surface area, a dose of 2400 mg is equivalent to 247 mg / kg in rats and 123 mg / kg in monkeys. At higher dose levels (500 mg / kg) in rats, effects included lymphoid atrophy and leukopenia. At 160 mg / kg in monkeys, the only effect was a slight decrease in heart rate (approximately 18%, or approximately 30 beats per minute, compared with vehicle). In conclusion, completed toxicology and safety pharmacology studies supported the administration of Compound A with a low starting dose of 150 mg, a planned maximum dose of 2400 mg, and careful and comprehensive monitoring.

[0132] Rationale for the control group: The placebo was included to allow for a comparative assessment of the safety, tolerability, and preliminary efficacy of Compound A and to facilitate evaluation of the balance of benefits and risks posed by Compound A.

[0133] Subject selection criteria: Inclusion Criteria (Part A or Part B subjects): - Subjects were required to understand the nature of the study and provide signed and dated written informed consent before undergoing any study-related procedures. Female subjects had to be postmenopausal or surgically sterile, or agree to use one or more of the following forms of contraception from the time they signed the informed consent form until at least 30 days after study article administration: hormonal (i.e., oral, transdermal, implant, or injectable); double-barrier (i.e., condom, spermicide-containing diaphragm); intrauterine device (IUD); or partner vasectomy (minimum 6 months). Postmenopausal women had to have spontaneous amenorrhea for ≥12 months and a follicle-stimulating hormone (FSH) level ≥30 mIU / mL. Surgically sterile women were defined as those who had undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. All women were required to have a negative pregnancy test before study article administration. - Male subjects who are biologically capable of bearing children (i.e., not vasectomized) will use one or more of the above forms of birth control, as appropriate, for themselves or one or more partners, from the time they sign the informed consent form until at least 90 days after administration of the study product. I had to agree with that. Subjects must have been able, in the opinion of the investigator, to participate in all scheduled evaluations and be likely to complete and comply with all required testing. -Subjects had to be fluent in English.

[0134] Inclusion Criteria (Part A subjects only): Subjects had to be between 18 and 55 years of age. Subjects had to have a body mass index (BMI) between 19 and 30.

[0135] Inclusion Criteria (Part B subjects only): Subjects had to be between 18 and 65 years of age. Subjects had to have a BMI between 19 and 35. Subjects were diagnosed with major depressive disorder (MDD) without psychotic features according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria based on clinical evaluation and confirmed by the Mini International Neuropsychiatric Interview (MINI). - Subjects had to have had an inadequate response to at least one but no more than four antidepressants (stable, adequate dose, at least 6 weeks of treatment) in their current depressive episode. Antidepressant treatment response was assessed using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ). Less than a 50% improvement was considered an inadequate response. - Subjects were required to have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 21 or greater at screening and at all assessments from screening through dose administration (Day 1). Subjects were required to have a Ruskin Depression Rating Scale score of 9 or greater at screening and at all assessments from screening through dose administration (Day 1). Subjects had to be willing to discontinue antidepressant use at least 2 weeks prior to dose administration (Day 1). For fluoxetine, a washout period of at least 3 weeks was required for doses of 20 mg / day or less, and at least 4 weeks for doses greater than 20 mg / day.

[0136] Exclusion Criteria: Subjects did not participate in the study if they met any of the following exclusion criteria:

[0137] Exclusion Criteria (Part A or Part B subjects): - Positive pregnancy test or breastfeeding. - Clinically significant illness (including chronic, persistent, or acute infection), medical / surgical procedure, or trauma within 30 days prior to screening or from screening through dose administration (Day 1). - History or presence of clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, respiratory, immune, hematological, cutaneous, or neurological abnormality. - History or presence of any disease, condition, or surgery that may affect drug absorption, distribution, metabolism, or excretion. - Clinically significant abnormalities on physical examination, neurological examination, electrocardiogram (ECG), or laboratory evaluation at screening or from screening through dose administration (Day 1). - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal (ULN) at screening or from screening to dose administration (Day 1). Creatine kinase (CK) levels greater than 1.5 times the ULN at screening or from screening through dose administration (Day 1). Additionally, clinically significant CK levels (as determined by the investigator) at screening or from screening through dose administration (Day 1) were excluded. Creatinine clearance less than 60 mL / min by Cockcroft-Gault formula. - Leukocyte or neutrophil count below the lower limit of normal (LLN) at screening or from screening through dose administration (Day 1). - Clinically significant vital sign abnormalities at screening or from screening through dose administration (Day 1), including, but not limited to, the following while supine (after at least 5 minutes of supine controlled rest): (a) systolic blood pressure >150 mmHg, (b) diastolic blood pressure >95 mmHg, or (c) heart rate <45 beats / min or >85 beats / min. Corrected QT interval measurement (QT c F) >450 msec in men and >470 msec in women, or a family history of long QT syndrome. Any clinically significant abnormality in rhythm, conduction, or morphology of the resting ECG, and abnormal ST-T wave morphology or QT disturbances, including left ventricular hypertrophy, as determined by the investigator c Any abnormality on the 12-lead ECG that may interfere with the interpretation of interval changes. - PR(PQ) interval shortening less than 120 msec (PR<120 msec but >110 msec was allowed if there was no evidence of ventricular preexcitation). - Prolonged PR(PQ) interval (>240 msec), intermittent second-degree (not excluding Wenckebach-type block during sleep or deep rest) or third-degree atrioventricular block. - Persistent or intermittent complete bundle branch block (BBB) ​​or intraventricular conduction delay (IVCD) with a QRS >110 msec. Subjects with a QRS >110 msec but <115 msec were allowed if there was no evidence of ventricular hypertrophy or pre-excitation. - Significant (>10%) weight loss or gain within 30 days prior to screening or from screening to dose administration (Day 1). - History of seizures. - History of clinically significant head trauma, including closed head injury with loss of consciousness. - History of clinically significant symptomatic orthostatic hypotension (i.e., orthostatic syncope). - History of neuroleptic malignant syndrome. - History of chronic urinary tract infection. - Any personal history of cancer (excluding non-metastatic basal cell carcinoma and / or squamous cell carcinoma of the skin), renal cell carcinoma or breast cancer, or family history of lymphangioleiomyomatosis associated with tuberous sclerosis complex (TSC-LAM) within 5 years prior to screening or from screening to randomization. - Any disease or condition that, in the opinion of the investigator, (a) significantly increases the potential risks associated with the subject's participation in the study, (b) reduces the likelihood that the subject will complete the study, and / or (c) may confound the results of the study. -Diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation. Use of prescription or non-prescription medications for attention deficit hyperactivity disorder (ADHD), narcolepsy, or cognitive enhancement (e.g., methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 1 month prior to screening or from screening through dose administration (Day 1). Use of any vitamin or herbal supplement within 2 weeks prior to dose administration (Day 1) unless approved by the investigator and medical monitor. Alcohol consumption or use of any over-the-counter medication (excluding paracetamol / acetaminophen up to 3g per day) within 7 days prior to screening or from screening through dose administration (Day 1). Regular consumption of excessive amounts of xanthine-containing beverages (e.g., more than 5 cups of coffee or equivalent per day) within 30 days prior to screening or between screening and dose administration (Day 1) (e.g., more days consumed than days not consumed). - Donated blood or plasma within 6 weeks prior to screening or between screening and dose administration (Day 1). Use of any experimental drug, device, or biologic within 3 months or 5 half-lives (whichever is longer) prior to dose administration (Day 1). - Currently employed by Navitor Pharmaceuticals, Inc. or a clinical trial site participating in this study, or was a first-degree relative of a Navitor Pharmaceuticals, Inc. employee or an employee of a participating clinical trial site. Any condition that, in the opinion of the investigator or medical monitor, makes the subject unsuitable for the study. - Strenuous physical activity within 1 week prior to dose administration (Day 1). - Inadequate venous access. - Known or suspected hypersensitivity or idiosyncratic reaction to the investigational product or investigational product excipients.

[0138] Exclusion Criteria (Part A subjects only): - Clinically significant abnormalities on EEG at screening (e.g., epileptiform activity). - Positive urine drug screen for drugs of abuse. Use of any prescription medication (other than hormonal contraceptives) within 2 weeks prior to screening or from screening through dose administration (Day 1). - Frequent use of any tobacco-containing product (e.g., cigars, cigarettes, or snuff) or nicotine-containing product (e.g., nicotine chewing gum, nicotine bandages, or other products used for smoking cessation) within 3 months prior to screening. Frequent use is defined as 3 or more days per week. Use of any tobacco- or nicotine-containing product was prohibited within 1 week of dose administration (Day 1). - Any history of psychiatric disorders, including substance use disorders, according to DSM-5 criteria.

[0139] Exclusion Criteria (Part B subjects only): - Positive urine drug screen for drugs of abuse, excluding cannabis. Prior cannabis use was permitted only if the subject agreed to abstain from smoking or cannabis intake within 1 week of dose administration (Day 1) and for the duration of the study (including follow-up periods) and, in the investigator's judgment, was likely to comply with this restriction. Use of any psychopharmacological medication (including antidepressants) within 2 weeks prior to dose administration (Day 1), except for use of hypnotics within 1 month prior to screening and less than 4 days per week between screening and dose administration (Day 1). For fluoxetine, a washout period of at least 3 weeks was required for doses of 20 mg / day or less and at least 4 weeks for doses greater than 20 mg / day. - History of psychotic disorder according to DSM-5 criteria, MDD with psychosis, bipolar disorder or related disorder, post-traumatic stress disorder, obsessive-compulsive disorder (if primary), intellectual disability (DSM-5 diagnostic code 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder, or any other psychiatric or neurological disorder or condition that may pose undue risk to the subject or jeopardize the study. - Moderate or severe substance use disorder according to DSM-5 criteria within 1 year prior to screening. - Acute suicidality, manifesting as active suicidal thoughts with any intent to act, evidenced by answering "yes" to question 4 ("in the past year") or question 5 ("in the past year") of the C-SSRS at screening or between screening and dose administration (Day 1). - History of suicidal behavior, as evidenced by a "yes" decision for "actual attempt," "interrupted attempt," "aborted attempt," or "preparatory acts or behaviors" in the suicidal behavior section of the C-SSRS ("in the past year"). - A score of 5 on the 10-item MADRS at screening or from screening through dose administration (Day 1). --More than a 25% change in MADRS total score from Day 4 (admission) to Baseline (Day 1, pre-dose). - Covi Anxiety Scale score ≥ Ruskin Depression Rating Scale score at screening or from screening to dose administration (Day 1). - History of clinically significant physical, sexual, or psychological abuse (age ≤ 7 years). - Determined ineligible by facility-independent review.

[0140] Conduct of the study: Concomitant Treatments and Study Limitations (Part A Subjects Only)

[0141] During the study and designated period, you must not: - Frequent use of tobacco or nicotine-containing products within 3 months prior to screening, and use of tobacco or nicotine-containing products within 1 week prior to dose administration (Day 1). - Any experimental drug, device, or biologic within 3 months or 5 half-lives (whichever is longer) prior to dose administration (Day 1). - Any prescription or non-prescription medication for ADHD, narcolepsy, or cognitive enhancement (e.g., methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 1 month prior to screening or from screening through dose administration (Day 1). - Any vitamin or herbal supplement within 2 weeks prior to dose administration (Day 1) unless approved by the investigator and medical monitor. - Any prescription medication (other than hormonal contraceptives) within 2 weeks prior to screening or from screening through dose administration (Day 1). Alcohol or any over-the-counter medication (except paracetamol / acetaminophen up to 3g per day) within 7 days prior to screening or from screening through dose administration (Day 1).

[0142] Concomitant Treatments and Study Restrictions (Part B Subjects Only)

[0143] During the study and designated period, you must not: - Any experimental drug, device, or biologic within 3 months or 5 half-lives (whichever is longer) prior to dose administration (Day 1). - Any prescription or non-prescription medication for ADHD, narcolepsy, or cognitive enhancement (e.g., methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine A) within 1 month prior to screening or from screening through dose administration (Day 1). - Any vitamin or herbal supplement within 2 weeks prior to dose administration (Day 1) unless approved by the investigator and medical monitor. - Any psychopharmacological medication (including antidepressants) within 2 weeks of dose administration (Day 1), except for hypnotic medications used within 1 month prior to screening and less than 4 days per week between screening and dose administration (Day 1). For fluoxetine, a washout period of at least 3 weeks was required for doses of 20 mg / day or less and at least 4 weeks for doses greater than 20 mg / day. Hypnotic medications were permitted during the study, but should not be administered more than 3 days per week and, if possible, should not be administered on Days -1 or 1. Investigators were required to contact the medical monitor to discuss the intended treatment before administering hypnotic medications. Alcohol or any over-the-counter medication (except paracetamol / acetaminophen up to 3g per day) within 7 days prior to screening or from screening through dose administration (Day 1).

[0144] treatment: Compound A was provided as a bottled powder and compounded by the facility's pharmacist or other appropriately qualified staff member in accordance with local regulations. For the Compound A oral solution, the compounded materials consisted of Compound A (20–50 mg / g; this represents milligrams of Compound A per gram of total liquid weight), USP purified water (70%), and Flavor Sweet-SF™ (flavor masking agent; 30%). The placebo oral solution contained USP purified water (70%) and Flavor Sweet-SF™ (30%). To maintain double-blind requirements, the volume of placebo administered was equal to the volume of Compound A administered per dose. The study drug entities are listed in Table 3 below. [Table 3]

[0145] Dosage and treatment schedule: Part A of the study (SAD portion of healthy volunteers): Subjects were randomized to receive Compound A: a single fixed dose of 150, 300, 600, 1000, 1600, or 2400 mg of Compound A was administered orally as a liquid on Day 1. Subjects were asked to refrain from eating or drinking for 2 hours before and after administration. Subjects were randomized to receive placebo (purified water and Flavor Sweet-SF™): A single dose of placebo was administered orally as a liquid on Day 1. Subjects were asked to refrain from eating or drinking for 2 hours before and after administration.

[0146] Part B of the study (single-dose portion of subjects with TRD): Subjects were randomized to receive Compound A: each subject received a single fixed dose of 2400 mg Compound A on Day 1 with a single-blind placebo QD from Day -3 to Day -1. Compound A and placebo were administered orally as liquids. The Compound A dose level (2400 mg) was based on safety, tolerability, and PK data from Part A of the study. Subjects were randomized to receive placebo (purified water and Flavor Sweet-SF™): each subject received single-blind placebo QD from day -3 to day -1 and a single dose of placebo on day 1. Placebo was administered orally as a liquid.

[0147] Collection of study variables: Unless otherwise stated, the following items were assessed for each patient: 1.ECG 2.Respiration rate and oral temperature 3. Blood pressure and pulse rate 4.PK blood samples 5. EEG (Part A only) 6. Clinical testing safety samples 7. Neurological and physical examination 8. Psychiatric evaluation

[0148] Definitions of adverse events (AEs), treatment-emergent AEs (TEAEs), and adverse drug reactions (ADRs)

[0149] An AE is any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporarily associated with the use of a medical procedure or procedure, regardless of whether it is considered related to the medical procedure or procedure. In clinical studies, AEs can include undesirable medical conditions that occur at any time, including during lead-in or washout periods, even when the study treatment is not being administered. The term AE is a specific description of a specific event used in medical documentation and scientific analysis.

[0150] A TEAE is an AE that began after the initiation of study treatment or that was present before study treatment but increased in frequency or severity after the initiation of study treatment.

[0151] An adverse drug reaction (ADR) is considered to be related to any dose of a medicinal product, i.e., any AE for which there is at least a reasonable possibility of a causal relationship between the medicinal product and the AE (a relationship cannot be excluded).

[0152] Serious Adverse Event (SAE) Definition: A serious adverse event (SAE) is an AE that occurs during any study phase (i.e., run-in, treatment, washout, or follow-up) and meets one or more of the following criteria: leading to death Immediately life-threatening Hospitalization or extension of existing hospitalization is required Leads to persistent or significant disability / impairment or substantial disruption of the ability to perform normal life functions Have a congenital abnormality or birth defect A significant medical event that may endanger the subject or require medical intervention to prevent one of the outcomes listed above.

[0153] Psychiatric evaluation: Brief Psychiatric Rating Scale-Positive Symptoms Subscale [BPRS(+)]: The BPRS(+) is a clinician-administered scale used to measure psychotic behaviors ("positive" symptoms) that are not typically seen in healthy individuals. The scale contains four items, each scored on a scale of 1 to 7.

[0154] Clinician-Administered Dissociative Status Scale (CADSS): The CADSS is a clinician-administered instrument used to measure current dissociative symptoms. It consists of 23 items, all rated on a scale of 0 to 4. It has three factors assessing symptoms of amnesia, depersonalization, and derealization.

[0155] Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a unique, simple, and short instrument that assesses both behavior and ideation, tracks all suicidal events, and provides an overview of suicidality. It assesses the lethality of attempts and other ideation characteristics (frequency, duration, controllability, reasons for ideation, and deterrence), all of which significantly predict completed suicide. The C-SSRS was administered at screening, daily while in study custody, and at follow-up visits to determine the presence of suicidality.

[0156] Childhood Trauma Questionnaire-Short Form (CTQ-SF): The CTQ-SF is a self-administered questionnaire used to assess a wide range of maltreatment experiences. It contains 28 items (25 clinical and 3 validity items) scored on a scale of 1 to 5 and is derived from a longer (78-item) questionnaire.

[0157] Covi Anxiety and Ruskin Depression Scale (Covi-Ruskin): The Covi Anxiety and Ruskin Depression Scale is a clinician-administered scale used to assess overall levels of anxiety and depression. Each scale contains three items, each scored from 1 to 5.

[0158] Preliminary Efficacy Assessments: Other psychiatric assessments were conducted to assess preliminary efficacy in Part B only. These assessments included the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale-6 items (HAM-D6), the Clinical Global Impression-Severity Scale (CGI-S), and the Inventory of Depressive Symptoms (30-item, self-rating version) (IDS-SR). 30 ) were included. The Montgomery-Asberg Depression Rating Scale (MADRS).

[0159] The MADRS is a clinician-administered scale used to assess the range of symptoms most frequently observed in patients with major depression. The scale contains 10 items, each scored on a scale of 0 to 6. The MADRS was centrally administered by a third-party independent rater who was blinded to protocol, visits, and treatment.

[0160] Hamilton Depression Rating Scale-6 Items (HAM-D6): The HAM-D6 is a clinician-administered scale used to assess major domains of depressive symptoms. The HAM-D6 is an improved version of the original 17-item scale (HAM-D 17 Five of the six items were scored on a scale of 0 to 4, and one was scored on a scale of 0 to 2.

[0161] Clinical Global Impression-Severity (CGI-S): The CGI-S is a clinician-administered 7-point scale used to rate the severity of a patient's illness at the time of evaluation compared with the clinician's previous experience seeing patients with the same diagnosis.

[0162] Depressive Symptoms Questionnaire (30 items, self-rating version) (IDS-SR 30 ):IDS-SR 30 The is a self-rating scale used to assess the severity of depressive symptoms. The scale contains 30 items, each scored on a scale of 0 to 3.

[0163] Research results Breakdown: 48 randomized subjects; 6 drug groups (n=36 total) and 1 placebo group (n=12). All subjects completed the study.

[0164] Part A - Safety: Compound A: Compound A was well tolerated with no serious adverse events and no discontinuations due to adverse events. All adverse events were mild and typical of a Phase 1 study. The maximum tolerated dose was not reached. Vital, laboratory, and ECG findings were unremarkable. BPRS+ and CADSS scores were comparable between treatment groups. TEAE data are provided in Table 4 below for each cohort. [Table 4]

[0165] Breakdown: 40 planned subjects; the study ultimately randomized 32 subjects, 31 of whom were included in the efficacy sample. See Table 5 below. [Table 5]

[0166] Part B - Patient demographics in the ITT (intent to treat) population: See Table 6 below. [Table 6]

[0167] Part B - Safety: Compound A: Compound A was well tolerated with no serious adverse events and no discontinuations due to adverse events. All adverse events were mild to moderate. Vital, laboratory, and ECG findings were unremarkable. BPRS+ and CADSS scores were comparable between treatment groups. A safety summary is shown below in Table 7, and TEAE data is shown below in Table 8. [Table 7] [Table 8]

[0168] Table 9 below shows the timing of efficacy assessments. The MADRS total score was centrally administered. The HAM-D6 was administered at the facility. The CGI-S was administered by a physician at the facility. The IDS-SR was self-administered by the patient. The MADRS-6 and MADRS-8 scores were then post-hoc estimated from the MADRS total score. [Table 9]

[0169] The MADRS-10 items include outward sadness, expressed sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal thoughts. The MADRS-6 items include outward sadness, expressed sadness, inner tension, fatigue, inability to feel, and pessimistic thoughts. The MADRS-8 items include outward sadness, expressed sadness, inner tension, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal thoughts. The HAM-D6 items include depressed mood, low self-esteem / guilt, work and interests, psychomotor developmental delay, mental anxiety, and somatic symptoms.

[0170] It is recommended to use standardized effect size statistics when determining clinically significant antidepressant effects. The correct use of depression rating scales in antidepressant clinical trials is to indicate effect sizes for specific depression items, with effect sizes of 0.40 or higher being accepted as clinically significant. The effect sizes for this study are shown in Table 10 below. An effect size of 0.2 or greater indicates early improvement. An effect size of 0.4 or greater indicates a clinical response. [Table 10]

[0171] The efficacy signal for younger, more severely depressed patients measured at baseline is shown in Table 11 below. [Table 11]

[0172] Figure 2 presents HAM-D6 scores demonstrating rapid and sustained efficacy with a single dose of Compound A. Efficacy was observed as early as 2 hours after administration, with numerical benefits persisting for up to 24-72 hours. Table 12 provides a summary of effect sizes at each time interval. [Table 12]

[0173] Figure 3 shows the response rate of Compound A 2 hours after administration as measured by HAM-D6. Figure 4 shows the response rate of Compound A 12 hours after administration as measured by HAM-D6. Figure 5 shows the response rate of Compound A 24 hours after administration as measured by HAM-D6.

[0174] Five of the six items in the HAM-D6 address the same symptoms in a similar or overlapping manner as the MADRS. For the five common items, changes in HAM-D6 item scores correlated well with changes in MADRS item scores in subjects treated with Compound A. See Table 13 below for common items between the scales. Also see Figure 6, which depicts the correlation between the HAM-D6 and MADRS scales in measuring core symptoms of depression. [Table 13]

[0175] Table 14 below provides the MADRS item scores 24 hours after administration. MADRS-6 items are marked with a double asterisk ( ** ) Compound A showed a significant improvement in concentration scores despite having substantially lower baseline scores. Placebo subjects showed more severe symptoms overall. [Table 14]

[0176] Table 15 below contains efficacy signal data observed with Compound A for several MADRS items related to core symptoms of depression. MADRS-6 items are marked with a double asterisk ( ** ) is shown. [Table 15]

[0177] Compound A was found to have a greater effect than placebo on inner tension, concentration, pessimistic thoughts, and inability to have emotions.

[0178] Example 2. Randomized, double-blind, placebo-controlled, single-dose pharmacokinetic study of oral Compound A in plasma and cerebrospinal fluid of healthy male volunteers The blood-brain barrier restricts the flow of many small molecules, not just proteins, into and out of the brain. Approximately 150 mL of CSF is in direct contact with the extracellular space of the brain. Systemically administered drugs can reach the central nervous system (CNS) by directly passing through the choroid plexus or indirectly through the blood-brain barrier. Once across these barriers, drugs diffuse through the interstitial fluid into the CSF. Once in the CSF, drugs are transported throughout the CNS by convection through the ventricular system. After leaving the fourth ventricle, drugs flow through the cerebellomedullary cistern, down the spinal cord, and across the cerebral hemispheres. Because CSF is in direct contact with brain tissue, it is assumed that it readily equilibrates with brain interstitial fluid concentrations. CSF has been used as a useful surrogate for in vivo assessment of CNS exposure in clinical pharmacology studies.

[0179] Although no seizures have been observed in non-clinical studies with Compound A, to mitigate the potential risk of seizures, subjects with a history of seizures were excluded from this clinical study.

[0180] NMDA antagonists, particularly ketamine, are associated with altered mental status similar to psychotic or dissociative symptoms seen in psychiatric disorders. Although Compound A did not demonstrate NMDA antagonist activity in preclinical studies, this study included precautions regarding potential dissociative and other psychiatric adverse effects by excluding subjects with a psychiatric history. Research purpose:

[0181] Primary Objective: The primary objective of this study was to evaluate the PK profile of Compound A in plasma and CSF of healthy normal male volunteers.

[0182] Secondary Objectives: The secondary objective of this study was to evaluate the safety and tolerability of a single oral dose of 2400 mg of Compound A in healthy normal male volunteers.

[0183] Exploratory Objective(s): Using CSF and plasma samples collected in the same time frame as the PK samples, the exploratory objectives of this study were: -Unbiased metabolomic analysis was performed using validated methods as described here: https: / / www.metabolon.com / what-we-do / our-technology. -Unbiased proteomic analysis was performed using validated methods as described here: https: / / www.biognosys.com / technology.

[0184] Study endpoints: Safety Endpoints: The following safety variables were recorded at regular intervals during the study: Vital signs (supine BP, HR, temperature, and respiratory rate [RR]) 12-lead ECG: PR interval, QRS interval, RR interval, QT interval, and QT interval corrected for heart rate (QTc) (Bazett's correction [QTcB] and Fridericia's correction [QTcF]) Clinical laboratory tests (clinical chemistry, hematology, and coagulation) AE evaluation Neurological examination Physical examination

[0185] Pharmacokinetic Endpoints: The following PK parameters for Compound A were determined in serum and CSF as appropriate: C max : Maximum concentration of compound A determined directly from the concentration-time profile T max : Time of maximum concentration of compound A determined directly from the concentration-time profile AUC last : Time from pre-dose (time 0) to last quantifiable concentration (t last ) area under the concentration-time curve AUC inf : Area under the concentration-time curve (AUC) extrapolated from pre-dose (time 0) to infinity, calculated using the linear-logarithmic trapezoidal rule last +C last / λ z ) AUC %extrap :t last AUC due to extrapolation beyond inf Percentage of λ z : Terminal elimination rate constant determined by selecting at least three data points in the terminal phase of the concentration-time curve · t 1 / 2 :ln2 / λ z Terminal elimination half-life, calculated as · CL / F: Dose / AUC inf Apparent body clearance, calculated as · Vz / F: Dose / (AUC inf * λ z ) the apparent volume of distribution, calculated as MRT: Mean residence time (unchanged drug in systemic circulation): AUC / AUC R A(AUC) :AUC τ,ss / AUC τ,sd The steady-state AUC, calculated as inf,ss and AUC after a single dose τ,sdThe accumulated CSF / plasma ratio was calculated as the ratio of R A(Cmax) :C max,ss / C max,sd The steady-state C is calculated as max,ss and C after a single dose max,sd The accumulated CSF / plasma ratio was calculated as the ratio of The ratio of CSF Compound A concentrations over time compared to time-matched plasma concentrations was also assessed. The ratio of CSF Compound A concentrations over time compared to time-matched plasma concentrations was also assessed.

[0186] Overall study design: This was a phase 1, double-blind, placebo-controlled, single-dose study to evaluate the PK, metabolomic, and proteomic profiles of Compound A in plasma and CSF of healthy male subjects aged 18 to 55 years. Subjects attended a screening visit within 28 days prior to study drug administration. Upon meeting eligibility criteria and signing an ICF, subjects were admitted to the CRU on Day -1. On Day 1, intrathecal and venous catheters were inserted, and subjects were randomly assigned to double-blind treatment with a single oral dose of 2400 mg Compound A or placebo. Catheter insertion sites were periodically assessed for early signs of local infection or cerebrospinal fluid leak. Time-matched CSF and blood samples were then collected for 36 hours, after which the intrathecal and venous catheters were removed. See Figure 7 for a flowchart of the study.

[0187] Study design rationale: This study was conducted to evaluate the safety, tolerability, and PK of a single dose of Compound A versus placebo. The design of this clinical study followed the recommendations of the U.S. Food and Drug Administration (FDA) guidance document for double-blind, placebo-controlled studies. The study evaluated the safety, tolerability, PK, metabolomics, and proteomics of Compound A administered in liquid form as a single oral dose (2400 mg).

[0188] Rationale for dose selection: The dose level for this study (2400 mg) was based on preliminary safety, tolerability, and PK data from the single ascending dose study (see Example 1, Part A above).

[0189] Research period: Each subject participated for approximately 38 days. The estimated study duration is as follows: 1. Screening period: up to 28 days 2. Treatment period: up to day 2 3. Discharge: At least 36 hours after removal of the intrathecal catheter 4.EOS: 7 days (+ / - 1 day) after discharge from CRU

[0190] Research completed: Subjects were considered to have completed the study if they completed all scheduled procedures and provided all scheduled CSF and blood samples. Study completion was defined as the date of the last scheduled procedure on the final subject's activity schedule.

[0191] Subject selection criteria: The study population consisted of healthy male volunteers. Subjects were required to provide written informed consent, meet all inclusion criteria, and meet none of the exclusion criteria. Thirteen subjects were randomized, 13 subjects were evaluated for safety, and 12 subjects were evaluated for CSF.

[0192] Inclusion Criteria: Subjects who met the following criteria were considered eligible to participate in the clinical study. - Subjects were required to understand the nature of the study and provide signed and dated written informed consent before undergoing any study-related procedures. Subjects had to be aged 18 years or older and 55 years or younger at the time of signing informed consent. Subjects had to be non-smokers (i.e., abstain from tobacco [e.g., cigars, cigarettes, or snuff] or nicotine-containing [e.g., nicotine chewing gum, nicotine bandages, or other products used for smoking cessation] or e-cigarette products) within 12 months prior to screening. Subjects must be >19 30 kg / m 2 Participants were required to have a BMI of: Subjects who were biologically capable of having children (i.e., not vasectomized) had to agree to use one or more adequate forms of contraception, either for themselves or for one or more partners, from the time they signed the informed consent until at least 90 days after administration of the study article. Subjects must have been able, in the opinion of the principal investigator, to participate in all scheduled evaluations and be likely to complete and comply with all required testing.

[0193] Exclusion Criteria: Subjects did not participate in the study if they met any of the following exclusion criteria: - Clinically significant illness (including chronic, persistent, or acute infection), medical / surgical procedure, or trauma within 30 days prior to screening or from screening to before randomization (Day 1). - History or presence of clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, respiratory, immune, hematological, cutaneous, or neurological abnormality. - History or presence of any disease, condition, or surgery that may affect drug absorption, distribution, metabolism, or excretion. - Clinically significant physical, neurological, electrocardiogram (ECG), or laboratory test abnormalities at screening or between screening and Day -1. Procedures were to be repeated once at the discretion of the principal investigator. - History of seizures. - History of clinically significant head trauma, including closed head injury with loss of consciousness. - Positive serologic test results for human immunodeficiency virus antibody, hepatitis B surface antigen, or hepatitis C antibody. - Positive urine drug screen, alcohol screen, or cotinine test at screening or on Day -1. - Clinically significant vital sign abnormalities at screening or from screening through Day -1. This included the following after at least 5 minutes of supine controlled rest: (a) systolic BP >150 mmHg, (b) diastolic BP >95 mmHg, or (c) heart rate <50 beats / min or >90 beats / min (bpm). Vitals were to be repeated once at the discretion of the principal investigator. - Unknown (>10%) weight loss or gain within 6 months prior to screening or from screening to admission to the CRU (day -1). - History of clinically significant symptomatic orthostatic hypotension (i.e., orthostatic syncope). - History of neuroleptic malignant syndrome. - Any personal history of cancer (excluding non-metastatic basal cell carcinoma and / or squamous cell carcinoma of the skin), any personal history of renal cell carcinoma or breast cancer, or a family history of lymphangioleiomyomatosis associated with tuberous sclerosis within 5 years prior to screening or from screening to randomization. Any disease or condition at screening or from screening through to randomization (Day 1) that, in the opinion of the principal investigator, a) significantly increased the potential risks associated with the subject's participation in the study, b) reduced the likelihood that the subject will complete the study, and / or c) could confound the results of the study. - A diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation; any history of psychiatric disorder, including substance use disorder, according to DSM-5 criteria; and a history of taking prescription or non-prescription medications for attention deficit hyperactivity disorder, narcolepsy, or cognitive enhancement (e.g., methylphenidate, atomoxetine, modafinil, ginkgo biloba, and huperzine) a) within 1 month prior to screening or b) from screening to before randomization (Day 1). Use of any vitamin or herbal supplement within 2 weeks prior to randomization (Day 1) unless approved by the principal investigator and medical monitor. Alcohol consumption or use of any over-the-counter medication (excluding paracetamol / acetaminophen up to 2g per day) within 7 days prior to randomization (Day 1). Regular consumption of excessive amounts of xanthine-containing beverages (e.g., more than 5 cups of coffee or equivalent per day) (e.g., more days with consumption than days without consumption) within 72 hours prior to randomization (Day 1). - Have donated blood or plasma within 6 weeks prior to randomization (Day 1). Use of any experimental drug, device, or biologic within 30 days for non-biologics, 3 months for biologics, or 5 half-lives, whichever is longer, prior to randomization (Day 1). -Currently employed by Navitor or a CRU participating in this study, or was a first-degree relative of a Navitor employee or a CRU employee. Any condition that, in the opinion of the Principal Investigator or Medical Monitor, makes the subject unsuitable for the study. - Strenuous physical activity within 1 week prior to randomization (Day 1). - Inadequate or difficult venous access or unwillingness or inability to undergo direct venipuncture or catheterization. -Known or suspected hypersensitivity or idiosyncratic reaction to the investigational drug or investigational drug excipients.-Known or suspected hypersensitivity or idiosyncratic reaction to anesthetic agents used during lumbar puncture (e.g., lidocaine). Use of any prescription medication within 2 weeks prior to randomization (Day 1). - Contraindication to lumbar puncture or cerebrospinal fluid sampling as determined by the principal investigator and / or anesthesiologist (e.g., lumbar scoliosis, coagulopathy, skin infection at the puncture site, etc.). -Unwilling or unable to comply with required lifestyle restrictions. treatment:

[0194] Compound A and placebo bottles were provided by Sherpa Clinical Packaging (PCI) as filled and empty powder bottles and were reconstituted by the facility's pharmacist or other appropriately qualified staff member in accordance with local regulations. For Compound A oral solution, the clinical dose consisted of 2400 mg of Compound A reconstituted with approximately 42 mL of United States Pharmacopoeia (USP) purified water and 18 mL of Flavor Sweet-SF™ (flavor masking agent). The placebo dose contained these same ingredients without the active ingredient. The investigational drug entity is listed in Table 16 below. [Table 16]

[0195] Dose and Treatment Schedule: Subjects abstained from all food and drink (except water) for at least 8 hours prior to dosing on Day 1. Fluids were permitted up to 1 hour prior to administration of study drug. Fasting continued for at least 2 hours post-dose. Water was available for unlimited consumption beginning 1 hour post-dose.

[0196] Pharmacokinetic, Metabolomic, and Proteomic Variables: Pharmacokinetic, Metabolomic, and Proteomic Variables: Blood and CSF samples for PK, metabolomic, and proteomic analysis of Compound A were collected at various time points, processed, and analyzed by validated methods to determine Compound A concentrations.

[0197] Research results: The results demonstrate rapid uptake of Compound A into the circulation and rapid exposure to the brain. The results also indicate a half-life of 10-13 hours, making it suitable for daily dosing. See Figure 8, which shows human CSF levels consistent with rodent levels at effective doses. Figures 9 and 10 show CSF BDNF and BDNF receptor (NTRK2) fragment levels, respectively, after a single dose. mTORC1 activation resulted in rapid release of BDNF and receptor degradation.

[0198] A single dose of Compound A rapidly affected the turnover of key neurotransmitters, including GABA, histamine, serotonin, and dopamine, within 2 hours of treatment, a level that persisted for 36 hours after administration. Low CSF concentrations of HVA have been reported to be a marker of depressive symptoms. Table 17 shows the metabolomics of CSF neurotransmitters after a single dose. Values ​​represent the ratio of metabolite concentrations at each time point compared to baseline. Increases from baseline are indicated by a single asterisk ( * ) is shown. [Table 17]

[0199] Conclusions: In summary, this study provides important biomarker evidence that a single 2400 mg dose of Compound A achieves effective concentrations in the brain and activates neural pathways important for depression.

[0200] Example 3. A randomized, double-blind, placebo-controlled study of the effects of two consecutive doses of Compound A on quantitative electroencephalography and event-related potentials in healthy adult males. Single ascending doses of Compound A were evaluated in healthy adult males and females in Part A of a two-part, randomized, double-blind, placebo-controlled, first-in-human study (Part A, see Example 1). Based on preliminary blinded results from Part A, single ascending doses of Compound A up to 2400 mg were found to be generally safe and well-tolerated. A preliminary evaluation of dose linearity and PK parameters compared with dose from Part A of the study (see Example 1) revealed the following: Plasma compound A concentrations increased rapidly. max Median values ​​ranged from 0.5 to 1.5 hours after administration. Plasma Compound A exposure parameters (C max and AUC ∞ ) increased slightly less than dose-proportionally from 150 mg to 2400 mg. The estimated CL / F and Vz / F of Compound A increased with dose, but the estimated terminal elimination half-life was similar between cohorts (12.7-15.9 hours), consistent with a decrease in relative bioavailability with increasing dose. Modeling based on single-dose pharmacokinetic data supports the expectation of minimal accumulation with every-other-day or every-third-day dosing.

[0201] The research hypothesis for this study was that, compared with placebo, two consecutive oral doses of 2400 mg of Compound A administered approximately 48 hours apart would be generally safe and well tolerated and would be associated with specific spectral power changes in qEEG, supporting the safety and tolerability of consecutive oral doses of Compound A and the utility of qEEG as a functional indicator (biomarker) of the pharmacodynamic activity of Compound A. Preclinical changes in qEEG suggest depressive activity and higher frequency activity in spectral analysis.

[0202] Preclinical data suggest that alterations in signaling downstream of the mTORC1 pathway should result in improved signal processing of stimuli, as reflected in changes in selected ERP paradigms.

[0203] Compound A is intended to be developed for the treatment of TRD. As described above, single ascending doses of Compound A were evaluated in healthy adult men and women in the first part of a two-part, randomized, double-blind, placebo-controlled trial (Part A, see Example 1). Based on preliminary results from the first part of the study, single ascending doses of Compound A up to 2400 mg were found to be safe and well-tolerated. The study was designed to investigate the safety, tolerability, pharmacodynamics, and pharmacokinetics of two consecutive doses (2 days apart) of 2400 mg of Compound A compared with placebo in 24 healthy adult men (12 receiving Compound A and 12 receiving placebo). Pharmacodynamic evaluations included qEEG and event-related potential (ERP) measurements.

[0204] Although no seizures have been observed in nonclinical studies or limited clinical trials with Compound A to date, subjects with a history of seizures were excluded from this clinical study to mitigate the potential risk of seizures. Furthermore, to exclude subjects with potential seizures, a safety EEG was read by a neurologist at screening before the first dose, and EEGs were collected continuously for 8 hours after administration (Days 1 and 3). These continuous EEG recordings were subsequently reviewed by an experienced registered EEG technician (R.EEG T). Recordings showing signs of epileptiform activity during review were sent to a neurologist. Suspicious clinical signs indicating seizures observed by clinical staff during EEG acquisition also potentially triggered a review of the EEG recordings by a neurologist and / or transfer of the subject to a hospital facility at the discretion of the principal investigator.

[0205] NMDA antagonists, particularly ketamine, are associated with altered mental status similar to psychotic or dissociative symptoms seen in psychiatric disorders. Although Compound A did not demonstrate NMDA antagonist activity in preclinical studies, this study included precautions regarding potential dissociative and other psychiatric adverse effects, including exclusion of subjects with a psychiatric history, clinical evaluation of psychiatric symptoms throughout the course of the study, and evaluation of psychiatric symptoms.

[0206] Some drugs, including the NMDA antagonist ketamine, are associated with a risk of abuse. While the potential abuse liability of Compound A appears low based on available nonclinical data, specific nonclinical and clinical abuse liability studies have not yet been conducted with Compound A. Therefore, this study included precautions related to potential abuse liability, including the exclusion of subjects with a history of psychiatric disorders (including substance use disorders) and clinical evaluation of psychiatric symptoms throughout the study.

[0207] In nonclinical studies (rats), oral administration of high doses of Compound A (≥500 mg / kg Q3D for 14 days) was associated with lymphoid atrophy and decreased white blood cell counts. In this clinical study, precautions related to hematological findings in nonclinical studies with Compound A included exclusion of subjects with absolute white blood cell or neutrophil counts clinically significant below the normal range. Additionally, this clinical study included frequent clinical laboratory testing.

[0208] In a cardiovascular study in cynomolgus monkeys, oral administration of a single dose (≥160 mg / kg) of Compound A was associated with decreased heart rate and body temperature. Increased blood pressure was observed at higher dose levels (≥500 mg / kg). In a toxicology study in cynomolgus monkeys, oral administration of Compound A (≥500 mg / kg Q3D for 14 days) was associated with decreased heart rate. Cardiovascular safety precautions in this clinical study included frequent measurement of vital signs (e.g., blood pressure, pulse, and body temperature) and frequent electrocardiograms (ECGs). Research purpose:

[0209] Primary Objectives: The primary objectives of this study were to (1) evaluate the safety and tolerability and (2) evaluate the pharmacodynamics (assessed by qEEG) of two consecutive doses of 2400 mg Compound A versus placebo in healthy male volunteers.

[0210] Secondary Objectives: The secondary objectives were to (1) evaluate the pharmacodynamics (assessed by ERP); (2) evaluate the pharmacokinetics of two consecutive doses of 2400 mg Compound A in healthy male volunteers, and (3) develop a PK / PD model that measures changes in qEEG and ERP as a function of plasma concentration of Compound A and determines if there are any PK / PD differences between the effects of Dose 1 and Dose 2.

[0211] Exploratory objective(s): The exploratory objective was to evaluate the potential association between a single nucleotide polymorphism in the BDNF gene (substitution of valine [Val] by methionine [Met] at codon 66; Val66Met) and pharmacodynamic parameters.

[0212] Study endpoints: Safety Endpoint: The safety endpoint was to evaluate the safety and tolerability of sequential administration of Compound A versus placebo in healthy male volunteers, as assessed by clinical laboratory parameters, physical, neurological, and psychiatric examinations, vital signs, ECG, EEG, and adverse events.

[0213] Pharmacodynamic Endpoints: The primary pharmacodynamic endpoint was the change from baseline in the difference between the Compound A and placebo groups in the following qEEG parameters:

[0214] Fractals and oscillatory EEG band amplitudes

[0215] Intra- and interhemispheric coherence of fractal and oscillatory EEG bands

[0216] Secondary pharmacodynamic endpoints were the change from baseline in the difference between the Compound A and placebo groups in the following ERP parameters: Mismatch negativity (MMN) amplitude and latency P300a amplitude and latency P300b amplitude and latency N100 amplitude and latency N200 amplitude and latency P200 amplitude and latency Peak-to-peak amplitude of the auditory steady-state response (ASSR) ASSR Event-Related Spectral Perturbation (ERSP) ASSR Intertrial Phase Coherence (ITPC) qEEG Parallel Factor Analysis (PARAFAC) atomic endpoint mean time scores

[0217] Pharmacokinetic Endpoint: The pharmacokinetic endpoint was to evaluate the pharmacokinetics of repeated doses of Compound A in healthy male volunteers.

[0218] Pharmacogenetic endpoint: The pharmacogenetic endpoint was to evaluate the potential association between a single nucleotide polymorphism (Val66Met) in the BDNF gene and pharmacodynamic parameters. Overall study design:

[0219] This study was a randomized, double-blind, placebo-controlled trial of two doses of Compound A administered 48 hours ± 30 minutes apart in healthy adult male volunteers. The study included a screening period of up to 28 days, an in-hospital period during which Compound A or placebo was administered, and a follow-up period of 3 to 7 days after discharge.

[0220] Up to approximately 24 healthy male volunteers were randomly assigned (1:1) to double-blind treatment with either 2400 mg of Compound A or placebo. Each subject received one dose of either 2400 mg of Compound A or placebo on day 1, and a second dose of the same treatment on day 3.

[0221] The first dose of double-blind treatment was administered between 7:00 AM and 10:00 AM on Day 1. The second (Day 3) dose was administered 48 hours ± 30 minutes after the first (Day 1) dose. Pre-dose assessments were performed up to 120 minutes prior to dosing on Days 1 and 3, with the exception of pre-dose dECG, which was performed within 30 minutes prior to dosing on both Days 1 and 3, pre-dose qEEG and ERP, which was performed within 60 minutes prior to dosing on Days 1 and 3, and pre-dose PK blood sampling, which was performed within 15 minutes prior to dosing on Day 3.

[0222] Initially, one subject received Compound A (days 1 and 3) and one subject received placebo (days 1 and 3) in a blinded fashion. Additional subjects received Compound A unless clinically significant safety issues were identified within 24 hours after the first two subjects received Compound A. The in-hospital period was 8 days / 7 nights. Each subject's participation period, including screening and follow-up, was a maximum of 41 days. [Table 18]

[0223] Study design rationale: This study was designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of two consecutive doses (2 days apart) of 2400 mg of Compound A compared with placebo in 24 healthy adult males (12 receiving Compound A and 12 receiving placebo). The study included standard safety and tolerability assessments, such as physical, neurological, and psychiatric examinations, vital signs, oral temperature, respiratory rate, weight, 12-lead electrocardiogram (pECG), dECG, clinical laboratory tests, monitoring of adverse events (AEs) and concomitant medications, and safety EEG. The study also included safety and tolerability assessments specific to drugs with potential psychiatric effects, such as the Columbia-Suicide Severity Rating Scale (C-SSRS), Brief Psychiatric Rating Scale-Positive Symptoms Subscale [BPRS(+)], and Clinician-Administered Dissociative States Scale (CADSS).

[0224] Pharmacodynamics were assessed by qEEG and event-related potentials (ERPs). Frequent PK sampling was included in the study to evaluate the PK of two doses of Compound A given approximately 48 hours apart. A PK / PD model was developed that measured changes in qEEG and ERPs as a function of plasma concentration of Compound A to determine if there were any PK / PD differences between the effects of Dose 1 and Dose 2.

[0225] Rationale for dose selection: The selected dose of 2400 mg of Compound A was found to be generally safe and well tolerated in healthy adult male and female subjects in Example 1, Part A. This is the highest dose tested.

[0226] Rationale for the control group: The placebo was included to allow for a comparative evaluation of the safety, tolerability, and pharmacodynamics of Compound A and to facilitate evaluation of the balance of benefits and risks posed by Compound A.

[0227] Subject selection criteria: Inclusion Criteria: Subjects who met the following criteria were considered eligible to participate in the clinical study. - Subjects were required to understand the nature of the study and provide signed and dated written informed consent before undergoing any study-related procedures. Subjects were male and aged between 18 and 55 years. - Biologically childbearing (i.e., non-vasectomized) subjects had to agree to use one or more of the following forms of contraception, for either themselves or one or more partners, as appropriate, from the time they signed the informed consent form until at least 90 days after the last dose of study article: hormonal (i.e., oral, transdermal, implant, or injectable); double barrier (i.e., condom, spermicide-containing diaphragm); intrauterine device (IUD). Vasectomized men had to have had a vasectomy at least 6 months prior to the first dose (Day 1) or had agreed to use one or more of the above forms of contraception, for either themselves or one or more partners, as appropriate, from the time they signed the informed consent form until at least 90 days after the last dose of study article. Subjects were required to be able, in the opinion of the investigator, to participate in all scheduled assessments (including qEEG and ERP) and to be likely to complete and comply with all required testing. -Subjects had to be fluent in English. Subjects had to have a body mass index (BMI) between 19 and 30.

[0228] Exclusion Criteria: Subjects did not participate in the study if they met any of the following exclusion criteria: - Clinically significant illness (including chronic, persistent, or acute infection), medical / surgical procedure, or trauma within 30 days prior to screening or from screening through administration of the first dose (Day 1) - History or presence of clinically significant hepatic, renal, gastrointestinal, cardiovascular, endocrine, respiratory, immune, hematological, cutaneous, or neurological abnormalities - History or presence of any disease, condition, or surgery that may affect drug absorption, distribution, metabolism, or excretion - History or presence of any psychiatric disorder according to DSM-5 criteria, including but not limited to any psychotic disorder, substance use disorder, depressive disorder, anxiety disorder, bipolar disorder, or attention-deficit / hyperactivity disorder (ADHD). - History or presence of suicidality as evidenced by answering "yes" to question 4 ("lifetime") or question 5 ("lifetime") on the Columbia-Suicide Severity Rating Scale (C-SSRS) and indicating active suicidal thoughts with the intent to act on them at screening or between screening and the first dose (Day 1), or by answering "yes" to question 3 ("past year") on the C-SSRS and indicating active suicidal thoughts in any way (not a plan) without the intent to act on them at screening or between screening and the first dose (Day 1). - History or presence of suicidal behavior resulting in a "yes" decision for "actual attempt," "interrupted attempt," "aborted attempt," or "preparatory acts or behaviors" in the suicidal behavior section of the C-SSRS ("lifetime"). - Clinically significant abnormalities on evaluation of physical examination, neurological examination, electrocardiogram (ECG), or laboratory values ​​at screening or from screening through administration of the first dose (Day 1). - Clinically significant findings noted by a neurologist on screening EEG for epileptiform activity, or one or more other findings suggesting neurological disorders or other abnormalities that may endanger the subject, interfere with the qEEG or ERP testing, or confound the interpretation of the data - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal (ULN) at screening or from screening through first dose administration (Day 1). Creatine kinase (CK) levels greater than 1.5 times the ULN at screening or from screening through first dose administration (Day 1). Additionally, any clinically significant CK levels (as determined by the investigator) were excluded. Creatinine clearance less than 60 mL / min by Cockcroft-Gault formula. * Clinically significant absolute white blood cell or neutrophil counts below the normal range at screening or from screening through the first dose (Day 1). - Clinically significant vital sign abnormalities at screening or from screening through first dose administration (Day 1), including, but not limited to, the following while supine (after at least 5 minutes of supine controlled rest): (a) systolic blood pressure >150 mmHg, (b) diastolic blood pressure >95 mmHg, or (c) heart rate <45 beats / min or >95 beats / min. - A corrected QT interval measurement (QTcF), corrected according to the Fridericia method during controlled rest, of >450 msec at screening or between screening and the first dose (Day 1) or a family history of long QT syndrome. - Any clinically significant abnormality in rhythm, conduction, or morphology on the resting ECG and any abnormality on the 12-lead ECG that, in the investigator's judgment, could interfere with the interpretation of changes in the QTc interval, including abnormal ST-T wave morphology or left ventricular hypertrophy. - PR(PQ) interval shortening less than 120 msec (PR<120 msec, but >110 msec was acceptable if there was no evidence of ventricular preexcitation). - Prolonged PR(PQ) interval (>240 msec), intermittent second-degree (not excluding Wenckebach block during sleep or deep rest) or third-degree atrioventricular block. - Persistent or intermittent complete bundle branch block (BBB) ​​or intraventricular conduction delay (IVCD) with QRS >110 msec. - Significant (>10%) weight loss or gain within 30 days prior to screening or from screening to first dose administration (Day 1). - History of seizures, loss of consciousness from unknown cause, or any other known neurological disorder that places the subject at risk for seizures. - History of clinically significant head trauma, including closed head injury with loss of consciousness. - History of clinically significant symptomatic orthostatic hypotension (i.e., orthostatic syncope). - History of neuroleptic malignant syndrome. - Any personal history of cancer (excluding non-metastatic basal cell carcinoma and / or squamous cell carcinoma of the skin), renal cell carcinoma or breast cancer, or family history of lymphangioleiomyomatosis associated with tuberous sclerosis complex (TSC-LAM) within 5 years prior to screening or from screening to randomization. - Any disease or condition that, in the opinion of the investigator, (a) significantly increases the potential risks associated with the subject's participation in the study, (b) reduces the likelihood that the subject will complete the study, and / or (c) may confound the results of the study. -Diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation. Alcohol consumption within 7 days prior to screening or from screening through first dose administration (Day 1). Regular consumption of excessive amounts of xanthine-containing beverages (e.g., more than 5 cups of coffee or equivalent per day) within 30 days prior to screening or between screening and first dose administration (Day 1) (e.g., more days consumed than days not consumed). - Donated blood or plasma within 6 weeks prior to screening or between screening and the first dose (Day 1). Use of any experimental drug, device, or biologic within 3 months or 5 half-lives (whichever is longer) prior to administration of the first dose (Day 1). - Currently employed by Navitor Pharmaceuticals, Inc. or a clinical trial site participating in this study, or was a first-degree relative of a Navitor Pharmaceuticals, Inc. employee or an employee of a participating clinical trial site. Any condition that, in the opinion of the investigator or medical monitor, makes the subject unsuitable for the study. - Strenuous physical activity (e.g., exercise, weightlifting, and moving furniture) within 1 week prior to administration of the first dose (Day 1). - Inadequate venous access. -Known or suspected hypersensitivity or idiosyncratic reaction to the investigational product or investigational product excipients. -Positive urine drug screen for drugs of abuse (including cannabis) or cotinine, or positive urine alcohol screen. Use of any prescription medication within 2 weeks or 5 half-lives (whichever is longer) prior to screening or from screening until administration of the first dose (Day 1). Use of any non-prescription medication (except paracetamol / acetaminophen up to 3g per day) within 2 weeks or 5 half-lives (whichever is longer) prior to administration of the first dose (Day 1). Use of any vitamin or herbal supplement within 2 weeks prior to administration of the first dose (Day 1) unless approved by the investigator and medical monitor. Use of any tobacco-containing product (e.g., cigars, cigarettes, or snuff) or nicotine-containing product (e.g., nicotine chewing gum, nicotine bandages, or other products used for smoking cessation) within 3 months prior to screening or from screening through administration of the first dose. - Inadequate hearing on hearing testing administered at screening. treatment:

[0229] Compound A was provided as a powder in a bottle that was compounded by the facility's pharmacist or other appropriately qualified staff member in accordance with local regulations. For Compound A oral solution, the clinical dose consisted of 2400 mg of Compound A reconstituted with approximately 42 mL of United States Pharmacopoeia (USP) purified water and 18 mL of Flavor Sweet-SF™ (flavor masking agent). The placebo dose contained these same ingredients without the active ingredient. The investigational drug entity is shown in Table 19 below. [Table 19]

[0230] Dose and Treatment Schedule: Subjects were randomized to receive Compound A: a single dose of 2400 mg Compound A administered orally as a liquid on each of days 1 and 3. Subjects were asked to refrain from eating or drinking for 2 hours before and 2 hours after dose administration.

[0231] Subjects were randomized to receive placebo (purified water and Flavor Sweet-SF™): on days 1 and 3, a single dose of placebo was administered orally as a liquid.

[0232] result: A single dose of Compound A showed rapid and significant neural activation in qEEG versus placebo. Increased band effects are associated with arousal or alertness, suggesting positive mood states and improved cognitive function. Increased coherence is associated with activation of functional brain networks. See Figures 11 and 12, which show changes in qEEG band amplitude and changes in qEEG band coherence, respectively. Symbols indicate either no significant change (-), a slight to large increase (↑, ↑↑, ↑↑↑), a slight to large decrease (↓, ↓↓, ↓↓↓) or a mixed decrease and increase (↓↑) in the mean difference. Changes identified as significant treatment effects in a formal ANOVA model are marked with a double asterisk (** ) is shown.

[0233] Regarding plasma concentration-time data for Compound A, on Day 1, quantifiable plasma Compound A concentrations were achieved in all subjects by the 0.5-hour sampling time, the first sample post-dose. All subjects had quantifiable concentrations up to 24 hours post-dose, and all but one subject had quantifiable concentrations 36 hours post-dose. The peak concentration in the mean profile occurred 1 hour post-dose, with mean plasma concentrations subsequently declining in a roughly biphasic manner.

[0234] All subjects demonstrated quantifiable pre-dose concentrations on Day 3, and concentrations remained quantifiable in all subjects throughout the 72-hour sampling window. The maximum concentration for the mean profile occurred 0.5 hours post-dose, with concentrations declining in an approximately biphasic manner thereafter. The mean plasma concentration versus time profiles of Compound A on Days 1 and 3 were nearly superimposable (see Figure 13).

[0235] Key PK parameters for Compound A in plasma by day of dosing are summarized in Table 20. The geometric mean exposure to Compound A, as measured by Cmax, AUC(0-24), and AUC(0-48), was similar (within 5%) on Day 1 and Day 3. Absorption of Compound A was rapid. This was due to the individual T max values ​​were between 0.5 and 1.0 hours for all subjects on both dosing days. Geometric mean terminal elimination half-life values ​​were approximately 20% greater on Day 3 than on Day 1. Intersubject variability was low, with geometric CV% less than 30% for all primary parameters. [Table 20]

[0236] Pharmacodynamics: Nearly all significant qEEG, PARAFAC, and ASSR changes related to time post-dose were limited to the Compound A group; the placebo group showed little or no evidence of a time post-dose effect in either method. The Compound A group showed significant decreases in delta and theta band amplitude, decreases in alpha band amplitude within 1 hour post-dose, a decrease in the theta-to-beta ratio, and increases in high-frequency band amplitude (higher beta and gamma bands). The Compound A group also showed increases in alpha, beta, and gamma band coherence.

[0237] Compound A produced a dose-dependent decrease in low-frequency EEG bands (delta, theta) and an increase in high-frequency EEG bands (gamma). A decrease in amplitude (or desynchronization) was observed in the alpha band 1 hour after administration. All of these changes are signs of EEG activation and did not occur in the placebo group. Increased wakefulness, vigilance, and alertness are associated with an "activated" EEG spectrum characterized by desynchronized alpha waves (low alpha amplitude) and the absence of delta and theta waves, and may also exhibit high-frequency band amplitudes (high beta and gamma bands). EEG activation occurred within 1 hour of the first and second doses, as indicated by decreases from baseline in delta, theta, and alpha band amplitudes. EEG activation was also evidenced by increases in beta-2, high beta, and all gamma band amplitudes. Activation is associated with increased alertness and wakefulness. Increased beta-gamma band amplitude may also indicate increased levels of perceptual or cognitive processes.

[0238] Overall, the most significant and consistent changes in qEEG band coherence were treatment-related increases in the high frequency bands from alpha to gamma 3 with eyes closed and from high beta to gamma 3 with eyes open.

[0239] Changes in other qEEG and ERP endpoints. Significant changes in PARAFAC atomic time scores confirmed this pattern. Compound A was associated with an increase in ASSR high-frequency harmonic resonance, which was not evident in the placebo group. This was consistent with an increase in gamma-band amplitude and may indicate facilitation of functional networks for perception and cognition. Furthermore, Compound A reduced the peak latencies of the N100, P200, and P300A (AUC also decreased) components in an auditory oddball task, which was not evident in the placebo group. This may indicate improved attention, alertness, or sensory-perceptual processing speed.

[0240] Changes in EEG endpoints as a function of plasma Compound A concentration. Changes in EEG endpoints as a function of plasma concentration scale for Compound A were generally consistent with the mean post-dose changes for the placebo vs. Compound A treatment groups. The predominant pattern of qEEG effects showed: (1) a decrease in delta and theta band amplitude values ​​post-dose with increasing plasma levels of Compound A; (2) an increase in Compound A plasma concentration associated with an increase in gamma band amplitude post-dose, with different time constants for eyes-closed and eyes-open conditions; and (3) a decrease in PARAFAC delta atomic mean time score with increasing plasma concentration of Compound A.

[0241] Conclusion: Pharmacokinetics:

[0242] Compound A demonstrated significant improvement in individual T max Absorption was rapid as observed by values ​​ranging from 0.5 to 1.0 hours.

[0243] The accumulation of Compound A from days 1 to 3 was negligible, as the geometric mean values ​​of exposure parameters were within 5% between days.

[0244] · Geometric mean t 1 / 2Values ​​were slightly higher (approximately 20%) on day 3 than on day 1, but this may be an artifact of the longer sampling window after dosing on day 3.

[0245] · Variability in key PK parameters of Compound A was low (geometric CV<30%) across both dosing days.

[0246] Pharmacodynamics:

[0247] Compound A produced a dose-dependent decrease in low-frequency EEG bands (delta, theta) and an increase in high-frequency EEG bands (gamma). In the alpha band, a decrease in amplitude (or desynchronization) was observed 1 hour after administration. These changes, all signs of EEG activation, did not occur in the placebo group.

[0248] Increased wakefulness, vigilance, and alertness are associated with an "activated" EEG spectrum, characterized by asynchronous alpha waves (low alpha amplitude) and an absence of delta and theta waves, and which may also show high frequency band amplitudes (high beta and gamma bands).

[0249] -EEG activation occurred within 1 hour of the first and second doses, as indicated by decreases from baseline in delta, theta, and alpha band amplitudes.

[0250] -EEG activation was also evidenced by increases in beta-2, high beta and all gamma band amplitudes.

[0251] -Activation is associated with increased alertness and wakefulness.

[0252] -An increase in beta-gamma band amplitude may also indicate an increase in the level of perceptual or cognitive processes.

[0253] Compound A was associated with an increase in ASSR high-frequency resonance that was not evident in the placebo group.

[0254] -This is consistent with an increase in gamma band amplitude.

[0255] -It may show facilitation of functional networks for perception and cognition.

[0256] Compound A reduced the peak latencies of the N100, P200, and P300A components in an auditory oddball task, which was not evident in the placebo group.

[0257] This may indicate increased attention, alertness, or sensory-perceptual processing speed.

[0258] Changes in EEG endpoints as a function of plasma concentration scale for Compound A were generally consistent with mean post-dose changes for the placebo vs. Compound A treatment groups. The predominant pattern of qEEG effects showed the following:

[0259] - A decrease in post-dose values ​​of delta and theta band amplitude with increasing plasma levels of Compound A

[0260] - Increased plasma concentrations of Compound A are associated with increased gamma band amplitude following administration, with different time constants for eyes closed and eyes open.

[0261] - A decrease in PARAFAC delta atomic mean time score with increasing plasma concentrations of Compound A.

[0262] Safety:

[0263] Two doses of 2400 mg of Compound A administered 48 hours apart were generally safe and well tolerated in healthy male subjects.

[0264] There were no deaths or other SAEs, discontinuations due to TEAEs, or moderate (grade 2) or severe (grade 3) TEAEs in this study.

[0265] All TEAEs reported in subjects treated with Compound A were mild (Grade 1).

[0266] The incidence of TEAEs was higher in the placebo group (15.4%) than in the Compound A group (8.3%), as was the incidence of drug-related TEAEs (15.4% for placebo vs. 0 for Compound A). No dissociative effects were reported.

[0267] There were no clinically significant abnormalities in laboratory test results, vital signs, ECG data, safety EEG data, BPRS(+) or CADSS scores, or neurological or physical examination findings. There was no evidence of proconvulsant activity in the safety EEG.

[0268] Example 4. Blinded Multiple Ascending Dose (MAD) Study of Safety and Tolerability Navitor Pharmaceuticals, Inc. (Navitor) is currently conducting a study to evaluate the safety, tolerability, and PK of multiple ascending doses (400 mg, 800 mg, 1600 mg, 2400 mg, and potentially 3000 mg) of Compound A versus matching placebo in healthy volunteers. The study includes assessment of CSF and clinical biomarkers, as well as cognitive function testing.

[0269] The study will have four cohorts and one additional cohort on an as-needed basis. Up to approximately 40 healthy volunteers will be randomly assigned for double-blind treatment. In the first four cohorts, eight subjects will be randomized (3:1; Compound A:placebo) to each of four dose-level cohorts (800 mg, 1600 mg, 2400 mg, and 400 mg) administered as an oral solution. Within each cohort, six subjects will be randomized to receive Compound A and two subjects will be randomized to receive placebo. Each randomized subject will receive Compound A or placebo once daily for seven days. Subjects will receive their dose in the morning, at the same time each day. For Cohort 3 (2400 mg), each subject will return to the unit after a minimum five-day washout period to receive an additional single dose of Compound A or placebo under fed conditions in Period 2. Safety, tolerability, and PK as well as exploratory biomarkers and clinical measures will be assessed.

[0270] If sufficient safety and tolerability are observed in the first four cohorts, a fifth cohort, evaluating doses up to 3000 mg, may be conducted to characterize the safety, tolerability, and PK of daily doses above 2400 mg. In this fifth cohort, one subject will receive Compound A and one subject will receive placebo in a blinded manner. If no clinically significant safety or tolerability issues are observed 24 hours after dosing in the first two subjects, the other six subjects may be dosed. In this optional cohort, only safety, tolerability, and PK will be evaluated. Exploratory biomarkers and clinical measures will not be evaluated. PK samples may be analyzed after a specific cohort, and PK data analysis may be performed in a blinded manner to generate PK parameters.

[0271] This study will be overseen by a Safety Review Committee (SRC). The SRC aims to ensure that treatment does not pose undue risk to subjects. Safety and tolerability will be assessed by the SRC before moving from one dose level cohort to the next higher dose level cohort. Additionally, the SRC may choose to modify the dose or dose escalation schedule depending on its review of available data.

[0272] Inclusion Criteria: Subjects who met the following criteria were considered eligible to participate in the clinical study.

[0273] All volunteers must meet the following criteria to be considered for participation in the study: 1. Subjects must understand the nature of the study and provide signed and dated written informed consent before undergoing any study-related procedures. 2. Subjects must be aged 18 years or older and under 65 years. 3. Subjects must have a body mass index (BMI) of 18 kg / m 2 More than 35kg / m 2 Must be less than or equal to: 4. Female subjects must be postmenopausal or surgically sterile, or agree to use one or more of the following forms of contraception from the time they sign the informed consent form until at least 30 days after the last dose of study drug: hormonal (i.e., oral, transdermal / subcutaneous, implant, or injectable); double barrier (i.e., condom, spermicide-containing diaphragm); intrauterine device (IUD); or partner vasectomy (minimum 6 months). Postmenopausal women must have had spontaneous amenorrhea for 12 months or more and a follicle-stimulating hormone (FSH) of 30 mIU / mL or greater. Surgically sterile women are defined as those who have undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation. All women must have a negative pregnancy test prior to administration of study drug. 5. Male subjects who are biologically capable of having children (i.e., not vasectomized) must agree to use one or more of the above forms of contraception, as appropriate, for themselves and one or more partners from the time they sign the informed consent form until at least 90 days after the last dose of study drug. They must also agree to abstain from sperm donation from the first dose of study drug until 90 days after the last dose of study drug. 6. Potential subjects must, in the opinion of the principal investigator, be able to participate in all scheduled evaluations and be likely to complete and comply with all required study procedures.

[0274] Exclusion Criteria: Subjects who met the following criteria were considered ineligible to participate in the clinical study.

[0275] A volunteer will be excluded from participating in the study for any of the following reasons: 1. Any past or ongoing medical condition, medical history, physical or neurological findings, ECG, EEG, laboratory or vital sign abnormalities that, in the opinion of the principal investigator, may adversely affect the subject's safety. 2. History (within the past year) or presence of suicidality (Type 4-5) with suicidal thoughts as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS) at screening or prior to Day 1 dosing 3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 1.5 times the upper limit of normal (ULN) at screening or day -1 4. Creatine kinase (CK) levels greater than 1.5 × ULN at screening or day -1 5. Creatinine clearance of less than 80 mL / min by Cockcroft-Gault formula 6. Clinically significant absolute leukocyte or neutrophil counts below the normal range at screening or day -1 7. QT interval measurement corrected according to Fridericia's method during controlled rest at screening or from screening through first dose administration (Day 1) c F) >450 msec in men and >470 msec in women, or a family history of long QT syndrome. 8. PR (PQ) interval shortening of less than 120 msec (PR < 120 msec, but > 110 msec is acceptable if there is no evidence of ventricular preexcitation). 9. Prolongation of the PR (PQ) interval (>240 msec), intermittent second-degree (not excluding Wenckebach block during sleep or deep rest) or third-degree atrioventricular block. 10. Persistent or intermittent complete bundle branch block (BBB) ​​or intraventricular conduction delay (IVCD) with QRS > 110 msec. 11. History of seizures, loss of consciousness from unknown cause, or any other known neurological disorder that places the subject at risk for seizures. 12. History of clinically significant head trauma, including closed head injury with loss of consciousness. 13. History of clinically significant symptomatic orthostatic hypotension (i.e., orthostatic syncope or dizziness). 14. History of neuroleptic malignant syndrome. 15. Personal history of cancer (excluding non-metastatic basal cell carcinoma and / or squamous cell carcinoma of the skin), any personal history of renal cell carcinoma or breast cancer, or family history of tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) within 5 years prior to screening or from screening to randomization. 16. Diagnosis of intellectual disability (intellectual developmental disorder) or mental retardation. 17. History of alcohol use disorder within 6 months prior to screening, defined as an average weekly intake of >21 units for men and >14 units for women (1 unit is equivalent to half a pint of beer, 1 shot of hard liquor, or 1 glass of wine). 18. Regularly consumed excessive amounts of xanthine-containing beverages (e.g., more than 5 cups of coffee or equivalent per day) within 30 days prior to screening or between screening and administration of the first dose of study drug (Day 1) (e.g., more days with consumption than days without consumption). 19. Have donated blood or plasma within 3 months prior to screening or between screening and administration of the first dose of investigational drug (Day 1). 20. Use of any experimental drug, device, or biologic within 3 months or 5 half-lives (whichever is longer) prior to administration of the first dose of investigational drug (Day 1). 21. Strenuous physical activity (e.g., exercise, weightlifting, and moving furniture) within 1 week prior to administration of the first dose of study drug (Day 1). 22. Inadequate venous access. 23. Known or suspected hypersensitivity or idiosyncratic reaction to the investigational product or investigational product excipients. 24. Known or suspected substance use disorder as determined by a positive urine drug screen for drugs of abuse (including but not limited to cannabis, cotinine, alcohol, and psychostimulants) at the time of screening. 25. Use of any prescription medication within 2 weeks or 5 half-lives (whichever is longer) prior to screening or from screening until administration of the first dose of investigational drug (Day 1). 26. Use of any non-prescription medication (except paracetamol / acetaminophen up to 3g per day) within 2 weeks or 5 half-lives (whichever is longer) prior to administration of the first dose (Day 1). 27. Use of any vitamins, herbal supplements, or grapefruit or berry (juice / capsules) within 2 weeks prior to first dose administration (Day 1) unless approved by the principal investigator and medical monitor. 28. Use of any tobacco-containing product (e.g., cigars, cigarettes, or snuff) or nicotine-containing product (e.g., nicotine chewing gum, nicotine bandages, or other products used for smoking cessation) within 3 months prior to screening or from screening through administration of the first dose of investigational drug. 29. Previously participated in a clinical trial in which Compound A was administered For subjects in Cohort 3: 30. Unable to consume an entire FDA-standard high-fat, high-calorie meal within 30 minutes prior to administration.

[0276] Cohort 1 (800 mg) and Cohort 2 (1600 mg) have been completed. In these cohorts, healthy volunteers were randomized to either Compound A or placebo (6:2). Cohort 1a consisted of 2 subjects Cohort 1b consisted of 3 subjects Cohort 1c consisted of 3 subjects Cohort 2a consisted of 2 subjects Cohort 2b consisted of 3 subjects Cohort 2c consisted of 3 subjects

[0277] Preliminary safety data from these cohorts were reviewed by a safety review committee. No clinically significant abnormalities were observed in laboratory values, vital signs, or ECGs. All AEs were mild; none were serious. No subjects experienced events that met the pre-specified protocol stopping criteria listed below.

[0278] Review of pre-specified stopping criteria: [Table 21]

[0279] As no subjects met the stopping criteria, the decision was made to proceed to evaluation of the higher dose of 2400 mg.

[0280] While several embodiments of the present invention have been described, it will be apparent that our basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of the present invention is defined by the appended claims rather than by the specific embodiments that have been represented by way of example. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating depression in a patient in need thereof, comprising administering a therapeutically effective amount of Compound A: [ka] or a pharmaceutically acceptable salt thereof. (Item 2) Item 1. The method according to item 1, wherein the therapeutically effective amount comprises a total daily dose of about 100 mg to about 3000 mg. (Item 3) 3. The method of claim 2, wherein the therapeutically effective amount comprises a total daily dose of about 150 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1600 mg, about 2400 mg, or about 3000 mg. (Item 4) 4. The method of either item 2 or 3, wherein the total daily dose is administered QD. (Item 5) 5. The method of any of items 1 to 4, comprising administering a single dose. (Item 6) 5. The method of any of items 1 to 4, comprising administering at least two doses. (Item 7) 5. The method of any of items 1 to 4, comprising administering compound A daily for at least 2, 3, 4, 5, 6, or 7 consecutive days. (Item 8) 7. The method of claim 6, comprising administering the first dose about 48 hours before administering the second dose. (Item 9) 9. The method according to any of items 2 to 8, wherein the total daily dose is administered under fasting conditions. (Item 10) 9. The method according to any of items 2 to 8, wherein the total daily dose is administered under fed conditions. (Item 11) 11. The method of any of items 1 to 10, wherein the depression is treatment-resistant depression ("TRD"). (Item 12) The method according to any one of items 1 to 11, wherein the depression is resistant to first-line treatment. (Item 13) The method according to any one of items 1 to 12, wherein the depression is resistant to second-line treatment. (Item 14) 14. The method of any of items 1 to 13, wherein the patient has been diagnosed with major depressive disorder ("MDD"). (Item 15) 15. The method according to any of items 1 to 14, wherein the patient is experiencing a depressive episode and has had at least one inadequate response to at least one antidepressant during the depressive episode. (Item 16) 16. The method according to any of items 1 to 15, wherein the patient is experiencing a depressive episode and has had at least one inadequate response to at least two, three, or four different antidepressants during the depressive episode. (Item 17) 17. The method of any of items 1 to 16, wherein the patient is assessed prior to treatment as having a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 21 or greater. (Item 18) 18. The method of any of items 1 to 17, wherein the patient is assessed prior to treatment as having a score of 9 or greater on the Ruskin Depression Rating Scale. (Item 19) 19. The method according to any of items 1 to 18, wherein the administration is oral. (Item 20) 20. The method according to any of items 2 to 19, wherein the total daily dose is a single unit dosage form. (Item 21) 21. The method of any of items 2 to 20, wherein the total daily dose comprises a liquid unit dosage form containing about 150 mg, about 300 mg, about 400 mg, about 600 mg, about 800 mg, about 1000 mg, about 1600 mg, about 2400 mg, or about 3000 mg of Compound A or a pharmaceutically acceptable salt thereof. (Item 22) 22. The method according to any of items 2 to 21, wherein the total daily dose comprises a liquid unit dosage form containing about 2400 mg of Compound A or a pharmaceutically acceptable salt thereof.

Claims

[Claim 1] The invention described in the specification.

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