Reduction of side effects of NMDA antagonists

Abstract

To provide a reduction in the side effects of NMDA antagonists. [Solution] This disclosure relates to compositions comprising racemiketamine or a pharmaceutically acceptable salt thereof for use in the treatment of mental disorders such as suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. Some embodiments provide a method for treating suicidal tendencies in subjects requiring treatment of suicidal tendencies, comprising intranasal administration of a therapeutically effective amount of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

Description

[Technical Field]

[0001] This disclosure relates to compositions and methods for treating mental disorders such as suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. [Background technology]

[0002] Depression is one of the most debilitating medical disorders and a major public health issue. It frequently begins in childhood and can be chronic throughout life, potentially negatively impacting the prognosis of other medical conditions, such as cardiovascular and neurological disorders.

[0003] While antidepressant medication and cognitive behavioral therapy are effective for people with depression, up to 20% do not respond to these interventions, and many of those who do eventually relapse. Similarly, an estimated 50% of people with depression are only partially (insufficiently) treated by available clinical interventions. See Al Harbi, Patient Prefer. Adherence, Vol. 6, pp. 369-388 (2012). In the NIMH's Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study for alleviating depression, about half of patients treated with first-line antidepressant therapy reduced their symptoms to at least half of their original severity, and only about one-third achieved remission (Chan 2013). While these patients may eventually recover, many require trial-and-error approaches to therapy, and many eventually develop treatment-resistant depression over time. See, for example, Sackheim, J. Clin. Psychiatry, Vol. 62, Suppl. 16, pp. 10-17 (2001). This can lead to more serious conditions, such as suicidal ideation and suicidal tendencies. Suicide remains a clearly present and growing public health problem, despite being a potentially avoidable tragedy. The incidence of suicide is particularly high among people with undiagnosed or inadequately treated mental disorders. The discovery of treatments with tricyclic antidepressants and monoamine oxidase inhibitors has revolutionized the treatment of depression. However, even recently developed drugs for treating depression can take weeks to months to achieve full effect, and no safe dose is effective for all subjects. For example, most antidepressants require an average of six weeks to begin to affect depressive symptoms. Some patients do not respond to antidepressants at all, while others appear to have some effect in improving symptoms. In the meantime, people continue to suffer from depression, are at risk of self-harm, and experience negative impacts on their personal and professional lives. See, for example, Burcusa and Iacono, Clin. Psycho. Rev. Vol. 27, No. 8, pp. 959-985 (2007). Providing rapidly developing and sustained antidepressant effects would have a significant impact on public health. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Al Harbi,Patient Prefer.Adherence,Vol.6,pp.369-388(2012) [Non-Patent Document 2] Sackheim, J. Clin. Psychiatry, Vol. 62, Suppl. 16, pp. 10-17 (2001) [Non-Patent Document 3] Burcusa and Iacono,Clin.Psychol.Rev.Vol.27,No.8,pp.959-985(2007) [Overview of the project] [Means for solving the problem]

[0005] Details of one or more embodiments are described below. Other features, purposes, and advantages of the present invention will become apparent from the description and claims.

[0006] Some embodiments provide a method for treating suicidal tendencies in subjects requiring treatment of suicidal tendencies, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0007] Some embodiments provide a method for treating suicidal ideation in subjects requiring treatment of suicidal ideation, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0008] Some embodiments provide a treatment for major depressive disorder in subjects requiring treatment for major depressive disorder, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0009] Some embodiments provide methods for reducing one or more side effects of ketamine in subjects requiring reduction, the methods comprising intranasal administration of a therapeutically effective dose of racemic ketamine or a pharmaceutically acceptable salt thereof to the subject.

[0010] In some embodiments, the subject has been previously diagnosed with post-traumatic stress disorder and / or is currently suffering from post-traumatic stress disorder. In some embodiments, the subject has been previously diagnosed with major depressive disorder and / or is currently suffering from major depressive disorder. [Brief explanation of the drawing]

[0011] Abbreviation N: Number of observations; SD: Standard deviation; Min: Minimum value; Max: Maximum value; IN: Inside the nasal cavity.

[0012] [Figure 1A] This table shows the pharmacokinetic parameters of ketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 1A), 75 mg of racemiketamine (Figure 1B), or 90 mg of racemiketamine (Figure 1C). [Figure 1B] This table shows the pharmacokinetic parameters of ketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 1A), 75 mg of racemiketamine (Figure 1B), or 90 mg of racemiketamine (Figure 1C). [Figure 1C] This table shows the pharmacokinetic parameters of ketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 1A), 75 mg of racemiketamine (Figure 1B), or 90 mg of racemiketamine (Figure 1C). [Figure 2A] This table shows the pharmacokinetic parameters of ketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 2A), 75 mg of racemiketamine (Figure 2B), or 90 mg of racemiketamine (Figure 2C). [Figure 2B] This table shows the pharmacokinetic parameters of ketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 2A), 75 mg of racemiketamine (Figure 2B), or 90 mg of racemiketamine (Figure 2C). [Figure 2C] This table shows the pharmacokinetic parameters of ketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 2A), 75 mg of racemiketamine (Figure 2B), or 90 mg of racemiketamine (Figure 2C). [Figure 3A] This table shows the pharmacokinetic parameters of ketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 3A), 75 mg of racemiketamine (Figure 3B), or 90 mg of racemiketamine (Figure 3C). [Figure 3B] This table shows the pharmacokinetic parameters of ketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 3A), 75 mg of racemiketamine (Figure 3B), or 90 mg of racemiketamine (Figure 3C). [Figure 3C]This table shows the pharmacokinetic parameters of ketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 3A), 75 mg of racemiketamine (Figure 3B), or 90 mg of racemiketamine (Figure 3C). [Figure 4A] This table shows the pharmacokinetic parameters of norketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 4A), 75 mg of racemiketamine (Figure 4B), or 90 mg of racemiketamine (Figure 4C). [Figure 4B] This table shows the pharmacokinetic parameters of norketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 4A), 75 mg of racemiketamine (Figure 4B), or 90 mg of racemiketamine (Figure 4C). [Figure 4C] This table shows the pharmacokinetic parameters of norketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 4A), 75 mg of racemiketamine (Figure 4B), or 90 mg of racemiketamine (Figure 4C). [Figure 5A] This table shows the pharmacokinetic parameters of norketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 5A), 75 mg of racemiketamine (Figure 5B), or 90 mg of racemiketamine (Figure 5C). [Figure 5B] This table shows the pharmacokinetic parameters of norketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 5A), 75 mg of racemiketamine (Figure 5B), or 90 mg of racemiketamine (Figure 5C). [Figure 5C] This table shows the pharmacokinetic parameters of norketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 5A), 75 mg of racemiketamine (Figure 5B), or 90 mg of racemiketamine (Figure 5C). [Figure 6A]This table shows the pharmacokinetic parameters of norketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 6A), 75 mg of racemiketamine (Figure 6B), or 90 mg of racemiketamine (Figure 6C). [Figure 6B] This table shows the pharmacokinetic parameters of norketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 6A), 75 mg of racemiketamine (Figure 6B), or 90 mg of racemiketamine (Figure 6C). [Figure 6C] This table shows the pharmacokinetic parameters of norketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 6A), 75 mg of racemiketamine (Figure 6B), or 90 mg of racemiketamine (Figure 6C). [Figure 7A] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 7A), 75 mg of racemiketamine (Figure 7B), or 90 mg of racemiketamine (Figure 7C). [Figure 7B] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 7A), 75 mg of racemiketamine (Figure 7B), or 90 mg of racemiketamine (Figure 7C). [Figure 7C] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 1 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 7A), 75 mg of racemiketamine (Figure 7B), or 90 mg of racemiketamine (Figure 7C). [Figure 8A] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 8A), 75 mg of racemiketamine (Figure 8B), or 90 mg of racemiketamine (Figure 8C). [Figure 8B]This table shows the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 8A), 75 mg of racemiketamine (Figure 8B), or 90 mg of racemiketamine (Figure 8C). [Figure 8C] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 8A), 75 mg of racemiketamine (Figure 8B), or 90 mg of racemiketamine (Figure 8C). [Figure 9A] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 9A), 75 mg of racemiketamine (Figure 9B), or 90 mg of racemiketamine (Figure 9C). [Figure 9B] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 9A), 75 mg of racemiketamine (Figure 9B), or 90 mg of racemiketamine (Figure 9C). [Figure 9C] This table shows the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the study described in Example 1, for 30 mg of racemiketamine (Figure 9A), 75 mg of racemiketamine (Figure 9B), or 90 mg of racemiketamine (Figure 9C). [Figure 10A] This table illustrates the pharmacokinetic parameters of ketamine on day 1 (Figure 10A), day 4 (Figure 10B), or day 8 (Figure 10C) of Part B of the study described in Example 1 for racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 10B]This table illustrates the pharmacokinetic parameters of ketamine on day 1 (Figure 10A), day 4 (Figure 10B), or day 8 (Figure 10C) of Part B of the study described in Example 1 for racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 10C] This table illustrates the pharmacokinetic parameters of ketamine on day 1 (Figure 10A), day 4 (Figure 10B), or day 8 (Figure 10C) of Part B of the study described in Example 1 for racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 11A] This table illustrates the pharmacokinetic parameters of norketamine on day 1 (Figure 11A), day 4 (Figure 11B), or day 8 (Figure 11C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 11B] This table illustrates the pharmacokinetic parameters of norketamine on day 1 (Figure 11A), day 4 (Figure 11B), or day 8 (Figure 11C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 11C] This table illustrates the pharmacokinetic parameters of norketamine on day 1 (Figure 11A), day 4 (Figure 11B), or day 8 (Figure 11C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 12A]This table illustrates the pharmacokinetic parameters of hydroxynorketamine on day 1 (Figure 12A), day 4 (Figure 12B), or day 8 (Figure 12C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 12B] This table illustrates the pharmacokinetic parameters of hydroxynorketamine on day 1 (Figure 12A), day 4 (Figure 12B), or day 8 (Figure 12C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 12C] This table illustrates the pharmacokinetic parameters of hydroxynorketamine on day 1 (Figure 12A), day 4 (Figure 12B), or day 8 (Figure 12C) of Part B of the study described in Example 1 for racemiketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemiketamine (equivalent dose to 60 mg IN) + placebo IN. [Figure 13A] These are a table (Figure 13A) and a graph (Figure 13B) illustrating the MADRS depression scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 13B] These are a table (Figure 13A) and a graph (Figure 13B) illustrating the MADRS depression scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 14A] These are a table (Figure 14A) and a graph (Figure 14B) illustrating the CGIS-SI / B suicidal ideation scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 14B] These are a table (Figure 14A) and a graph (Figure 14B) illustrating the CGIS-SI / B suicidal ideation scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 15A]These are a table (Figure 15A) and a graph (Figure 15B) illustrating the S-STS suicidal tendency scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 15B] These are a table (Figure 15A) and a graph (Figure 15B) illustrating the S-STS suicidal tendency scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 16A] These are a table (Figure 16A) and a graph (Figure 16B) illustrating the PGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 16B] These are a table (Figure 16A) and a graph (Figure 16B) illustrating the PGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 17] This table explains the CGIC-SI / B suicidal ideation scores for Subject 1 and Subject 2 from day 1 to day 8, as described in Study Example 3. [Figure 18] This table explains the PGIC-SI / B scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 19A] These are a table (Figure 19A) and a graph (Figure 19B) illustrating the MADRS item 10 scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 19B] These are a table (Figure 19A) and a graph (Figure 19B) illustrating the MADRS item 10 scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 20A] These are a table (Figure 20A) and a graph (Figure 20B) illustrating the STS CMCM ("Current Suicide Risk") scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 20B] These are a table (Figure 20A) and a graph (Figure 20B) illustrating the STS CMCM ("Current Suicide Risk") scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 21A] These are a table (Figure 21A) and a graph (Figure 21B) illustrating the STS CMCM ("risk of suicide within the next 7 days") scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 21B] These are a table (Figure 21A) and a graph (Figure 21B) illustrating the STS CMCM ("risk of suicide within the next 7 days") scores for Subject 1 and Subject 2 from day 1 to day 9, as described in Study Example 3. [Figure 22] This table illustrates the MOAA / S alertness / sedation scores for Subject 1 and Subject 2 from 24 hours prior to administration on days 1 and 4, as described in Study Example 3. [Figure 23] This table explains the CADSS dissociation status scores for Subject 1 and Subject 2 24 hours prior to administration on days 1 and 4, as described in Study Example 3. [Figure 24] This table shows the C-SSRS scores for S from day 1 to day 9 for Subject 1, and from day 1 to day 4 for Subject 2, as described in Study Example 3. [Modes for carrying out the invention]

[0013] definition To facilitate a more readily understandable understanding of this disclosure, certain terms are defined first. Where used in this application, unless otherwise expressly provided herein, the following terms shall have the meanings set forth below. Additional definitions are provided throughout the application.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. For the purposes of this disclosure, the following terms are defined:

[0015] Units, prefixes, and symbols are shown in the format recognized by the Systeme International de Unites (SI). Numerical ranges include the numerical values ​​that define the ranges. The headings provided herein do not limit the various aspects of this disclosure that can be had by referring to the entire specification. Thus, the terms defined immediately thereunder are more fully defined by referring to the entire specification.

[0016] As used herein, the terms “a,” “an,” and “the” include not only embodiments having one member but also embodiments having two or more members. As used herein, the singular forms “a,” “an,” and “the” include multiple referents unless otherwise explicitly indicated in the context. Thus, for example, a reference to “cells” includes multiple such cells, and a reference to “drugs” includes a reference to one or more drugs known to those skilled in the art, and so on.

[0017] Where used herein, the term “and / or” should be interpreted as each of two specific features or components, with or without the other. Thus, where used in phrases such as “A and / or B” herein, the term “and / or” is intended to include “A and B,” “A or B,” “A” (only), and “B” (only). Similarly, where used in phrases such as “A, B, and / or C,” the term “and / or” is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (only); B (only); and C (only).

[0018] As used herein, the terms “about” and “approximately” generally mean the degree of acceptable error of a measured quantity, taking into account the nature or precision of the measurement. A typical exemplary degree of error is within 10% or 5% of a given value or range of values. A reference to “about X” specifically indicates at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” is intended to provide supplementary written explanation to the limitation of the claims, for example, “0.98X.” The terms “about” and “approximately” encompass and describe the given quantity itself, particularly with respect to a given quantity.

[0019] When "approximately" is applied to the beginning of a numerical range, it applies to both ends of the range. Therefore, "approximately 5-20%" is equivalent to "approximately 5%-approximately 20%". When "approximately" is applied to the first value in a set of values, it applies to all values ​​in that set. Therefore, "approximately 5, 10, or 15 mg" is equivalent to "approximately 5, approximately 10, or approximately 15 mg".

[0020] "Rasemic ketamine" refers to a 1:1 mixture of the two enantiomers of ketamine: (R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone.

[0021] "Equivalent dose" refers to the equivalent dose of an activator based on its bioavailability. The equivalent dose based on bioavailability is determined, for example, by comparing the degree and rate of drug absorption of two or more doses of an activator (e.g., doses formulated as intranasal and intravenous formulations, respectively), using, for example, the area under the drug blood or plasma concentration-time curve (AUC) and / or maximum concentration (C). max This can be determined by determining the AUC and / or C of each dosage, where each dosage is within approximately 80% to approximately 125% of the other. max In cases where this is indicated, an equivalent dose based on bioavailability exists.

[0022] "Suicidal ideation" refers to a mental disorder in which the subject experiences one or more of the following: a desire to die, an unclear active suicidal thought, an unintentional suicidal ideation, an intended suicidal ideation, and an intentional active suicidal ideation with a specific plan or intent. The presence and frequency of these thoughts and / or experiences can be assessed using several psychiatric tests known in the art, such as the Columbia Suicide Severity Rating Scale. See, for example, Ghasemi, et al., Health Promot. Perspect., Vol. 5, No. 3, pp. 156-168 (2015), which is incorporated herein by reference in its entirety.

[0023] "Suicidal tendencies" refers to individuals experiencing suicidal thoughts that involve taking active steps toward suicide, such as suicide attempts. For example, see Klonsky, et al., Annu. Rev. Clin. Psycho. Vol. 12, pp. 307-330 (2016), which is incorporated herein by reference in its entirety.

[0024] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on the subject, or administration of an activator to the subject, with the aim of reversing, alleviating, improving, inhibiting, or slowing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical signs associated with the disease. In some embodiments, "treatment" includes the resolution of a particular disorder, including the reduction of one or more symptoms of the disorder and / or the reduction of the severity of one or more symptoms associated with the disorder.

[0025] "Administering" or "dosing" refers to the physical delivery of a therapeutic agent to a subject using any of the various methods and delivery systems known to those skilled in the art. Routes of administration may include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as injection or infusion (e.g., intravenous infusion). Administration may also be, for example, a single dose, multiple doses, and / or over a period of time longer than one.

[0026] The term "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, non-human primates, sheep, dogs, and vertebrates such as mice, rats, and guinea pigs. In some embodiments, the subject is human.

[0027] The “effective dose” or “therapeutic effective dose” of a therapeutic agent is the amount of any drug used alone or in combination with additional therapies that delays the onset of a mental disorder or promotes disease regression, as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-asymptomatic periods, or an improvement in functional impairment or disability due to the distress of the disease. The ability of one or more additional therapies to promote disease regression can be assessed using a variety of methods known to experienced practitioners, for example, by evaluating the activity of a drug in human subjects during clinical trials, in animal model systems to predict efficacy in humans, or in in vitro assays.

[0028] Where used herein, measures of therapeutic effect are “clinically meaningful” based on the practical importance of the therapeutic effect. For example, whether the therapeutic effect has a true, genuine, tangible, and / or significant effect on the subject (for example, a lack of clinically meaningful effect occurs if the difference in the subject, such as before and after administration of the treatment provided herein, is small enough to be considered similar). Those skilled in the art will recognize whether a particular effect is “clinically meaningful.” For example, a subject having a baseline score indicating severe depression and / or suicidal tendency (using one of the scales described herein) and a post-treatment score indicating remission of severe depression and / or suicidal tendency is a clinically meaningful effect.

[0029] When used herein, "AUC" 0-t " refers to the area under the plasma concentration-time curve from time = 0 to the time at which the last measurable concentration occurs. In some embodiments, the last measurable concentration occurs at t = 32 hours (e.g., AUC). 0-t =AUC 0~32 ).

[0030] An "unresponsive" subject is one who has been treated or is currently being treated with one or more therapies that do not produce a clinically meaningful change toward the desired outcome (for example, an unresponsive subject is resistant to a particular treatment). For instance, a subject may not show any measurable change in response to treatment. An unresponsive subject may, for example, show a positive change in a depression scale score, but that change is not clinically significant.

[0031] Where used herein, a reference score and any psychiatric evaluation or adverse event profile test score that is "substantially similar" or "substantially the same" correspond to the same score, and those skilled in the art will understand that, for example, due to experimental error, routine inter-subject evaluations, and routine statistical analysis, a particular test score may vary within a reasonable range (e.g., ±10%) while describing a specific value.

[0032] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals treated with it.

[0033] As used herein, the term “pharmaceutically acceptable carrier” refers to a substance that assists in the delivery of an activator to a cell, organism, or subject. “pharmaceutically acceptable carrier” means a carrier or excipient that can be included in the compositions of this disclosure and does not cause a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, ordinary saline, Ringer’s lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and colorants, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic agents, and absorption retardants. Carriers may also be substances for providing stability, sterility, and isotonicity to a formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), for preventing microbial action (e.g., antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid), or for providing edible flavorings to a formulation. In some cases, the carrier is a drug that facilitates the delivery of small molecule drugs or antibodies to target cells or tissues. Those skilled in the art will recognize that other pharmaceutical carriers are useful in this disclosure.

[0034] As used herein in the methods described herein, the term “reduce” means a reduction of a parameter compared to baseline measurements (or multiple measurements) of the same parameter in a subject taken prior to the initiation of administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the same parameter is measured in a healthy subject (e.g., a subject without the mental disorders described herein). In some embodiments, the same parameter is measured in comparison to another treatment (e.g., a standard treatment for the mental disorders described herein).

[0035] Similarly, as used herein, the term “increase” refers to an increase in a parameter compared to a baseline measurement (or multiple measurement) of the same parameter in a subject taken prior to the initiation of administration of racemiketamine or a pharmaceutically acceptable salt thereof, or an increase in a parameter compared to a baseline measurement (or multiple measurement) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (e.g., a subject without the mental disorders described herein). In some embodiments, the same parameter is measured in comparison to a different treatment (e.g., a standard treatment for the mental disorders described herein).

[0036] The terms “synergistic” or “synergistic” are used herein to mean that the effect of a combination of two therapeutic agents in combination therapy is greater than the sum of the effects of each agent when administered individually. “Synergistic dose” or “synergistic effective dose” is the amount of the combination of two combination partners that produce a synergistic effect, as “synergistic” is defined herein. By determining the synergistic interaction between two combination partners, the optimal range of effect and the absolute dose range of each component of the effect can be reliably measured by administering the combination partners at different w / w (weight / weight) ratio ranges and doses to the subject requiring treatment. However, observation of synergistic effects in in vitro or in vivo models can predict effects in humans and other species, and in vitro or in vivo models exist to measure synergistic effects, as described herein. Examples of synergistic effects include, but are not limited to, enhanced therapeutic effects, reduced doses at equivalent or increased levels of potency, reduced or delayed development of drug resistance, and simultaneous enhanced or equivalent therapeutic effects (e.g., the same therapeutic effect as at least one of the therapeutic agents) and reduced undesirable drug effects (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0037] For example, the synergistic ratio of two therapeutic agents can be identified, for instance, by determining the synergistic effect in a technically accepted in vivo model (e.g., an animal model) (e.g., a despair-system, reward-system, or anxiety-system mouse model) of depression.

[0038] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer values ​​within the listed ranges, and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0039] Unless otherwise specified, any reference to the amount of ketamine in this disclosure is based on the free equivalent of ketamine. For example, 30 mg of ketamine refers to 30 mg of ketamine in its free form or an equivalent amount of ketamine in its salt form (e.g., ketamine hydrochloride).

[0040] Various aspects of this disclosure are described in further detail herein.

[0041] Prologue Depression is characterized by a depressed mood and a markedly reduced interest in or enjoyment of activities. Other symptoms include significant weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired thinking or concentration or judgment, recurring thoughts about death, suicidal ideation or attempts. See Kennedy, Dialogues Clin. Neurosci., Vol.10, No.3, pp.271-277 (2008). Various physical symptoms may also be present. While the feelings of depression are common, a depressive disorder is diagnosed only when symptoms reach a threshold and persist for at least two weeks. The severity of depression varies from mild to very severe. In most cases it is temporary, but it can be recurrent or chronic. More than 50% of people who initially suffer a single major depressive episode eventually develop another episode. Unfortunately, current pharmacological interventions for depression take weeks to months to achieve complete therapeutic effect, and many patients are resistant to or become resistant to these treatments. See, for example, Kupfer, Dialogues Clin. Neurosci., Vol.7, No.3, pp.191-205 (2005).

[0042] Ketamine has been used as a short-acting intravenous anesthetic in both humans and animals. In addition to analgesia, ketamine creates a state of “dissociative anesthesia” and is also used as a pleasure drug to induce these effects. See, for example, Li and Vlisides, Front. Hum. Neurosci., Vol. 10, Article 612, pp. 1-15 (2016), and the Spravato® (S)-Ketamine Package Insert dated February 11, 2020; www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 211243s003lbl.pdf, which is incorporated herein by reference in its entirety.

[0043] At low doses, ketamine causes mild sedation and euphoria, while at high doses, individuals experience dissociative effects similar to those of phencyclizine hydrochloride (PCP). Other physical effects of ketamine include vertigo, difficulty maintaining balance, nausea, vomiting, sweating, tremors, dystonic movements, respiratory depression, and sleep apnea. See Zanos, et al., Pharmacol. Rev., Vol.70, No.3, pp.621-660 (2018). The most frequently observed adverse events after ketamine administration are mental manifestations such as floating sensations, vivid dreams, hallucinations, hypertonia, and delirium. These effects may last up to 24 hours after administration. See Perumal, et al., J.Res.Pharm.Pract., Vol.4, No.2, pp.89-93 (2015).

[0044] After administration, ketamine is demethylated to form norketamine, and both ketamine and norketamine are hydroxylated to form hydroxyphenylketamine, 6-hydroxyketamine, hydroxyphenylnorketamine, and 6-hydroxynorketamine (also known herein as hydroxynorketamine). The structures of these (racemic) compounds are shown below. [ka]

[0045] Each of these metabolites has a unique receptor binding profile and pharmacological activity. See, for example, Zanos, et al., Pharmacol. Rev., Vol.70, No.3, pp.621-660 (2018). For example, racemicketamine has a receptor binding profile of approximately 1.06 μM. i (S)-norketamine and (R)-norketamine bind to the NMDA receptor, and contain approximately 2.25 μM and 26.46 μM of K, respectively. i It contains (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine, with K content exceeding approximately 21.19 μM and 100 μM, respectively. iSee Moaddel, et al., Eur. J. Pharmacol., Vol. 698, pp. 228-234 (2013). Both ketamine and norketamine have anesthetic activity, and subjects administered ketamine or norketamine show increased motor activity during the recovery phase from anesthesia. In contrast, the same dose of 6-hydroxynorketamine does not provide anesthetic activity or spontaneous motor activity. See Leung and Baillie, J. Med. Chem., Vol. 29, pp. 2396-2399 (1986). However, like ketamine, 6-hydroxynorketamine exhibits antidepressant properties. See Pham, et al., Biol. Psychiatry, Vol. 84, No. 1, pp. e3-e6 (2018).

[0046] This application is partly based on the remarkable finding that intranasal administration of racemic ketamine offers advantageous properties compared to intravenous administration of racemic ketamine or intranasal administration of (R)- or (S)-ketamine (e.g., at least about 95% of (R)-ketamine or at least about 95% of (S)-ketamine). Furthermore, by leveraging the different physiological and psychological effects of each enantiomer of ketamine and their corresponding metabolites, it may be possible to provide beneficial treatments for various mental disorders, including treatments with reduced negative side effects.

[0047] formulation Some embodiments provide a pharmaceutical composition comprising about 5% (w / v) to about 20% (w / v) of racemiketamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is formulated for intranasal administration.

[0048] In some embodiments, the pharmaceutical composition contains an aqueous solution of racemiketamine or a pharmaceutically acceptable salt thereof in an amount of about 7.5% (w / v) to about 15% (w / v), for example, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, or any value in between. In some embodiments, the pharmaceutical composition contains an aqueous solution of about 7.5% (w / v) racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains an aqueous solution of about 15% (w / v) racemiketamine or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the formulation provides about 30 mg to about 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. For example, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or any value in between. In some embodiments, the formulation provides about 45 mg to about 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 60 mg to about 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 30 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 60 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides about 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose.

[0050] In some embodiments, the formulation provides a total amount of approximately 30 mg to approximately 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses (e.g., two spray releases from an intranasal delivery device). For example, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, or any value in between. In some embodiments, the formulation provides a total amount of approximately 45 mg to approximately 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses. In some embodiments, the formulation provides a total amount of approximately 60 mg to approximately 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof per single dose. In some embodiments, the formulation provides a total amount of approximately 30 mg, approximately 60 mg, approximately 75 mg, or approximately 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses. In some embodiments, the formulation provides approximately 60 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses. In some embodiments, the formulation provides approximately 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses. In some embodiments, the formulation provides approximately 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof over two doses.

[0051] In some embodiments, the composition further comprises a preservative. Exemplary preservatives include, but are not limited to, parabens (e.g., alkylparabens), benzyl alcohol, chlorobutanol, benzoic acid, sorbic acid, propylene glycol, and quaternary ammonium salts (e.g., benzalkonium chloride and benzethonium chloride). In some embodiments, the preservative is benzalkonium chloride. In some embodiments, racemiketamine is in the form of a pharmaceutically acceptable salt, such as a hydrochloride. In some embodiments, the composition further comprises about 0.01 mg / mL to about 0.04 mg / mL of benzalkonium chloride. In some embodiments, the composition further comprises about 0.02 mg / mL of benzalkonium chloride.

[0052] In some embodiments, the composition further comprises one or more excipients selected from the group consisting of surfactants, antioxidants, buffers, and absorption enhancers.

[0053] Exemplary surfactants include, but are not limited to, ionic, nonionic, and amphoteric surfactants. For example, Tween®, PEG, sorbitan esters, and ethoxylated fatty acids. In some embodiments, the composition further comprises a surfactant in an amount of about 1% to about 10% (w / v) of the surfactant.

[0054] Exemplary antioxidants include, but are not limited to, tocopherol, butylhydroxytoluene, sodium metabisulfite, potassium metabisulfite, and ascorbyl palmitate. In some embodiments, the composition further comprises an antioxidant in an amount of about 0.001% to about 5% (w / w).

[0055] Exemplary absorption enhancers include, but are not limited to, chitosan, caproate, and cyclopentadecalactone. In some embodiments, the composition further comprises an absorption enhancer in an amount of about 1% to about 10% (w / w).

[0056] Exemplary buffers include, but are not limited to, citrate, phosphate, acetate, lactate, fumarate, tartrate, malate, and amino acid-based buffers. In some embodiments, the composition further comprises a buffer in an amount of about 0.1% to about 5% (w / w).

[0057] In some embodiments, the pharmaceutically acceptable carrier is water or physiological saline.

[0058] In some embodiments, the formulation is as described in Table 1.

Table 1

[0059] The formulations listed in Table 1 offer doses of 15 mg per spray, 30 mg for two sprays, 60 mg for four sprays, and 90 mg for six sprays.

[0060] In some embodiments, the formulations are as shown in Table 2. [Table 2]

[0061] The formulations listed in Table 2 offer doses of 7.5 mg per spray, 30 mg for 4 sprays, 60 mg for 8 sprays, and 90 mg for 12 sprays.

[0062] Treatment method Some embodiments provide a method for treating a mental disorder (e.g., suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder) in a subject requiring treatment, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0063] Some embodiments provide a method for treating suicidal tendencies in subjects requiring treatment of suicidal tendencies, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0064] Some embodiments provide a method for treating suicidal ideation in subjects requiring treatment of suicidal ideation, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0065] Some embodiments provide a method for treating major depressive disorder in subjects requiring treatment for major depressive disorder, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject.

[0066] In some embodiments described herein, the mental disorder resolves more rapidly compared to the resolution observed after administration of an equivalent dose of intravenous racemiketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder of the subject resolve more rapidly. In some embodiments, the mental disorder resolves about 1.2 times faster to about 10 times faster, for example, 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, 10 times faster, or any value in between, compared to the resolution observed after administration of an equivalent dose of intravenous racemiketamine or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments described herein, the mental disorder resolves more rapidly compared to the resolution observed after administration of an equivalent dose of (S)-ketamine (e.g., intranasal (S)-ketamine) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject's suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder resolves more rapidly. In some embodiments, the mental disorder resolves about 1.2 times faster to about 10 times faster, for example, 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7 times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, 10 times faster, or any value in between, compared to the resolution observed after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments described herein, compliance with the treatment of a subject for a mental disorder is improved compared to an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. For example, compliance with the treatment of a subject for suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder is improved.

[0069] Numerous methods can be used to measure a subject's suicidal tendencies and / or suicidal ideation. Non-exclusive examples include the Mini International Psychiatric Interview Version 7.02 for Suicidality Disorders (MINI), Clinical Global Impression (CGI), Patient Global Impression (PGI), Columbia Suicide Severity Rating Scale (CSSRS), Montgomery-Asberg Depression Rating Scale (MADRS), and the Sheehan Suicide Tracking Scale Clinically Meaningful Change Measure (STS-CMCM). See, for example, Ghasemi et al., Health Promot. Perspect., Vol. 5, No. 3, pp. 156-168 (2015), which is incorporated herein by reference in its entirety.

[0070] DSM-5 MINI for Suicidal Disorder The MINI (Mini-International Neuropsychiatric Interview; for DSM-5 Disorders) is a semi-structured clinical interview that can be administered (e.g., at screening) to assess current suicidal ideation and behavior (SI / B) and to determine co-occurring neuropsychiatric disorders, and can confirm the primary diagnosis of MDD. The MINI can inform and complement a full psychiatric intake examination when administered by a qualified trained person. See, for example, Sheehan et al. J. Clin Psychiatry, 1998; 59(suppl 20):22-33, Sheehan and Giddens (2015). Suicidality: A Roadmap for Assessment and Treatment. (1st ed.). Tampa, FL: Harm Research Press. Nov. 2015 (available from HarmResearch.org) ISBN: 978-0-9969729-0-1, and Sheehan and Giddens. (2016). Suicidality Assessment and Documentation for Healthcare Providers: A Brief, Practical Guide. (1st ed.). Tampa, FL: Harm Research Press. April 2016. (available from HarmResearch.org) ISBN: 978-0-9969729-1-8).

[0071] The S-STS CMCM (version 01 / 01 / 19) is a clinician-assessed outcome scale that uses a standard 22-item assessment scale, as well as multiple patient- and clinician-assessed items to evaluate SI / B. The first 16 items are assessed on a Likert scale ranging from "not at all" (0) to "very serious" (4), where selected scores (i.e., four specific items are scored based on the two highest scores of those items) result in a total score ranging from 0 to 52. The last six items are used only if the patient missed an outpatient visit and is unable to complete the scale, with a maximum possible score of 100 if the missed visit was due to a suicide attempt or completion. CMCM also provides five different single-item global assessments: 1) the likelihood of the subject attempting suicide, 2) the treatment required for the subject, 3) the clinician's overall severity of suicidal impulses, thoughts, and behaviors, 4) the clinician's assessment of the current suicide risk and the level of control required for suicide, and 5) the clinician's assessment of the likelihood that the subject will attempt suicide or die by suicide in the next seven days.

[0072] In some embodiments, the target S-STS CMCM total score decreases by approximately 15 to 25 points 24 hours after intranasal administration of racemiketamine. In some embodiments, the S-STS CMCM total score decreases from approximately 15 to 20 points, from approximately 17 to 22 points, or from approximately 20 to 25 points.

[0073] The CGIS-SI / B scale is a five-item scale of clinician-assessed severity of suicidal tendency-specific symptoms. Clinicians assess the most severe level of suicidal tendency experienced by the subject during a specified recall period (e.g., at screening, baseline, or before intranasal administration of racemiketamine as described herein), and responses are reported on a 5-point Likert scale ranging from 1 (not suicidal at all) to 5 (most suicidal). The clinician can then assess how much the subject's suicidal tendency has changed compared to the baseline state on a 5-point Likert scale ranging from 1 (very improved) to 5 (very worsened). See, for example, Meltzer et al. Arch Gen Psychiatry. 2003;60(1):82-91.

[0074] In some embodiments, the CGIS-SI / B score of the subject is 4 or higher prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score of the subject is 4 or higher approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score in question is 4, 5, 6, or 7 approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, or 5 to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the target CGIS-SI / B score decreases by 1 to 4 (e.g., 1 to 4 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CGIS-SI / B score decreases by 1 to 3 (e.g., 1 to 3 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CGIS-SI / B score decreases by 1 to 2 (e.g., 1 to 2 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CGIS-SI / B score decreases by 3 or 4 points 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CGIS-SI / B score decreases by 3 points. In some embodiments, the target CGIS-SI / B score decreases by 4 points.

[0076] In some embodiments, the CGIS-SI / B score is 3 or higher (e.g., 3, 4, or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 4 or higher (e.g., 4 or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4, e.g., 1, 2, 3, or 4 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 2 to 5 (e.g., 2, 3, 4, or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4, e.g., 1, 2, 3, or 4 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 2, 3, 4, or 5 about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1, 2, 3, or 4 about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 2, 3, 4, or 5 about 1 to 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1, 2, 3, or 4 about 1 to 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the first CGIS-SI / B score is determined approximately 1 to 12 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the second CGIS-SI / B score is determined approximately 1 to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first CGIS-SI / B score from the subject is determined approximately 4 to 8 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the second CGIS-SI / B score from the subject is determined approximately 4 to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first and second CGIS-SI / B scores are determined at equivalent times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, e.g., 4 hours. In some embodiments, the first CGIS-SI / B score and the second CGIS-SI / B score are determined at different times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0078] The PGIS-SI / B is a 5-point subjective assessment scale for evaluating a subject's general perception of the severity of the disease, assessed on a single-item Likert scale ranging from 1 (not suicidal at all) to 5 (very suicidal). The PGIS-SI / B and PGIC-SI / B scales can be administered at various points in time (e.g., before intranasal administration of racemiketamine as described herein, or after one or more doses of racemiketamine). See, for example, Mohebbi et al. Eur Psychiatry. 2018;53:17-22.

[0079] In some embodiments, the PGIS-SI / B score of the subject is 3 or higher prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score of the subject is 3 or higher approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score in question is 3, 4, or 5 approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, or 5 to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the PGIS-SI / B score of the subject decreases by 1 to 4 (e.g., 1 to 4 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score of the subject decreases by 1 to 3 (e.g., 1 to 3 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score of the subject decreases by 1 to 2 (e.g., 1 to 2 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the PGIS-SI / B score is 3 or higher (e.g., 3, 4, or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 4 or higher (e.g., 4 or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4, e.g., 1, 2, 3, or 4 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 3 to 5 (e.g., 3, 4, or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4, e.g., 1, 2, 3, or 4 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 2, 3, 4, or 5 about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1, 2, 3, or 4 about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 2, 3, 4, or 5 about 1 to 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1, 2, 3, or 4 about 1 to 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target PGIS-SI / B score decreases by 3 or 4 points 24 hours after intranasal administration of racemiketamine. In some embodiments, the target PGIS-SI / B score decreases by 3 points. In some embodiments, the target PGIS-SI / B score decreases by 4 points.

[0082] In some embodiments, the first PGIS-SI / B score is determined approximately 1 to 12 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the second PGIS-SI / B score is determined approximately 1 to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first PGIS-SI / B score from the subject is determined approximately 4 to 8 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the second PGIS-SI / B score from the subject is determined approximately 4 to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first and second PGIS-SI / B scores are determined at equivalent times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, e.g., 4 hours. In some embodiments, the first PGIS-SI / B score and the second PGIS-SI / B score are determined at different times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the CSSRS is used to measure suicidal tendencies and / or suicidal ideation in subjects. The CSSRS can assess both suicidal behavior and suicidal ideation in subjects. For example, the CSSRS can assess the lethality of suicide attempts and other characteristics of suicidal ideation, such as frequency, duration, controllability, reasons for suicide, and deterrents, all of which can predict suicide completion to a considerable extent. See, for example, www.med.upenn.edu / cbti / assets / user-content / documents / Columbia-Suicide%20Severity%20Rating%20Scales%20(C-SSRS).pdf. In some embodiments, the CSSRS can be used to provide an overview of suicidal ideation and behavior in subjects.

[0084] The CSSRS provides several questions directed at suicidal ideation, to which the subject answers "yes" or "no." Such questions are directed at the desire to die, non-specific active suicidal thoughts, active suicidal ideation in any way (not a plan) without the intention to act, active suicidal ideation with some intention to act but without a specific plan, and active suicidal ideation with a specific plan or intention. In addition, the CSSRS includes indicators that are assessed by the subject to help assess the intensity of the ideation. Such signs include questions about frequency (e.g., less than once a week, once a week, 2-5 times a week, daily or almost daily, several times a day), duration (e.g., brief, less than an hour, 1-4 hours, 4-8 hours, 8 hours or more), controllability (e.g., easily able to control thoughts, able to control thoughts with little difficulty, able to control thoughts with some difficulty, very difficult to control thoughts, unable to control thoughts, and not attempting to control thoughts), deterrents (e.g., deterrents definitely stopped you from attempting suicide, deterrents probably stopped you, uncertain deterrents stopped you, deterrents probably didn't stop you, and deterrents definitely didn't stop you), as well as the reasons for the thought (e.g., entirely to attract attention, primarily to attract attention, equally to attract attention and to end / stop the pain, primarily to end / stop the pain, and entirely to end / stop the pain). The CSSRS may also include questions about suicidal behavior and actual suicide attempts, such as asking whether a suicide attempt took place, whether anything was done to harm the subject, and whether the subject did anything dangerous in a place where they could have died.

[0085] In some embodiments, the CSSRS score is 3 or higher prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the subject answers "yes" to 3, 4, 5, 6, or 7 questions prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to 4, 5, 6, or 7 questions relating to the CSSRS described herein, approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to one of the 3, 4, 5, 6, or 7 questions relating to the CSSRS described herein about 1 to 4 hours, about 1.5 to 5 hours, about 2 to 6 hours, or about 5 to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the CSSRS score decreases by 1 to 7 (e.g., 1 to 7 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, a subject answers "yes" to questions 1, 2, 3, 4, 5, 6, or 7 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score decreases by 1 to 5 (e.g., 1 to 5 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score decreases by 1 to 3 (e.g., 1 to 3 units) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the CSSRS score is 3 or higher (e.g., 3, 4, 5, 6, or 7) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 7 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, a subject answers "yes" to 3, 4, 5, 6, or 7 questions before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score is 6 or higher (e.g., 6 or 7) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 7, for example, 1, 2, 3, 4, 5, 6, or 7 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score is 3–5 (e.g., 3, 4, or 5) before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and decreases by 1–5 (e.g., 1, 2, 3, 4, or 5) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject answers "yes" to 3, 4, 5, 6, or 7 questions relating to the CSSRS described herein about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, a subject answers "yes" to 3, 4, 5, 6, or 7 questions related to CSSRS approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the subject answers "yes" to 3, 4, 5, 6, or 7 questions relating to the CSSRS described herein about 1 to 4 hours, about 1.5 to 5 hours, about 2 to 6 hours, or about 5 to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions about 1 to 4 hours, about 1.5 to 5 hours, about 2 to 6 hours, or about 5 to 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, a first CSSRS score is determined about 1 to 12 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and a second CSSRS score is determined about 1 to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a first CSSRS score from a subject is determined about 4 to 8 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a second CSSRS score from a subject is determined about 4 to 8 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first and second CSSRS scores are determined at equivalent times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours. In some embodiments, the first and second CSSRS scores are determined at different times before and after administration of racemiketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0089] Two versions of the CSSRS can be used: the baseline version can assess the subject's life expectancy and suicidal ideation and behavior over the past 12 months, while the “since last visit” version can assess any suicidal ideation or behavior the subject may have had since the CSSRS was administered. For example, if a suicide attempt occurred after the baseline version of the CSSRS was administered, the subject would only need to answer “yes” when asked about attempting suicide in the “since last visit” version. In some embodiments, the subject receives the baseline version of the CSSRS prior to intranasal administration of racemiketamine, as described herein. For example, the baseline version of the CSSRS can be administered from about one hour to about six months prior to intranasal administration of racemiketamine, as described herein. In some embodiments, a baseline version of CSSRS is performed about 1 to 6 hours, 1 hour to 1 day, 1 hour to 1 week, 1 hour to 1 month, 1 hour to 3 months, 3 months to 6 months, 1 month to 6 months, 1 week to 5 months, or 1 day to 6 months prior to intranasal administration of racemiketamine as described herein.

[0090] In some embodiments, the occurrence of suicidal ideation after baseline is defined as answering "yes" to at least one of the five suicidal ideation subcategories (i.e., a desire to die, nonspecific active suicidal thoughts, active suicidal ideation in any way without intent to act, active suicidal ideation with some intent to act but without a specific plan, and active suicidal ideation with a specific plan or intent) when administering the CSSRS after baseline. In some embodiments, the occurrence of suicidal behavior after baseline is defined as answering "yes" to at least one of the four suicidal behavior subcategories (i.e., an actual attempt, interruption of an attempt, prevention of an attempt, and preparatory behavior or act) when administering the CSSRS after baseline. In some embodiments, a trained evaluator completes the CSSRS based on the subject's responses.

[0091] In some embodiments, a version of CSSRS since the previous visit is performed on the subject after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, CSSRS is performed on the subject approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof to the subject. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, CSSRS is performed on a subject approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof to the subject.

[0092] In some embodiments, the CSSRS score is about 0 to about 2 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, a subject answers "yes" to 0, 1, or 2 questions regarding the CSSRS after intranasal administration of racemiketamine, as described herein. In some embodiments, the subject's CSSRS score is about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, about 5 minutes to 1 hour, about 5 minutes to 6 hours, about 5 minutes to 12 hours, about 5 minutes to 18 hours, about 18 hours to 24 hours, about 12 hours to 24 hours, or about 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, subjects answer "yes" to 0, 1, or 2 questions regarding the CSSRS approximately 1 to 4 hours, 2 to 12 hours, 1.5 to 5 hours, 2 to 6 hours, 4 to 8 hours, 5 to 10 hours, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS is a version of the CSSRS since the previous visit.

[0093] In some embodiments, the subject has a CSSRS intensity of about 0 to about 5 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the subject's CSSRS intensity may be 0, 1, 2, 3, 4, or 5 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSSRS intensity is about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, about 5 minutes to 1 hour, about 5 minutes to 6 hours, about 5 minutes to 12 hours, about 5 minutes to 18 hours, about 18 hours to 24 hours, about 12 hours to 24 hours, or about 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the subject's thoughts is approximately 1 to 4 hours, approximately 1.5 to approximately 5 hours, approximately 2 to approximately 6 hours, or approximately 5 to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, a post-previous-visit version of CSSRS is performed after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0094] In some embodiments, the CSSRS score is approximately 1 to approximately 7 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, a subject may answer "yes" to one, two, three, four, five, six, or seven fewer questions regarding the CSSRS after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to the number of questions to which the subject answered "yes" regarding the CSSRS before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject answers "yes" to one, two, three, four, five, six, or seven fewer questions regarding the CSSRS described herein approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the CSSRS is administered approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions regarding the CSSRS described herein at approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, or 5 to 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof). In some embodiments, a version of the CSSRS since the previous visit is performed after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, a baseline version of CSSRS is performed prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the subject has a lower intensity of CSSRS after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the intensity of the subject's ideology may be reduced by about 1 to about 25 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to the intensity of the subject's ideology before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the subject's ideology may be reduced by about 1 to about 5, about 1 to about 10, about 1 to about 15, about 1 to about 20, about 20 to about 25, about 15 to about 25, about 10 to about 25, or about 5 to about 25 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to the intensity of the subject's ideology before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the ideation of the target described herein decreases approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the ideation of the target decreases as described herein approximately 1 hour to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to, for example, before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof). In some embodiments, a post-previous-visit version of CSSRS is administered after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, a baseline version of CSSRS is administered before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, subjects who received intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof had CSSRS scores approximately 1 to 7 points lower than subjects who received intravenous administration of racemiketamine or a pharmaceutically acceptable salt thereof, or an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the CSSRS score in subjects administered intranasally with racemiketamine or a pharmaceutically acceptable salt thereof improves at a faster rate than in subjects administered intravenously with an equivalent dose of racemiketamine, a pharmaceutically acceptable salt thereof, or (S)-ketamine or a pharmaceutically acceptable salt thereof. For example, the CSSRS score improves at a faster rate than in subjects administered intravenously with an equivalent dose of racemiketamine, a pharmaceutically acceptable salt thereof, or (S)-ketamine or a pharmaceutically acceptable salt thereof, by 0.25 points / hour, 0.5 points / hour, 0.75 points / hour, 1 point / hour, 1.25 points / hour, 1.5 points / hour, 1.75 points / hour, 2 points / hour, 2.25 points / hour, 2.5 points / hour, 2.75 points / hour, 3 points / hour, 3.25 points / hour, 3.5 points / hour, 3.75 points / hour, 4 points / hour, or any value in between.

[0098] Montgomery-Asberg Depression Rating Scale The Depression Rating Scale (MADRS) is a diagnostic questionnaire that can be used to measure the severity of a depressive episode in question. In some embodiments, the MADRS can be used to measure suicidal ideation. For example, the MADRS includes the following 10 items: 1) Outwardly expressed sadness (e.g., expressing discouragement, depression, or despair beyond normal temporary dejection reflected in speech, facial expressions, or posture); 2) Verbalized sadness (e.g., expressing verbal reports of depressed mood, whether outwardly expressed or not, including feelings of dejection, lethargy, or hopelessness); 3) Internal tension (e.g., expressing mental tension leading to any of the following: vague discomfort, irritability, internal confusion, panic, fear, or distress); 4) Sleep deprivation (e.g., expressing an experience of reduced sleep duration or depth compared to the person's normal pattern when healthy); 5) Loss of appetite (e.g., 6) Difficulty concentrating (e.g., difficulty gathering one's thoughts, leading to a lack of concentration), 7) Inhibition (e.g., difficulty in starting routine activities, or being slow to start and perform them), 8) Inability to feel (e.g., decreased interest in one's surroundings, or subjective experience of activities that would normally be pleasurable, and a reduced ability to respond to situations and people with appropriate feelings), 9) Pessimistic thinking (e.g., feelings of guilt, inferiority, self-blame, sinfulness, regret, and doom and death), 10) Suicidal thoughts (e.g., feeling that life has no meaning, being willing to die naturally at any time, suicidal thoughts, and preparation for suicide). Each item is rated from 0 to 6, where 0 indicates that the subject is not at all like what the item describes, and 6 indicates that the subject is very similar to what the item describes. For example, in the case of outwardly expressed sadness, a score of 0 indicates that the subject shows no sadness at all, while a score of 6 indicates that the subject always appears depressed, for example, that the subject is very discouraged.As another example, in the case of suicidal thoughts, a score of 0 may indicate that the subject is enjoying life or accepting life as it is, a score of 2 may indicate that the subject is fed up with life and may have fleeting suicidal thoughts, a score of 4 may indicate that the subject feels that death would probably be better (e.g., suicidal thoughts are common and suicide is considered a possible solution, but there is no specific plan or intention), and a score of 6 may indicate that the subject has a clear plan to commit suicide when the opportunity arises (e.g., the subject is actively preparing to commit suicide). Thus, the total score after summing each score for each item will be on a scale of 0 to 60. In some embodiments, a total MADRS score of about 0 to about 6 for a subject reflects that the subject does not have symptoms associated with depression, a score of about 7 to about 9 reflects that the subject has mild depression, a score of about 20 to about 34 reflects that the subject has moderate depression, and a score of about 34 to about 60 reflects that the subject has severe depression.

[0099] In some embodiments, the total MADRS score of the subject is about 10 to about 60 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof as described herein. For example, prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof as described herein, the total MADRS score of the subject is about 10 to about 20, about 10 to about 30, about 10 to about 40, about 10 to about 50, about 50 to about 60, about 40 to about 60, about 30 to about 60, or about 20 to about 60. In some embodiments, the total MADRS score of the subject is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 prior to intranasal administration of racemiketamine as described herein. In some embodiments, the total MADRS score of the subject is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the total MADRS score of the subject is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0100] In some embodiments, the total MADRS score of the subject is about 0 to about 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof as described herein, the scores are about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 5 to about 6, about 4 to about 6, about 3 to about 6, about 2 to about 6, or about 1 to about 6. In some embodiments, the total MADRS score of the subject is 0, 1, 2, 3, 4, 5, or 6 after intranasal administration of racemiketamine as described herein. In some embodiments, the total MADRS score of the subject is measured about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the MADRS scores in question are approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the total MADRS score in question is approximately 1 hour to 4 hours prior, 1.5 hours to 5 hours prior, 2 hours to 6 hours prior, 5 hours to 10 hours prior, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0101] In some embodiments, the total MADRS score of the subject is about 10 to about 60 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the total MADRS score of the subject is about 0 to about 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof as described herein, the scores are about 10 to about 20, about 10 to about 30, about 10 to about 40, about 10 to about 50, about 50 to about 60, about 40 to about 60, about 30 to about 60, or about 20 to about 60, and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof as described herein, the scores are about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 5 to about 6, about 4 to about 6, about 3 to about 6, about 2 to about 6, or about 1 to about 6. In some embodiments, the total score of the target MADRS is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 before intranasal administration of racemiketamine as described herein, and the total score of the target MADRS is 0, 1, 2, 3, 4, 5, or 6 after intranasal administration of racemiketamine as described herein. In some embodiments, the total score of the target MADRS is measured about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the total score of the MADRS in question is as described herein, approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the total score of the subject MADRS is reduced by about 1 to about 60 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the total score of the subject MADRS may be reduced by about 1 to about 60 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the total score of the subject MADRS is reduced by about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 50 to about 60, about 40 to about 60, about 30 to about 60, about 20 to about 60, or about 10 to about 60 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the total score of the MADRS in question is reduced as described herein approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the total score of the MADRS in question is reduced as described herein approximately 1 hour to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to, for example, before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the total score of the subject MADRS decreases by approximately 20 to 30 points, for example, approximately 20 to 25 points, approximately 22 to 27 points, or approximately 25 to 30 points, 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, suicidal ideation can be measured using item 10 of the MADRS, for example, suicidal thoughts. In some embodiments, the score of item 10 of the MADRS for a subject is 0 or 1 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the score of item 10 of the MADRS for a subject is approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of item 10 of the MADRS for the subject is as described herein, about 1 to 4 hours, about 1.5 to 5 hours, about 2 to 6 hours, about 5 to 10 hours, or about 45 minutes to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the score of item 10 for the subject regarding MADRS is reduced by 1 to 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the score of item 10 for the subject regarding MADRS may be reduced by about 1 to about 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of item 10 for the subject regarding MADRS is reduced by 1 to 5, 1 to 4, 1 to 3, 1 to 2, 5 to 6, 4 to 6, 3 to 6, or 2 to 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of item 10 for the subject regarding MADRS is reduced as described herein about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of item 10 on the MADRS for the subject is reduced as described herein approximately 1 to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to, for example, before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof).

[0105] In some embodiments, the score of the target MADRS item 10 is reduced by 4, 5, or 6 points 24 hours after intranasal administration of racemiketamine. In some embodiments, the score of the target MADRS item 10 is reduced by 4 points. In some embodiments, the score of the target MADRS item 10 is reduced by 5 points. In some embodiments, the score of the target MADRS item 10 is reduced by 6 points.

[0106] In some embodiments, MADRS is performed on the subject prior to the intranasal administration of racemiketamine as described herein. For example, MADRS may be performed on the subject from about 1 hour to about 6 months before the intranasal administration of racemiketamine as described herein. In some embodiments, MADRS may be performed on the subject from about 1 hour to about 6 hours, about 1 hour to about 1 day, about 1 hour to about 1 week, about 1 hour to about 1 month, about 1 hour to about 3 months, about 3 months to about 6 months, about 1 month to about 6 months, about 1 week to about 5 months, or from about 1 day to about 6 months before the intranasal administration of racemiketamine as described herein.

[0107] The STS-CMCM is a diagnostic questionnaire that can be used to measure changes in a subject's suicidal ideation and behavior. The STS-CMCM can also provide a comprehensive description of suicidal ideation and behavior. See, for example, Sheehan et al., Innov. Clin. Neurosci. Vol.11, No.9-10, pp.93-140 (2014). The STS-CMCM consists of four parts. The first part may include a 16-item scale that assesses the severity of suicidal phenomena on a scale of 0 to 4, from “not at all” (0) to “very much” (4). The second part presents a set of additional items to the subject, including: 1) a set of risk or protective items that may be significant aggravating or mitigating factors in the subject's suicidal ideation and behavior; 2) a set of 11-point (0-10) discretized visual analog (DISCAN) scales; and 3) items related to the overall severity of assessments of suicidal impulses, thoughts, and behaviors, and opportunities for the subject to provide a self-assessment of their treatment needs. The DISCAN scale may include subject assessments of the subject's ability and willingness to cope with suicidal tendencies, their ability and willingness to "maintain safety," the degree to which their suicidal tendencies are intentional or impulsive, the extent to which they affect their quality of life, and the extent to which they impair their work, social, or family life. The third section includes the clinician's assessment of the subject's suicide risk and the level of control required for the subject's suicidal ideation and behavior. The third section may also include a general assessment of suicidal tendencies based on all information collected in the previous sections of the scale, additional input from others, and additional exploratory questions that the clinician deems necessary to complete the assessment. If the subject misses a follow-up appointment and is unavailable, the clinician may complete a fourth section, which will allow the subject to complete the scale.

[0108] In some embodiments, the STS-CMCM score in question is reduced by at least 2 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the STS-CMCM score in question may be reduced by at least 2, at least 3, at least 4, or at least 5 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the STS-CMCM score in question is reduced as described herein about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, about 5 minutes to 1 hour, about 5 minutes to 6 hours, about 5 minutes to 12 hours, about 5 minutes to 18 hours, about 18 hours to 24 hours, about 12 hours to 24 hours, or about 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score is reduced as described herein approximately 1 to 4 hours, approximately 1.5 to approximately 5 hours, approximately 2 to approximately 6 hours, or approximately 5 to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to, for example, before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the subject undergoes STS-CMCM prior to intranasal administration of racemiketamine as described herein. For example, STS-CMCM may be performed on the subject approximately 1 hour to approximately 6 months before intranasal administration of racemiketamine as described herein. In some embodiments, STS-CMCM is administered to subjects approximately 1 to 6 hours, 1 hour to 1 day, 1 hour to 1 week, 1 hour to 1 month, 1 hour to 3 months, 3 months to 6 months, 1 month to 6 months, 1 week to 5 months, or 1 day to 6 months prior to intranasal administration of racemiketamine as described herein.

[0109] In some embodiments described herein, when a subject is undergoing one or more additional treatments, the subject does not experience clinically significant weight gain compared to the administration of one or more additional treatments in the absence of intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. Clinically significant weight gain refers to a weight gain over the course of treatment of, for example, approximately 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or any value in between.

[0110] In some embodiments, the methods described herein provide one or more synergistic effects when racemiketamine, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents.

[0111] In some embodiments, the efficacy of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapies is greater than the sum of the efficacy of each individual drug when administered alone. For example, in some embodiments, the change in CSSRS score after administration of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, compared to before administration of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapies, is greater than the change in CSSRS score after administration of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapies, compared to before administration of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapies. In some embodiments, the efficacy of ketamine, or a pharmaceutically acceptable salt thereof, is increased. In some embodiments, the efficacy of one or more additional therapies is increased. In some embodiments, the efficacy of both intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapies is increased. In some embodiments, the efficacy of one or more additional therapies administered with intranasal racemiketamine or a pharmaceutically acceptable salt thereof is increased compared to the efficacy observed after administration with an equivalent dose of intravenous racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the efficacy of one or more additional therapies administered with intranasal racemiketamine or a pharmaceutically acceptable salt thereof is increased compared to the efficacy observed after administration with an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the dose of intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and / or one or more additional therapeutic agents required to provide a therapeutic effect is reduced compared to the dose of each individual agent when administered alone. In some embodiments, the dose of one or more additional therapeutic agents required to provide a therapeutic effect is reduced compared to the dose of administering an equivalent dose of intravenous racemiketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of one or more additional therapeutic agents required to provide a therapeutic effect is reduced compared to the dose of administering an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of ketamine, or a pharmaceutically acceptable salt thereof, is reduced. In some embodiments, the dose of one or more additional therapeutic agents is reduced. In some embodiments, the doses of both intranasal racemiketamine, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents are reduced. For example, the dose of intranasal racemiketamine or a pharmaceutically acceptable salt thereof may be reduced by about 5% to about 95%, or any value in between, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. Similarly, the dose of one or more additional treatments may be reduced by approximately 5% to approximately 95%, or any value in between, for example, approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, or approximately 95%.

[0113] In some embodiments, the onset of resistance to treatment with intranasal racemiketamine or a pharmaceutically acceptable salt thereof, and one or more additional treatments, is delayed compared to the onset of resistance to treatment with each individual drug when administered alone. In some embodiments, the onset of resistance to treatment with one or more additional treatments is delayed compared to the onset of resistance when treated with intravenous racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the onset of resistance to treatment with one or more additional treatments is delayed compared to the onset of resistance when treated with (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, one or more side effects of intranasal racemic ketamine, or a pharmaceutically acceptable salt thereof, and / or one or more additional treatments required to provide a therapeutic effect are reduced compared to the side effects of each individual drug when administered alone. In some embodiments, one or more side effects of ketamine, or a pharmaceutically acceptable salt thereof are reduced. In some embodiments, one or more side effects of one or more additional treatments are reduced. In some embodiments, one or more side effects of one or more additional treatments are reduced compared to one or more side effects observed after administration with an equivalent dose of intravenous racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more side effects of one or more additional treatments are reduced compared to one or more side effects observed after administration with an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more side effects of both ketamine, or a pharmaceutically acceptable salt thereof, and one or more additional treatments are reduced. In some embodiments, the total number of side effects is reduced. In some embodiments, the magnitude of one or more side effects is reduced. In some embodiments, the total number of side effects is reduced, and the magnitude of one or more remaining side effects is also reduced.

[0115] In some embodiments, one or more side effects of ketamine include cognitive impairment, motor impairment, vertigo, nausea, vomiting, sweating, increased blood pressure, ulcerative cystitis, or interstitial cystitis.

[0116] In some embodiments, cognitive impairment includes one or more of the following: psychotropic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, auditory alteration, visual alteration, and hallucinations. In some embodiments, cognitive impairment consists of one or more of the following: psychotropic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, auditory alteration, visual alteration, and hallucinations. In some embodiments, cognitive impairment includes sedation. In some embodiments, cognitive impairment is sedation. In some embodiments, motor impairment includes tremor, balance problems, or dystonic movements. In some embodiments, motor impairment consists of one or more of the following: tremor, balance problems, and dystonic movements.

[0117] Many methods can be used to assess ketamine-related side effects. Non-exclusive examples of such methods include the Modified Observer's Assessment of Alertness / Sedation Scale (MOAA / S), the Bowdle Visual Analog Scale (VAS), the Clinician Administered Dissociative States Scale (CADSS), the Profile of Mood States (POMS), the Choice Reaction Time Test, the Sternberg Short-Term Memory Task, and the Intranasal Stimulation Target Assessment (SRAII) (for intranasal administration of ketamine).

[0118] In some embodiments, the MOAA / S can be used to measure the sedation of a subject. See, for example, Kim et al., Br J Anaesth, Vol.115, No.4, pp.569-577 (2015), which is incorporated herein by reference in its entirety. The MOAA / S is a scale from 0 to 5, where 0 indicates that the patient does not respond after painful compression of the trapezius muscle, 1 indicates that the subject responds only after painful compression of the trapezius muscle, 2 indicates that the patient responds only after a mild nod or tremor, 3 indicates that the subject responds only after their name is called loudly and / or repeatedly, 4 indicates that the subject shows a listless response to a name spoken in a normal tone, and 5 indicates that the subject responds immediately to a name spoken in a normal tone.

[0119] In some embodiments, the target MOAA / S is 5 or 6 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target MOAA / S score is measured approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MOAA / S score is approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0120] In some embodiments, the target MOAA / S is 5 or 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target MOAA / S score is measured approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MOAA / S score is approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0121] In some embodiments, the target MOAA / S is 5 or 6 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the target MOAA / S is 5 or 6 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MOAA / S score is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MOAA / S score is 5 or 6 approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the target MOAA / S score is 5 or 6 approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the MOAA / S score of the subject is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the MOAA / S score of the subject does not change (i.e., neither increase nor decrease) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the MOAA / S score of the subject is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the MOAA / S score of the subject is reduced by about 1 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the MOAA / S score of the subject may be reduced by 1, 2, 3, 4, or 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the MOAA / S score of the subject is reduced as described herein about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MOAA / S score is approximately 1 to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (e.g., compared to administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof), as described herein.

[0124] In some embodiments, the Bowdle Visual Analog Scale (VAS) can be used to measure psychedelic effects in a subject. See, for example, Bowdle, et al. Anesthesiology, Vol. 88, No. 1, pp. 82-88 (1998), which is incorporated herein by reference in its entirety. The Bowdle VAS is a questionnaire in which a subject is asked to rate their current emotions. For example, the questionnaire may include the following items regarding the subject being evaluated: 1) seeing one's body or body parts change shape or position; 2) seeing one's surroundings change in size, depth, or shape; 3) seeing the passage of time altered; 4) having unrealistic feelings; 5) having difficulty controlling one's thoughts; 6) seeing changes in the intensity of colors; 7) seeing changes in the intensity of sounds; 8) hearing voices or sounds that are not real; 9) having delusions that events, objects, or other people have a special particular meaning to oneself; 10) having doubtful thoughts or beliefs that others are against oneself; 11) feeling anxious; 12) feeling euphoric; and 13) feeling sleepy. Each item is scored by the subject from 0 to 100, with a maximum total score of 1300, which indicates that the subject is experiencing significant side effects. A score of 0 indicates that the subject did not feel anything at all as described in the item (i.e., had little to no side effects), while a score of 100 reflects that the subject felt the item strongly. Therefore, lower individual and overall scores indicate less mental development.

[0125] In some embodiments, items 1, 2, 3, 5, 6, and 7 are combined to evaluate the derived variable "subjective external perception." In some embodiments, items 4, 8, 9, 10, and 11 are combined to evaluate the derived variable "subjective internal perception." In some embodiments, items 12 and 13 are evaluated as individual VAS items.

[0126] In some embodiments, the target Bowdle VAS is about 0 to about 50 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 25 to about 75 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 50 to about 100 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100. In some embodiments, the target Bowdle VAS is about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60, before intranasal administration of racemiketamine as described herein. In some embodiments, the relevant Bowdle VAS score is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the relevant Bowdle VAS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the target Bowdle VAS is about 0 to about 50 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 25 to about 75 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 50 to about 100 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target Bowdle VAS is about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100. In some embodiments, the target Bowdle VAS is about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60 after intranasal administration of racemiketamine as described herein. In some embodiments, the relevant Bowdle VAS score is measured approximately 5 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the relevant Bowdle VAS score is measured approximately 1 hour to 4 hours, approximately 1.5 hours to 5 hours, approximately 2 hours to 6 hours, approximately 5 hours to 10 hours, or approximately 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the target Bowdle VAS is about 0 to about 50 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein, and the target Bowdle VAS is about 0 to about 50 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target Bowdle VAS is about 25 to about 75 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein, and the target Bowdle VAS is about 25 to about 75 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target Bowdle VAS is about 50 to about 100 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein, and the target Bowdle VAS is about 50 to about 100 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target bowlle VAS is administered before intranasal administration of racemiketamine as described herein, in a range of approximately 0 to 10, 0 to 20, 0 to 30, 0 to 40, 0 to 50, 0 to 60, 0 to 70, 0 to 80, 0 to 90, 90 to 100, 80 to 100, 70 to 100, 60 to 100, 50 to 100, 40 to 100, 30 to 100, 20 to 100, or The values ​​are approximately 10 to 100, and after intranasal administration of racemiketamine as described herein, they are approximately 0 to 10, 0 to 20, 0 to 30, 0 to 40, 0 to 50, 0 to 60, 0 to 70, 0 to 80, 0 to 90, 90 to 100, 80 to 100, 70 to 100, 60 to 100, 50 to 100, 40 to 100, 30 to 100, 20 to 100, or 10 to 100. In some embodiments, the target Bowdle VAS is about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60 before intranasal administration of racemiketamine as described herein, and the target Bowdle VAS is about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60 after intranasal administration of racemiketamine as described herein.In some embodiments, the relevant Bowdle VAS is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the relevant Bowdle VAS is measured approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the relevant Bowdle VAS score is measured approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the relevant Bowdle VAS score is measured approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the target Bowdle VAS score is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the target Bowdle VAS score changes by about 0 to about 10 points (i.e., increases or decreases) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to the target Bowdle VAS score before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target Bowdle VAS score is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the target Bowdle VAS score is reduced by approximately 10 to approximately 1300 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the target Bowdle VAS score may be reduced by approximately 10 to approximately 1300 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, and / or intravenous administration of an equivalent dose of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target Bowdle VAS score is approximately 10-100, 10-200, 10-300, 10-400, 10-500, 10-600, 10-700, 10-800, 10-900, 10-1000, and 10-1000 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. The score is reduced by 100, approximately 10 to approximately 1200, approximately 1200 to approximately 1300, approximately 1100 to approximately 1300, approximately 1000 to approximately 1300, approximately 900 to approximately 1300, approximately 800 to approximately 1300, approximately 700 to approximately 1300, approximately 600 to approximately 1300, approximately 500 to approximately 1300, approximately 400 to approximately 1300, approximately 300 to approximately 1300, approximately 200 to approximately 1300, or approximately 100 to approximately 1300. In some embodiments, the target Bowdle VAS score is reduced as described herein approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the relevant Bowdle VAS score is approximately 1 to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (compared to, for example, administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof), as described herein.

[0131] In some embodiments, the dissociative state in a subject can be measured using the Dissociative State Scale (CADSS) administered by a clinician. See, for example, Luckenbaugh, et al. J. Affect. Disord., Vol. 159, pp. 56-61 (2014), which is incorporated herein by reference in its entirety. Statements on the CADSS assessment include, but are not limited to, things appearing in slow motion, things appearing unreal, feeling detached from what is happening, out-of-body experiences, feeling like a spectator or observer, feeling separated from the body, feeling like the body has changed, people appearing motionless / dead / mechanical, objects appearing different, colors appearing less intense, things appearing like they are through a tunnel / wide-angle lens, things appearing to take longer, things appearing to happen quickly, things appearing to happen inexplicably, not knowing what is happening, sounds appearing to change in intensity, experiencing a peculiar clarity, feeling like one is looking through a fog, and colors appearing brighter. Typically, the CADSS includes 23 statements that the subject rates on a scale of 0 to 4, with scores ranging from 0 (no dissociation) to 92 (extreme dissociation). A score of 0 indicates that the subject did not feel at all as described in the item, while a score of 4 indicates that the subject agreed to the question raised to the maximum extent. For example, 0 reflects no agreement at all, 1 reflects mild agreement, 2 reflects moderate agreement, 3 reflects strict agreement, and 4 reflects the highest level of agreement to the question raised. Therefore, lower individual and overall scores indicate less dissociation. In some embodiments, parts of the scale are completed by the subject. In some embodiments, parts of the scale are completed by a trained observer of the subject.

[0132] In some embodiments, the target CADSS is about 0 to about 10 prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, prior to intranasal administration of racemiketamine as described herein, the target CADSS is about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. In some embodiments, the target CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8 prior to intranasal administration of racemiketamine as described herein. In some embodiments, the CADSS score of the subject is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CADSS scale score of the subject is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the target CADSS is about 0 to about 10 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, after intranasal administration of racemiketamine as described herein, the target CADSS is about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. In some embodiments, the target CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8 after intranasal administration of racemiketamine as described herein. In some embodiments, the CADSS score of the subject is measured approximately 5 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CADSS scale score of the subject is measured approximately 1 hour to 4 hours, approximately 1.5 hours to 5 hours, approximately 2 hours to 6 hours, approximately 5 hours to 10 hours, or approximately 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the target CADSS is about 0 to about 10 before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the target CADSS is about 0 to about 10 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, before intranasal administration of racemiketamine as described herein, the target CADSS is about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about The target CADSS is 10, and after intranasal administration of racemiketamine as described herein, it is about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. In some embodiments, the target CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8 before intranasal administration of racemiketamine as described herein, and the target CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8 after intranasal administration of racemiketamine as described herein. In some embodiments, the CADSS score of the subject is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the CADSS score of the subject is measured approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the CADSS scale score of the subject is measured approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and the CADSS scale score of the subject is measured approximately 1 to 4 hours, 1.5 to 5 hours, 2 to 6 hours, 5 to 10 hours, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the CADSS score in question is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the CADSS score in question changes by about 0 to about 5 points (i.e., increases or decreases) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CADSS score in question is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the CADSS score of the subject is reduced by about 1 to about 92 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the CADSS score of the subject may be reduced by about 10 to about 92 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, compared to administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, and / or intravenous administration of an equivalent dose of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CADSS score is reduced by approximately 1 to approximately 90, approximately 1 to approximately 80, approximately 1 to approximately 70, approximately 1 to approximately 60, approximately 1 to approximately 50, approximately 1 to approximately 40, approximately 1 to approximately 30, approximately 1 to approximately 20, approximately 1 to approximately 10, approximately 80 to approximately 92, approximately 70 to approximately 92, approximately 60 to approximately 92, approximately 50 to approximately 92, approximately 40 to approximately 92, approximately 30 to approximately 92, approximately 20 to approximately 92, or approximately 10 to approximately 92 after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target CADSS score is reduced approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the CADDS score is measured approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CADDS score is measured approximately 1 to 4 hours, 1.5 to 5 hours, 2 hours to 6 hours, or 5 to 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (or administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of racemiketamine or a pharmaceutically acceptable salt thereof).

[0137] In some embodiments, a Mood State Profile (POMS) (e.g., POMS 2nd Edition) can be used to measure transient emotions and moods in a subject. See, for example, Lin, et al. JPA Vol.32, No.3, pp.273-277 (2014), which is incorporated herein by reference in its entirety. The Mood State Profile may include items for monitoring changes in the subject's mood.

[0138] In some embodiments, the profile score of the mood state in question is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the profile score of the mood state in question is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, a Choice Reaction Time (CRT) test can be used to measure a subject's psychomotor function. See, for example, Hindmarch, et al. Br. J. Clin. Pharmcol., Vol. 49, No. 2, pp. 118-125 (2000), which is incorporated herein by reference in its entirety. The Choice Reaction Time test is performed using a computer, and the subject is shown a screen corresponding to a numeric keypad. When a key lights up on the screen, the subject presses the corresponding button on another keypad. In certain tests, 4 to 8 numbered squares spatially corresponding to the keys on the keypad light up on the computer screen. The order of key illumination can be randomized. In some embodiments, the sequence of key illumination follows a pattern of alternation between a central button and any button that is part of a set of stimulus buttons. In some embodiments, the size of the stimulus set progresses from 4 to 6 to 8 during the test. The number of alternative choices can increase beyond the block of responses in each cycle. The CRT test can include the following three outcome variables: Recognition Reaction Time (RRT), which is the time it takes for the subject to notice the light (e.g., from the start of the stimulus until the subject removes their finger from the start button); Motor Reaction Time (MRT), which is the time from when the subject removes their finger from the start button until they touch the response button; and Total Reaction Time (TRT), which is the sum of RRT and MRT. The precision of the response can also be recorded.

[0140] In some embodiments, the CRT test score in question is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CRT test score in question is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the Sternberg Short-Term Memory (SSTM) task can be used to measure a subject's immediate memory. See, for example, Sternberg, Science, Vol. 153, Issue 3736, pp. 652-654 (1966), which is incorporated herein by reference in its entirety. The SSTM may involve asking a subject to remember a sequence of numbers that are quickly displayed on a computer screen. For example, the SSTM may involve a rapid display (e.g., 1.2 seconds / digit) of target lists of stimulus digits of 2, 4, and 6, with a sequence of 24 probe digits displayed 2 seconds after the display of the list for each digit. The subject identifies as quickly as possible whether each probe appeared on the target list by pressing a button in a response box corresponding to "yes" or "no". Probes that appeared on the target list may be called "positive," and probes that did not appear on the target list may be called "negative." The SSTM may include three tests with digit sequence sizes of 2, 4, and 6. Performance can be evaluated by measures of response latency and accuracy.

[0142] In some embodiments, the SSTM score in question is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SSTM score in question is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the subject rating of intranasal irritation (SRAII) may be used to determine intranasal irritation in subjects administered intranasal ketamine (e.g., racemic ketamine or (S)-ketamine) or a pharmaceutically acceptable salt thereof. For example, SRAII can be used to assess the subjective effects of intranasal administration of a drug such as ketamine or a pharmaceutically acceptable salt thereof, as described herein. SRAII includes five categories for which subjects are asked to provide a rating. For example, the categories include: 1) burning sensation, 2) need to blow / sneeze, 3) runny nose and / or nasal discharge, 4) facial pressure or pain, and 5) nasal congestion. In some embodiments, each item is scored on a 6-point scale. For example, 0 indicates no problems at all, 1 means experiencing very mild difficulty, 2 means experiencing some / slight difficulty, 3 means experiencing moderate difficulty, 4 means experiencing serious difficulty, and 5 means experiencing very serious difficulty, for example, the worst possible situation.

[0144] In some embodiments, the target SRAII is about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, after intranasal administration of racemic ketamine as described herein, the SRAII is about 0 to about 1, about 0 to about 2, about 0 to about 3, about 0 to about 4, about 4 to about 5, about 3 to about 5, or about 2 to about 5. In some embodiments, the target SRAII is about 1, about 2, about 3, about 4, or about 5 after administration of ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the target SRAII score is measured about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the SRAII score may be measured approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, or 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SRAII score of the subject may be measured approximately 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, 5 hours to 10 hours, or 45 minutes to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the subject's SRAII score is substantially the same before and after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, the subject's SRAII score changes by about 0 to about 5 (i.e., increases or decreases) after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SRAII score is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, 5 minutes to 6 hours, 5 minutes to 12 hours, 5 minutes to 18 hours, 18 hours to 24 hours, 12 hours to 24 hours, 6 hours to 24 hours, 1 hour to 4 hours, 1.5 hours to 5 hours, 2 hours to 6 hours, or 5 hours to 10 hours before intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the subject's SRAII score is reduced by about 5 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, compared to intranasal administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's SRAII score may be reduced by about 5 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, compared to the score observed after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SRAII score is reduced by about 5 to about 20, about 5 to about 15, about 5 to about 10, about 20 to about 25, about 15 to about 25, or about 10 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SRAII score in question is reduced as described herein, approximately 5 minutes to approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SRAII score in question is measured approximately 1 hour to 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof (or administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof).

[0147] In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, no clinically significant dissociation is observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments where the subject exhibits suicidal ideation, the subject has been previously diagnosed with one or more of the following: suicidal tendency, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some embodiments where the subject exhibits suicidal ideation, the subject is currently suffering from one or more of the following: suicidal tendency, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

[0150] In some embodiments where the subject exhibits suicidal tendencies, the subject has been previously diagnosed with one or more of the following: suicidal tendency, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some embodiments where the subject exhibits suicidal tendencies, the subject is currently suffering from one or more of the following: suicidal tendency, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

[0151] In some embodiments, treatment-resistant depression is stage I through stage IV. In some embodiments, treatment-resistant depression is stage V. In some embodiments, the subject exhibits one or more of the following features: unwanted disturbance memories, nightmares, flashbacks, psychological distress following exposure to trauma reminders, or physical reactions following exposure to trauma reminders, trauma-related thoughts or feelings, and trauma-related external reminders.

[0152] In some embodiments, the subject exhibits two or more of the following characteristics: inability to recall the main features of the traumatic event; excessively negative thoughts and assumptions about oneself or the world; exaggerated blame on oneself or others for causing the traumatic event; negative impact; decreased interest in activities; feelings of isolation; and difficulty experiencing positive impact. In some embodiments, the subject exhibits one or more of the following characteristics: irritability or aggression; dangerous or destructive behavior; hyperarousal; heightened startle response; decreased concentration; and difficulty sleeping. In some embodiments, the characteristics are present for more than about one month, cause distress and / or impairment in social or occupational settings, and are not due to substance or drug abuse. In some embodiments, the characteristics are present for at least about one month to about twelve months.

[0153] In some embodiments, about 30 mg to about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to a subject. For example, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or any value therebetween. In some embodiments, about 30 mg to about 60 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to a subject. In some embodiments, about 45 mg to about 75 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to a subject. In some embodiments, about 60 mg to about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to a subject. In some embodiments, about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to a subject. In some embodiments, the formulation provides about 30 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, per administration. In some embodiments, the formulation provides about 60 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, per administration. In some embodiments, the formulation provides about 75 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, per administration. In some embodiments, the formulation provides about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, per administration.

[0154] Some embodiments provide a method of treating suicidal tendency in a subject that requires treatment of suicidal tendency, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof, wherein the intranasal administration of racemic ketamine is at least 1.5-fold higher in the AUC of norketamine than that shown by intravenous administration of an equivalent dose of racemic ketamine 0-t and at least 1.5-fold higher in the AUC of norketamine than that shown by intravenous administration of an equivalent dose of racemic ketamine 0-t , <~ at least 1.5-fold higher in the AUC of norketamine than that shown by intravenous administration of an equivalent dose of racemic ketamine 0-inf and at least 1.5-fold higher in the AUC of norketamine than that shown by intravenous administration of an equivalent dose of racemic ketamine0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0155] Some embodiments provide a method for treating suicidal ideation in subjects requiring treatment for suicidal ideation, the method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject, the intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0156] Some embodiments provide a method for treating major depressive disorder in subjects requiring treatment for major depressive disorder, the method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, the intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. maxNorketamine C is at least twice as high max Show one or more of the following.

[0157] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t AUC is approximately 1.7 to 2.5 times higher than 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t AUC is approximately 1.9 to 2.3 times higher than 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t AUC approximately 2.0 times higher than 0-t This indicates.

[0158] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf Norketamine's AUC is approximately 1.5 to 2.5 times higher than that of [another substance]. 0-inf This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf AUC is approximately 1.8 to 2.2 times higher than 0-inf This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf Norketamine's AUC is approximately 2.0 times higher than that of [another substance]. 0-inf This indicates.

[0159] In some embodiments, intranasal administration of racemiketamine is equivalent to the C2 of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Norketamine has a C content that is approximately 2.2 to 3.5 times higher than [another substance]. maxThis shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the C of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Norketamine has a C content that is approximately 2.4 to 3.2 times higher than [another substance]. max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the C of norketamine, as shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine has a C content that is approximately 2.9 times higher than that of [another substance]. max This indicates.

[0160] In some embodiments, intranasal administration of racemiketamine is equivalent to the T2 dose of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Approximately 80% to 125% of norketamine T max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the T2 of norketamine, as shown by intravenous administration of an equivalent amount of racemiketamine. max Norketamine's T is approximately 90% to 110% of max This indicates.

[0161] In some embodiments, norketamine AUC 0-t AUC 0-inf , C max , and T max One or more of these are determined after a single dose of racemiketamine. In some embodiments, the AUC of norketamine 0-t AUC 0-inf , C max , and T max One or more of these are determined after two doses of racemic ketamine. In some embodiments, the AUC of norketamine 0-t AUC 0-inf , C max , and T max One or more of these will be determined after three doses of racemiketamine.

[0162] Some embodiments provide a method for treating suicidal tendencies in subjects requiring treatment for suicidal tendencies, the method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject, the intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0163] Some embodiments provide a method for treating suicidal ideation in subjects requiring treatment for suicidal ideation, the method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject, the intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0164] Some embodiments provide a method for treating major depressive disorder in subjects requiring treatment for major depressive disorder, the method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, the intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0165] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is approximately 1.7 to 2.5 times higher than that of [another substance]. 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is approximately 1.9 to 2.3 times higher than that of [another substance]. 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is approximately 2.1 times higher than that of [another substance]. 0-t This indicates.

[0166] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-infAn AUC of hydroxynorketamine that is about 1.5 to about 2.5 times higher than 0-inf is shown. In some embodiments, intranasal administration of racemic ketamine results in an AUC of hydroxynorketamine that is 0-inf about 1.7 to about 2.1 times higher than the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. 0-t is shown. In some embodiments, intranasal administration of racemic ketamine results in an AUC of hydroxynorketamine that is 0-inf about 1.9 times higher than the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. 0-t is shown.

[0167] In some embodiments, intranasal administration of racemic ketamine results in a C of hydroxynorketamine that is about 2.2 to about 3.2 times higher than the C of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. In some embodiments, intranasal administration of racemic ketamine results in a C of hydroxynorketamine that is about 2.4 to about 2.8 times higher than the C of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. In some embodiments, intranasal administration of racemic ketamine results in a C of hydroxynorketamine that is about 2.6 times higher than the C of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. max is shown. In some embodiments, intranasal administration of racemic ketamine results in a C of hydroxynorketamine that is about 2.6 times higher than the C of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. max is shown.

[0168] In some embodiments, intranasal administration of racemic ketamine results in a T of hydroxynorketamine that is about 80% to about 125% of the T of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. In some embodiments, intranasal administration of racemic ketamine results in a T of hydroxynorketamine that is about 90% to about 110% of the T of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemic ketamine. max is shown. max is shown. max is shown.

[0169] In some embodiments, the relative ratios and percentages described herein are measured about 15 minutes to about 8 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the ratios described herein are measured at about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or any value in between. In some embodiments, the relative ratios and percentages described herein are measured over a period of about 24 hours to about 1 month. In some embodiments, the relative ratios and percentages described herein are measured over a period of about 24 hours to about 2 weeks. For example, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 2 weeks, or any value in between. In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice daily, once daily, once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once a week, or a combination thereof, for the measurement period (e.g., about 24 hours to about 1 month).

[0170] In some embodiments, the T of ketamine max The time interval is approximately 20 to 120 minutes after intranasal administration of racemic ketamine, for example, approximately 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, or any value in between. In some embodiments, the T of ketamine max The time interval is approximately 20 to 90 minutes after intranasal administration of racemic ketamine, for example, approximately 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, or any value in between. In some embodiments, the T of ketamine max This occurs approximately 30 to 90 minutes after intranasal administration of racemiketamine.

[0171] In some embodiments, norketamine T max The time interval after intranasal administration of racemiketamine is approximately 45 to 360 minutes, for example, approximately 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 135 minutes, 150 minutes, 165 minutes, 180 minutes, 195 minutes, 210 minutes, 225 minutes, 240 minutes, 255 minutes, 270 minutes, 285 minutes, 300 minutes, 315 minutes, 315 minutes, 330 minutes, 345 minutes, 360 minutes, or any value in between. In some embodiments, the T of norketamine max This occurs approximately 100 to 250 minutes after intranasal administration of racemiketamine.

[0172] In some embodiments, 6-hydroxynorketamine T max The time interval is approximately 45 minutes to 8 hours after intranasal administration of racemiketamine, for example, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, or any value in between. In some embodiments, the time interval of 6-hydroxynorketamine is approximately 45 minutes to 8 hours after intranasal administration of racemiketamine. max The time interval is approximately 2 to 4 hours after intranasal administration of racemiketamine, for example, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, approximately 3.5 hours, approximately 4 hours, or any value in between. In some embodiments, the time interval is approximately 2 to 4 hours after intranasal administration of racemiketamine. max This occurs approximately 3 to 4 hours after intranasal administration of racemiketamine.

[0173] In some embodiments, C of ketamine max The C15% of ketamine after intranasal administration of racemic ketamine is approximately 15 ng / mL to approximately 225 ng / mL, or any value in between. In some embodiments, the C15% of ketamine after intranasal administration of racemic ketamine is maxThe C12 ng / mL range is approximately 25 ng / mL to approximately 225 ng / mL, for example, approximately 25 ng / mL, approximately 35 ng / mL, approximately 45 ng / mL, approximately 55 ng / mL, approximately 65 ng / mL, approximately 75 ng / mL, approximately 85 ng / mL, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, approximately 155 ng / mL, approximately 165 ng / mL, approximately 175 ng / mL, approximately 185 ng / mL, approximately 195 ng / mL, approximately 205 ng / mL, approximately 215 ng / mL, approximately 225 ng / mL, or any value in between. In some embodiments, the C12 ng / mL of ketamine after intranasal administration of racemic ketamine is max The C12 ng / mL range is approximately 70 ng / mL to approximately 205 ng / mL, for example, approximately 85 ng / mL, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, approximately 155 ng / mL, approximately 165 ng / mL, approximately 175 ng / mL, approximately 185 ng / mL, approximately 195 ng / mL, approximately 205 ng / mL, or any value in between. In some embodiments, the C12 ng / mL of ketamine after intranasal administration of racemic ketamine is max The C120 ng / mL range is approximately 75 ng / mL to approximately 175 ng / mL, for example, approximately 75 ng / mL, approximately 100 ng / mL, approximately 125 ng / mL, approximately 150 ng / mL, approximately 175 ng / mL, or any value in between. In some embodiments, the C120 ng / mL of ketamine after intranasal administration of racemic ketamine is max This ranges from approximately 95 ng / mL to approximately 145 ng / mL, for example, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, or any value in between.

[0174] In some embodiments, norketamine C max The C100% of norketamine after intranasal administration of racemiketamine is approximately 40 ng / mL to approximately 375 ng / mL, or any value in between. In some embodiments, the C100% of norketamine after intranasal administration of racemiketamine is maxThe C12C of norketamine after intranasal administration of racemic ketamine is approximately 50 ng / mL to approximately 275 ng / mL, for example, approximately 50 ng / mL, approximately 75 ng / mL, approximately 100 ng / mL, approximately 125 ng / mL, approximately 150 ng / mL, approximately 175 ng / mL, approximately 200 ng / mL, approximately 225 ng / mL, approximately 250 ng / mL, approximately 275 ng / mL, or any value in between. In some embodiments, the C12C of norketamine after intranasal administration of racemic ketamine is max The C120 ng / mL range is approximately 90 ng / mL to approximately 180 ng / mL, for example, 90 ng / mL, approximately 100 ng / mL, approximately 110 ng / mL, approximately 120 ng / mL, approximately 130 ng / mL, approximately 140 ng / mL, approximately 150 ng / mL, approximately 160 ng / mL, approximately 170 ng / mL, approximately 180 ng / mL, or any value in between. In some embodiments, the C120 ng / mL of norketamine after intranasal administration of racemic ketamine is measured. max The C2 level of norketamine after intranasal administration of racemic ketamine is approximately 70 ng / mL to approximately 85 ng / mL. In some embodiments, the C2 level of norketamine after intranasal administration of racemic ketamine is max The concentration is approximately 90 ng / mL to approximately 130 ng / mL. In some embodiments, the C of norketamine after intranasal administration of racemiketamine is max The concentration is approximately 120 ng / mL to approximately 150 ng / mL. In some embodiments, the C of norketamine after intranasal administration of racemic ketamine is max The C2 level of norketamine after intranasal administration of racemic ketamine is approximately 160 ng / mL to approximately 195 ng / mL. In some embodiments, the C2 level of norketamine after intranasal administration of racemic ketamine is approximately 160 ng / mL to 195 ng / mL. max The concentration is approximately 140 ng / mL to approximately 180 ng / mL. In some embodiments, the C of norketamine after intranasal administration of racemic ketamine is max The concentration is approximately 215 ng / mL to 225 ng / mL.

[0175] In some embodiments, C6-hydroxynorketamine is administered intranasally after racemiketamine administration. max The C6-hydroxynorketamine concentration is approximately 15 ng / mL to approximately 275 ng / mL, or any value in between. In some embodiments, the C6-hydroxynorketamine concentration after intranasal administration of racemicketamine is measured. maxThe C6-hydroxynorketamine is approximately 40 ng / mL to approximately 275 ng / mL, or any value in between. In some embodiments, the C6-hydroxynorketamine is used. max The C60 ng / mL range after intranasal administration of racemicketamine is approximately 55 ng / mL to approximately 245 ng / mL, for example, approximately 55 ng / mL, approximately 65 ng / mL, approximately 75 ng / mL, approximately 85 ng / mL, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, approximately 155 ng / mL, approximately 165 ng / mL, approximately 175 ng / mL, approximately 185 ng / mL, approximately 195 ng / mL, approximately 205 ng / mL, approximately 215 ng / mL, approximately 225 ng / mL, approximately 235 ng / mL, approximately 245 ng / mL, or any value in between. In some embodiments, C60 ng / mL of 6-hydroxynorketamine is used. max The C60 concentration after intranasal administration of racemiketamine is approximately 55 ng / mL to approximately 100 ng / mL. In some embodiments, the C60 concentration of 6-hydroxynorketamine is used. max The C60 max The C60 concentration after intranasal administration of racemiketamine is approximately 130 ng / mL to approximately 155 ng / mL. In some embodiments, the C60 concentration of 6-hydroxynorketamine is used. max The C600 ng / mL is approximately 150 ng / mL to approximately 185 ng / mL after intranasal administration of racemiketamine. In some embodiments, the C600 ng / mL of 6-hydroxynorketamine is used. max The C6 concentration after intranasal administration of racemiketamine is approximately 175 ng / mL to approximately 215 ng / mL. In some embodiments, the C6 concentration of 6-hydroxynorketamine is used. max The blood glucose level after intranasal administration of racemiketamine is approximately 210 ng / mL to 245 ng / mL.

[0176] In some embodiments, the t1 / 2 of ketamine is approximately 2 to 9 hours after intranasal administration of racemic ketamine, for example, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, approximately 3.5 hours, approximately 4 hours, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, or any value in between. In some embodiments, the t1 / 2 of ketamine is approximately 4 to 7 hours after intranasal administration of racemic ketamine, for example, approximately 4 hours, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, or any value in between.

[0177] In some embodiments, the t1 / 2 of norketamine is approximately 4.5 hours to approximately 12.5 hours after intranasal administration of racemiketamine, for example, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 9.5 hours, approximately 10 hours, approximately 10.5 hours, approximately 11 hours, approximately 11.5 hours, approximately 12 hours, approximately 12.5 hours, or any value in between. In some embodiments, the t1 / 2 of norketamine is approximately 5 hours to approximately 10 hours after intranasal administration of racemiketamine, for example, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 0.5 hours, approximately 10 hours, or any value in between. In some embodiments, norketamine t1 / 2 is approximately 7 to 8 hours after intranasal administration of racemiketamine.

[0178] In some embodiments, the t1 / 2 of 6-hydroxynorketamine is approximately 5.5 hours to approximately 22.5 hours after intranasal administration of racemiketamine, for example, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 9.5 hours, approximately 10 hours, approximately 10.5 hours, approximately 11 hours, approximately 11.5 hours, approximately 12 hours, approximately 12.5 hours, approximately 13 hours, approximately 13.5 hours, approximately 14 hours, approximately 14.5 hours, approximately 15 hours, approximately 15.5 hours, approximately 16 hours, approximately 16.5 hours, approximately 17 hours, approximately 18.5 hours, approximately 19 hours, approximately 19.5 hours, approximately 20 hours, approximately 20.5 hours, approximately 21 hours, approximately 21.5 hours, approximately 22 hours, approximately 22.5 hours, or any value in between. In some embodiments, the t1 / 2 of 6-hydroxynorketamine is about 8 hours and about 15 hours after intranasal administration of racemiketamine, for example, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 13.5 hours, about 14 hours, about 14.5 hours, about 15 hours, or any value in between. In some embodiments, the t1 / 2 of 6-hydroxynorketamine is about 10 hours and about 12 hours after intranasal administration of racemiketamine.

[0179] In some embodiments, the apparent clearance of ketamine after intranasal administration of racemic ketamine is approximately 150 L / hour to approximately 350 L / hour, for example, approximately 150 L / hour, approximately 175 L / hour, approximately 200 L / hour, approximately 225 L / hour, approximately 250 L / hour, approximately 275 L / hour, approximately 300 L / hour, approximately 325 L / hour, approximately 350 L / hour, or any value in between. In some embodiments, the apparent clearance of ketamine after intranasal administration of racemic ketamine is approximately 195 L / hour to approximately 245 L / hour, for example, approximately 195 L / hour, approximately 200 L / hour, approximately 225 L / hour, approximately 230 L / hour, approximately 235 L / hour, approximately 240 L / hour, approximately 245 L / hour, or any value in between.

[0180] In some embodiments, the apparent V of ketamine d / F is approximately 2.5 L / kg to approximately 6 L / kg, or any value in between, after intranasal administration of racemic ketamine. In some embodiments, the apparent V of ketamine d / F is approximately 1,000L to approximately 2,500L after intranasal administration of racemic ketamine, for example, approximately 1,000L, approximately 1,250L, approximately 1,500L, approximately 1,750L, approximately 2,000L, approximately 2,250L, approximately 2,500L, or any value in between. In some embodiments, the apparent V of ketamine d / F is approximately 1,250L to 1,750L after intranasal administration of racemiketamine, for example, approximately 1,250L, 1,300L, 1,350L, 1,400L, 1,450L, 1,500L, 1,550L, 1,600L, 1,650L, 1,700L, 1,750L, or any value in between.

[0181] In some embodiments, the extinction rate constant (K) for ketamine is used. el (1 / h or h -1 )) approximately 0.1h after intranasal administration of racemiketamine-1 ~Approximately 0.25 hours -1 For example, approximately 0.1 hours. -1 , about 0.15h -1 , about 0.2h -1 Approximately 0.25 hours -1 or any value in between.

[0182] In some embodiments, the elimination rate constant (K) for norketamine is used. el (1 / h or h -1 )) approximately 0.05h after intranasal administration of racemiketamine -1 ~about 0.15h -1 For example, approximately 0.05h -1 Approximately 0.1 hours -1 , about 0.15h -1 or any value in between. In some embodiments, the elimination rate constant (K) for norketamine is used. el (1 / h or h -1 )) approximately 0.09h after intranasal administration of racemiketamine -1 ~Approximately 0.1 hours -1 That is the case.

[0183] In some embodiments, the elimination rate constant (K) for 6-hydroxynorketamine is used. el (1 / h or h -1 )) approximately 0.05h after intranasal administration of racemiketamine -1 ~about 0.15h -1 For example, approximately 0.05h -1 Approximately 0.1 hours -1 , about 0.15h -1 or any value in between. In some embodiments, the elimination rate constant (K) for 6-hydroxynorketamine is used. el (1 / h or h -1 )) approximately 0.09h after intranasal administration of racemiketamine -1 ~Approximately 0.1 hours -1 That is the case.

[0184] In some embodiments, the AUC for ketamine 0-tThe blood glucose levels after intranasal administration of racemiketamine range from approximately 70 ng*h / mL to approximately 675 ng*h / mL, for example, approximately 70 ng*h / mL, approximately 100 ng*h / mL, approximately 125 ng*h / mL, approximately 150 ng*h / mL, approximately 175 ng*h / mL, approximately 200 ng*h / mL, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, and approximately 3 50 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, or any value in between. In some embodiments, the AUC for ketamine is used. 0-t The AUC for ketamine is approximately 70 ng*h / mL to approximately 250 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-t The AUC for ketamine is approximately 200 ng*h / mL to approximately 450 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-t The AUC for ketamine is approximately 400 ng*h / mL to approximately 675 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 600 ng*h / mL to approximately 675 ng*h / mL.

[0185] In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-tThe AUC after intranasal administration of racemic ketamine is approximately 70 ng*h / mL to approximately 350 ng*h / mL, for example, approximately 70 ng*h / mL, approximately 100 ng*h / mL, approximately 125 ng*h / mL, approximately 150 ng*h / mL, approximately 175 ng*h / mL, approximately 200 ng*h / mL, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, approximately 350 ng*h / mL, or any value in between. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-t The AUC is approximately 70 ng*h / mL to approximately 150 ng*h / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is measured. 0-t The AUC is approximately 100 ng*h / mL to approximately 250 ng*h / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is measured. 0-t The concentration is approximately 200 ng*h / mL to 350 ng*h / mL.

[0186] In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-t The AUC after intranasal administration of racemic ketamine is approximately 225 ng*h / mL to approximately 525 ng*h / mL, for example, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, approximately 350 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, or any value in between. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is approximately 225 ng*h / mL to approximately 525 ng*h / mL. 0-t The AUC is approximately 225 ng*h / mL to approximately 325 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-tThe AUC is approximately 300 ng*h / mL to approximately 425 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is measured. 0-t The concentration ranges from approximately 400 ng*h / mL to approximately 525 ng*h / mL.

[0187] In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-t The blood glucose level after intranasal administration of racemicketamine is approximately 220 ng*h / mL to approximately 675 ng*h / mL, for example, approximately 220 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, approximately 350 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, or any value in between. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is 0-t The AUC is approximately 220 ng*h / mL to approximately 375 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is measured. 0-t The AUC is approximately 350 ng*h / mL to approximately 525 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC for ketamine is measured. 0-t The concentration ranges from approximately 500 ng*h / mL to approximately 675 ng*h / mL.

[0188] In some embodiments, the AUC for norketamine 0-tThe blood glucose level after intranasal administration of racemiketamine ranges from approximately 250 ng*h / mL to approximately 2,200 ng*h / mL, for example, approximately 250 ng*h / mL, approximately 350 ng*h / mL, approximately 450 ng*h / mL, approximately 550 ng*h / mL, approximately 650 ng*h / mL, approximately 750 ng*h / mL, approximately 850 ng*h / mL, approximately 950 ng*h / mL, approximately 1,050 ng*h / mL, and approximately 1,1 The values ​​are 50 ng*h / mL, approximately 1,250 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,450 ng*h / mL, approximately 1,550 ng*h / mL, approximately 1,650 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,850 ng*h / mL, approximately 1,950 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, or any value in between. In some embodiments, the AUC for norketamine is used. 0-t The AUC is approximately 250 ng*h / mL to approximately 950 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for norketamine is shown. 0-t The AUC is approximately 900 ng*h / mL to approximately 1,550 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for norketamine is shown. 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 1,500 ng*h / mL to approximately 2,200 ng*h / mL.

[0189] In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC after intranasal administration of racemiketamine is approximately 250 ng*h / mL to approximately 725 ng*h / mL, for example, approximately 250 ng*h / mL, approximately 300 ng*h / mL, approximately 350 ng*h / mL, approximately 400 ng*h / mL, approximately 450 ng*h / mL, approximately 500 ng*h / mL, approximately 550 ng*h / mL, approximately 600 ng*h / mL, approximately 650 ng*h / mL, approximately 700 ng*h / mL, approximately 725 ng*h / mL, or any value in between. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for norketamine is 0-tThe AUC is approximately 250 ng*h / mL to approximately 400 ng*h / mL. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC is approximately 375 ng*h / mL to approximately 550 ng*h / mL. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The concentration ranges from approximately 500 ng*h / mL to approximately 725 ng*h / mL.

[0190] In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC after intranasal administration of racemiketamine is approximately 675 ng*h / mL to approximately 1,800 ng*h / mL, for example, approximately 675 ng*h / mL, approximately 800 ng*h / mL, approximately 900 ng*h / mL, approximately 1,000 ng*h / mL, approximately 1,100 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,300 ng*h / mL, approximately 1,400 ng*h / mL, approximately 1,500 ng*h / mL, approximately 1,600 ng*h / mL, approximately 1,700 ng*h / mL, approximately 1,800 ng*h / mL, or any value in between. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for norketamine is 0-t The AUC is approximately 675 ng*h / mL to approximately 1,050 ng*h / mL. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC is approximately 1,000 ng*h / mL to approximately 1,450 ng*h / mL. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The concentration is approximately 1,400 ng*h / mL to 1,800 ng*h / mL.

[0191] In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for norketamine is 0-tThe AUC after intranasal administration of racemiketamine is approximately 850 ng*h / mL to approximately 2,200 ng*h / mL, for example, approximately 850 ng*h / mL, approximately 950 ng*h / mL, approximately 1,050 ng*h / mL, approximately 1,150 ng*h / mL, approximately 1,250 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,450 ng*h / mL, approximately 1,550 ng*h / mL, approximately 1,650 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,850 ng*h / mL, approximately 1,950 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, or any value in between. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC is approximately 850 ng*h / mL to approximately 1,350 ng*h / mL. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The AUC is approximately 1,300 ng*h / mL to approximately 1,850 ng*h / mL. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for norketamine is measured. 0-t The levels range from approximately 1,800 ng*h / mL to approximately 2,200 ng*h / mL.

[0192] In some embodiments, the AUC for 6-hydroxynorketamine 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 300 ng*h / mL to approximately 3,100 ng*h / mL, for example, approximately 300 ng*h / mL, approximately 450 ng*h / mL, approximately 600 ng*h / mL, approximately 750 ng*h / mL, approximately 900 ng*h / mL, approximately 1,050 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,350 ng*h / mL, and approximately The values ​​are 1,500 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value in between. In some embodiments, the AUC for 6-hydroxynorketamine is used. 0-tThe AUC is approximately 300 ng*h / mL to approximately 700 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 700 ng*h / mL to approximately 900 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 850 ng*h / mL to approximately 950 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 900 ng*h / mL to approximately 1,100 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 1,100 ng*h / mL to approximately 1,300 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 1,300 ng*h / mL to approximately 1,700 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The AUC is approximately 1,700 ng*h / mL to approximately 2,400 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 2,400 ng*h / mL to approximately 3,100 ng*h / mL.

[0193] In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The AUC after intranasal administration of racemiketamine is approximately 300 ng*h / mL to approximately 825 ng*h / mL, for example, approximately 300 ng*h / mL, approximately 400 ng*h / mL, approximately 500 ng*h / mL, approximately 600 ng*h / mL, approximately 700 ng*h / mL, approximately 800 ng*h / mL, approximately 825 ng*h / mL, or any value in between. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is0-t The AUC after intranasal administration of racemiketamine is approximately 300 ng*h / mL to approximately 450 ng*h / mL. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The AUC after intranasal administration of racemiketamine is approximately 400 ng*h / mL to approximately 550 ng*h / mL. In some embodiments, approximately 30 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 500 ng*h / mL to approximately 825 ng*h / mL.

[0194] In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC of 6-hydroxynorketamine is measured. 0-t The AUC after intranasal administration of racemiketamine is approximately 650 ng*h / mL to approximately 1,900 ng*h / mL, for example, approximately 650 ng*h / mL, approximately 750 ng*h / mL, approximately 850 ng*h / mL, approximately 950 ng*h / mL, approximately 1,050 ng*h / mL, approximately 1,150 ng*h / mL, approximately 1,250 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,450 ng*h / mL, approximately 1,550 ng*h / mL, approximately 1,650 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, or any value in between. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The AUC after intranasal administration of racemiketamine is approximately 450 ng*h / mL to approximately 950 ng*h / mL. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The AUC after intranasal administration of racemiketamine is approximately 900 ng*h / mL to approximately 1,400 ng*h / mL. In some embodiments, approximately 75 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is obtained. 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 1,350 ng*h / mL to approximately 1,900 ng*h / mL.

[0195] In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is 0-t The AUC after intranasal administration of racemiketamine is approximately 1,050 ng*h / mL to approximately 3,100 ng*h / mL, for example, approximately 1,050 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,500 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value in between. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is measured. 0-t The AUC after intranasal administration of racemiketamine is approximately 1,050 ng*h / mL to approximately 1,850 ng*h / mL. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is obtained. 0-t The AUC after intranasal administration of racemiketamine is approximately 1,800 ng*h / mL to approximately 2,600 ng*h / mL. In some embodiments, approximately 90 mg of racemiketamine is administered intranasally, and the AUC for 6-hydroxynorketamine is obtained. 0-t The blood glucose level after intranasal administration of racemiketamine is approximately 2,550 ng*h / mL to approximately 3,100 ng*h / mL.

[0196] In some embodiments, the AUC for ketamine 0-tThe blood glucose levels after intranasal administration of racemic ketamine range from approximately 70 ng*h / mL to approximately 675 ng*h / mL, for example, approximately 70 ng*h / mL, approximately 100 ng*h / mL, approximately 125 ng*h / mL, approximately 150 ng*h / mL, approximately 175 ng*h / mL, approximately 200 ng*h / mL, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, and approximately 325 ng*h / mL. The C levels are approximately 350 ng*h / mL, 375 ng*h / mL, 400 ng*h / mL, 425 ng*h / mL, 450 ng*h / mL, 475 ng*h / mL, 500 ng*h / mL, 525 ng*h / mL, 550 ng*h / mL, 575 ng*h / mL, 600 ng*h / mL, 625 ng*h / mL, 650 ng*h / mL, and 675 ng*h / mL, and the C of ketamine. max The AUC for ketamine is approximately 15 ng / mL to approximately 225 ng / mL, or any value in between, after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is used. 0-t The blood glucose levels after intranasal administration of racemic ketamine range from approximately 70 ng*h / mL to approximately 675 ng*h / mL, for example, approximately 70 ng*h / mL, approximately 100 ng*h / mL, approximately 125 ng*h / mL, approximately 150 ng*h / mL, approximately 175 ng*h / mL, approximately 200 ng*h / mL, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, and approximately 350 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, and the C of ketamine. maxThe AUC after intranasal administration of racemic ketamine is approximately 70 ng / mL to approximately 205 ng / mL, for example, approximately 70 ng / mL, approximately 85 ng / mL, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, approximately 155 ng / mL, approximately 165 ng / mL, approximately 185 ng / mL, approximately 205 ng / mL, or any value in between. In some embodiments, the AUC for ketamine is 0-t The C levels after intranasal administration of racemic ketamine were approximately 70 ng*h / mL to 250 ng*h / mL, approximately 200 ng*h / mL to 450 ng*h / mL, approximately 400 ng*h / mL to 675 ng*h / mL, and approximately 600 ng*h / mL to 675 ng*h / mL, indicating the C levels of ketamine. max The glycemic index (NGL) after intranasal administration of racemiketamine ranges from approximately 75 ng / mL to approximately 1755 ng / mL, for example, approximately 75 ng / mL, approximately 100 ng / mL, approximately 125 ng / mL, approximately 150 ng / mL, approximately 175 ng / mL, or any value in between.

[0197] In some embodiments, norketamine AUC 0-t The blood glucose levels after intranasal administration of racemic ketamine range from approximately 250 ng*h / mL to approximately 2,200 ng*h / mL, for example, approximately 250 ng*h / mL, 350 ng*h / mL, 450 ng*h / mL, 550 ng*h / mL, 650 ng*h / mL, 750 ng*h / mL, 850 ng*h / mL, 950 ng*h / mL, 1,050 ng*h / mL, and 1,150 ng*h / mL. *h / mL, approximately 1,250ng*h / mL, approximately 1,350ng*h / mL, approximately 1,450ng*h / mL, approximately 1,550ng*h / mL, approximately 1,650ng*h / mL, approximately 1,750ng*h / mL, approximately 1,850ng*h / mL, approximately 1,950ng*h / mL, approximately 2,050ng*h / mL, approximately 2,200ng*h / mL, or any value in between, and norketamine C max The AUC of norketamine is approximately 40 ng / mL to approximately 375 ng / mL, or any value in between, after intranasal administration of racemiketamine. In some embodiments, the AUC of norketamine 0-tThe blood glucose levels after intranasal administration of racemic ketamine range from approximately 250 ng*h / mL to approximately 2,200 ng*h / mL, for example, approximately 250 ng*h / mL, 350 ng*h / mL, 450 ng*h / mL, 550 ng*h / mL, 650 ng*h / mL, 750 ng*h / mL, 850 ng*h / mL, 950 ng*h / mL, 1,050 ng*h / mL, and 1,150 ng*h / mL. *h / mL, approximately 1,250ng*h / mL, approximately 1,350ng*h / mL, approximately 1,450ng*h / mL, approximately 1,550ng*h / mL, approximately 1,650ng*h / mL, approximately 1,750ng*h / mL, approximately 1,850ng*h / mL, approximately 1,950ng*h / mL, approximately 2,050ng*h / mL, approximately 2,200ng*h / mL, or any value in between, and norketamine C max The C levels after intranasal administration of racemic ketamine are approximately 50 ng / mL, 75 ng / mL, 100 ng / mL, 125 ng / mL, 150 ng / mL, 175 ng / mL, 200 ng / mL, 225 ng / mL, 250 ng / mL, 275 ng / mL, or any value in between. In some embodiments, the C levels of norketamine are max The AUC levels after intranasal administration of racemiketamine were approximately 50 ng / mL to 135 ng / mL, approximately 130 ng / mL to 15 ng / mL, approximately 210 ng / mL to 245 ng / mL, and approximately 240 ng / mL to 275 ng / mL, compared to norketamine. 0-t The AUC after intranasal administration of racemiketamine is 250 ng*h / mL to 950 ng*h / mL, 900 ng*h / mL to 1,550 ng*h / mL, or 1,500 ng*h / mL to 2,200 ng*h / mL. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-tThe blood glucose levels after intranasal administration of racemiketamine range from 300 ng*h / mL to 3,100 ng*h / mL, for example, approximately 300 ng*h / mL to approximately 3,100 ng*h / mL, for example, approximately 300 ng*h / mL, approximately 450 ng*h / mL, approximately 600 ng*h / mL, approximately 750 ng*h / mL, approximately 900 ng*h / mL, approximately 1,050 ng*h / mL, approximately 1,200 ng*h / mL, and approximately 1,350 ng*h / mL. g*h / mL, approximately 1,500 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value in between, and C of 6-hydroxynorketamine. max The AUC after intranasal administration of racemiketamine is approximately 15 ng / mL to approximately 275 ng / mL, or any value in between. In some embodiments, the AUC for 6-hydroxynorketamine is used. 0-t The blood glucose levels after intranasal administration of racemiketamine range from 300 ng*h / mL to 3,100 ng*h / mL, for example, approximately 300 ng*h / mL, 450 ng*h / mL, 600 ng*h / mL, 750 ng*h / mL, 900 ng*h / mL, 1,050 ng*h / mL, 1,200 ng*h / mL, 1,350 ng*h / mL, and 1,500 ng*h / mL. / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value in between, and C of 6-hydroxynorketamine maxThe AUC after intranasal administration of racemic ketamine is approximately 55 ng / mL to approximately 245 ng / mL, for example, approximately 55 ng / mL, approximately 65 ng / mL, approximately 75 ng / mL, approximately 85 ng / mL, approximately 95 ng / mL, approximately 105 ng / mL, approximately 115 ng / mL, approximately 125 ng / mL, approximately 135 ng / mL, approximately 145 ng / mL, approximately 155 ng / mL, approximately 165 ng / mL, approximately 175 ng / mL, approximately 185 ng / mL, approximately 195 ng / mL, approximately 205 ng / mL, approximately 215 ng / mL, approximately 225 ng / mL, approximately 235 ng / mL, approximately 245 ng / mL, or any value in between. In some embodiments, the AUC for 6-hydroxynorketamine is 0-t The C levels after intranasal administration of racemiketamine were 700 ng*h / mL to 1,550 ng*h / mL, 1,500 ng*h / mL to 2,050 ng*h / mL, 2,000 ng*h / mL to 2,550 ng*h / mL, and 2,500 ng*h / mL to 3,100 ng*h / mL, and 6-hydroxynorketamine C max The levels after intranasal administration of racemiketamine are approximately 55 ng / mL to 125 ng / mL, approximately 120 ng / mL to 180 ng / mL, or approximately 175 ng / mL to 245 ng / mL.

[0198] In some embodiments, the AUC of ketamine 0-inf The AUC after intranasal administration of racemic ketamine is approximately 80 ng*h / mL to approximately 675 ng*h / mL, for example, approximately 80 ng*h / mL, approximately 125 ng*h / mL, approximately 175 ng*h / mL, approximately 225 ng*h / mL, approximately 275 ng*h / mL, approximately 325 ng*h / mL, approximately 475 ng*h / mL, approximately 525 ng*h / mL, approximately 575 ng*h / mL, approximately 625 ng*h / mL, approximately 675 ng*h / mL, or any value in between. In some embodiments, the AUC for ketamine is used. 0-inf The AUC for ketamine is approximately 80 ng*h / mL to approximately 175 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-inf The AUC for ketamine is approximately 150 ng*h / mL to approximately 275 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-infThe AUC for ketamine is approximately 250 ng*h / mL to approximately 375 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-inf The AUC for ketamine is approximately 350 ng*h / mL to approximately 475 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-inf The AUC for ketamine is approximately 450 ng*h / mL to approximately 575 ng*h / mL after intranasal administration of racemic ketamine. In some embodiments, the AUC for ketamine is shown. 0-inf The blood glucose level after intranasal administration of racemiketamine is approximately 550 ng*h / mL to approximately 675 ng*h / mL.

[0199] In some embodiments, the AUC for norketamine 0-inf The blood glucose levels after intranasal administration of racemic ketamine range from approximately 250 ng*h / mL to approximately 875 ng*h / mL, for example, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, approximately 350 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, and approximately 525 ng* h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, approximately 700 ng*h / mL, approximately 725 ng*h / mL, approximately 750 ng*h / mL, approximately 775 ng*h / mL, approximately 800 ng*h / mL, approximately 825 ng*h / mL, approximately 850 ng*h / mL, approximately 875 ng*h / mL, or any value in between. In some embodiments, the AUC for norketamine is used. 0-inf The AUC is approximately 250 ng*h / mL to approximately 475 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for norketamine is shown. 0-inf The AUC after intranasal administration of racemiketamine is approximately 450 ng*h / mL to approximately 675 ng*h / mL. In some embodiments, the AUC for norketamine is shown. 0-inf The blood glucose level after intranasal administration of racemiketamine is approximately 650 ng*h / mL to approximately 875 ng*h / mL.

[0200] In some embodiments, the AUC for 6-hydroxynorketamine 0-inf The blood glucose levels after intranasal administration of racemiketamine range from approximately 375 ng*h / mL to approximately 3,700 ng*h / mL, for example, approximately 375 ng*h / mL, approximately 500 ng*h / mL, approximately 650 ng*h / mL, approximately 900 ng*h / mL, approximately 1,050 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,500 ng*h / mL, approximately 1,650 ng*h / mL, approximately 1,800 ng*h / mL, and approximately 1,950 ng*h / mL. g*h / mL, approximately 2,100 ng*h / mL, approximately 2,250 ng*h / mL, approximately 2,400 ng*h / mL, approximately 2,550 ng*h / mL, approximately 2,700 ng*h / mL, approximately 2,850 ng*h / mL, approximately 3,000 ng*h / mL, approximately 3,150 ng*h / mL, approximately 3,300 ng*h / mL, approximately 3,450 ng*h / mL, approximately 3,600 ng*h / mL, approximately 3,700 ng*h / mL, or any value in between. In some embodiments, the AUC for 6-hydroxynorketamine is used. 0-inf The AUC is approximately 375 ng*h / mL to approximately 1,250 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-inf The AUC is approximately 1,200 ng*h / mL to approximately 1,400 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-inf The AUC is approximately 1,350 ng*h / mL to approximately 2,700 ng*h / mL after intranasal administration of racemiketamine. In some embodiments, the AUC for 6-hydroxynorketamine is shown. 0-inf The blood glucose level after intranasal administration of racemiketamine is approximately 2,600 ng*h / mL to approximately 3,700 ng*h / mL.

[0201] In some embodiments, the residual area for ketamine after intranasal administration of racemic ketamine is approximately 2.5% to approximately 8%, for example, approximately 2.5%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4.5%, approximately 5%, approximately 5.5%, 6%, approximately 6.5%, approximately 7%, approximately 7.5%, approximately 8%, or any value in between. In some embodiments, the residual area for ketamine is approximately 2.5% to approximately 5% after intranasal administration of racemic ketamine. In some embodiments, the residual area for ketamine is approximately 4% to approximately 6% after intranasal administration of racemic ketamine. In some embodiments, the residual area for ketamine is approximately 5% to approximately 8% after intranasal administration of racemic ketamine.

[0202] In some embodiments, the residual area for norketamine is about 6% to about 15% after intranasal administration of racemiketamine, for example, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, or any value in between. In some embodiments, the residual area for norketamine is about 2.5% to about 5% after intranasal administration of racemiketamine. In some embodiments, the residual area for norketamine is about 4% to about 6% after intranasal administration of racemiketamine. In some embodiments, the residual area for norketamine is approximately 5% to 8% after intranasal administration of racemiketamine.

[0203] In some embodiments, the residual area for 6-hydroxynorketamine is about 16% to about 34% after intranasal administration of racemiketamine, for example, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or any value in between. In some embodiments, the residual area for 6-hydroxynorketamine is about 16% to about 24% after intranasal administration of racemiketamine. In some embodiments, the residual area for 6-hydroxynorketamine is about 20% to about 30% after intranasal administration of racemiketamine. In some embodiments, the residual area for 6-hydroxynorketamine is approximately 26% to 34% after intranasal administration of racemiketamine.

[0204] In some embodiments, the AUC for intranasal racemiketamine 0-t This is the AUC of an equivalent dose of intravenous racemiketamine. 0-t This is approximately 80% to 125% of the AUC. For example, approximately 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, or any value in between. In some embodiments, the AUC for intranasal racemic ketamine is used. 0-t This is the AUC of an equivalent dose of intravenous racemiketamine. 0-t This is approximately 80% to 95% of the AUC. In some embodiments, the AUC for intranasal racemic ketamine is used. 0-inf This is the AUC of an equivalent dose of intravenous racemiketamine. 0-inf This is approximately 80% to 125% of the AUC. For example, approximately 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, or any value in between. In some embodiments, the AUC for intranasal racemic ketamine is used. 0-inf This is the AUC of an equivalent dose of intravenous racemiketamine. 0-inf It is approximately 80% to 95% of that.

[0205] In some embodiments, the AUC of norketamine after intranasal racemiketamine administration 0-t This is the AUC of norketamine after administration of an equivalent dose of intravenous racemiketamine. 0-t It is approximately 1.1 to 4.0 times larger than [the other value]. In some embodiments, the AUC of norketamine after administration of intranasal racemiketamine is [the other value]. 0-inf This is the AUC of norketamine after administration of an equivalent dose of intravenous racemiketamine. 0-inf It is approximately 1.1 to 4.0 times larger than the given value. For example, it is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3.9 times, or approximately 4.0 times larger, or any value in between.

[0206] In some embodiments, the AUC of 6-hydroxynorketamine after intranasal racemiketamine administration is measured. 0-t This is the AUC of norketamine after administration of an equivalent dose of intravenous racemiketamine. 0-t It is approximately 1.3 to 3.6 times larger than [the specified value]. For example, it is approximately 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, or approximately 3.6 times larger, or any value in between. In some embodiments, the AUC of 6-hydroxynorketamine after administration of intranasal racemicketamine is 0-inf This is the AUC of norketamine after administration of an equivalent dose of intravenous racemiketamine. 0-infIt is approximately 1.1 to 3.1 times larger than [the specified value]. For example, it is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, or 3.1 times larger, or any value in between.

[0207] In some embodiments, C for intranasal racemiketamine max This refers to the C for equivalent doses of intravenous racemiketamine. max This ranges from approximately 25% to approximately 125%. For example, approximately 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 105%, 110%, 115%, 120%, 125%, or any value in between. In some embodiments, C for intranasal racemic ketamine max This refers to the C for equivalent doses of intravenous racemiketamine. max It is approximately 25% to approximately 100% of the total. In some embodiments, the C of intranasal racemiketamine is max This refers to the C for equivalent doses of intravenous racemiketamine. max This is approximately 30% to 75% of the total. In some embodiments, the C of intranasal racemic ketamine is used. max This refers to the C for equivalent doses of intravenous racemiketamine. max It is approximately 50% to 70% of that.

[0208] In some embodiments, the C of norketamine after intranasal racemiketamine administration max This refers to the C of norketamine after administration of an equivalent dose of intravenous racemiketamine. maxApproximately 1.5 to 6.0 times larger. For example, approximately 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3. It is 9 times, approximately 4.0 times, approximately 4.1 times, approximately 4.2 times, approximately 4.3 times, approximately 4.4 times, approximately 4.5 times, approximately 4.6 times, approximately 4.7 times, approximately 4.8 times, approximately 4.9 times, approximately 5.0 times, approximately 5.1 times, approximately 5.2 times, approximately 5.3 times, approximately 5.4 times, approximately 5.5 times, approximately 5.6 times, approximately 5.7 times, approximately 5.8 times, approximately 5.9 times, or approximately 6.0 times larger, or any value in between.

[0209] In some embodiments, C6-hydroxynorketamine is administered after intranasal racemiketamine administration. max This refers to the C of 6-hydroxynorketamine after administration of an equivalent dose of intravenous racemiketamine. max It is approximately 1.4 to 5.0 times larger than [the other one]. For example, it is approximately 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3.0 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3.9 times, 4.0 times, 4.1 times, 4.2 times, 4.3 times, 4.4 times, 4.5 times, 4.6 times, 4.7 times, 4.8 times, 4.9 times, or approximately 5.0 times larger, or any value in between.

[0210] In some embodiments, T for intranasal racemic ketamine max This refers to the T250 maxIt is approximately 1.6 to 6.0 times larger than [the specified value]. For example, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, approximately 3.6 times, approximately 3.7 times, approximately 3.8 times, approximately 3.9 times, It is approximately 4.0 times, 4.1 times, 4.2 times, 4.3 times, 4.4 times, 4.5 times, 4.6 times, 4.7 times, 4.8 times, 4.9 times, 5.0 times, 5.1 times, 5.2 times, 5.3 times, 5.4 times, 5.5 times, 5.6 times, 5.7 times, 5.8 times, 5.9 times, or approximately 6.0 times larger, or any value in between.

[0211] In some embodiments, the T of norketamine after intranasal racemiketamine administration max This refers to the T2 of norketamine after administration of an equivalent dose of intravenous racemiketamine. max This ranges from approximately 30% to approximately 550%. For example, approximately 30%, 45%, 60%, 75%, 90%, 105%, 120%, 140%, 155%, 170%, 185%, 200%, 215%, 230%, 245%, 260%, 275%, 290%, 305%, 320%, 340%, 355%, 370%, 385%, 400%, 415%, 430%, 445%, 460%, 475%, 490%, 505%, 520%, 540%, 550%, or any value in between. In some embodiments, the T of norketamine after intranasal racemiketamine administration max This refers to the T2 of norketamine after administration of an equivalent dose of intravenous racemiketamine. max This is approximately 80% to 240%. For example, approximately 80%, 100%, 120%, 140%, 160%, 180%, 200%, 220%, 240%, or any value in between. In some embodiments, the T of norketamine after administration of intranasal racemicketamine max This refers to the T2 of norketamine after administration of an equivalent dose of intravenous racemiketamine. maxIt is approximately 90% to 180%. For example, approximately 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, or any value in between.

[0212] In some embodiments, the T of 6-hydroxynorketamine after intranasal racemiketamine administration max This refers to the T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous racemiketamine. max This ranges from approximately 20% to approximately 200%. For example, approximately 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, or any value in between. In some embodiments, the T of 6-hydroxynorketamine after administration of intranasal racemicketamine is present. max This refers to the T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous racemiketamine. max It is approximately 50% to 100%. For example, approximately 50%, 60%, 70%, 80%, 90%, 100%, or any value in between. In some embodiments, the T of 6-hydroxynorketamine after administration of intranasal racemiketamine max This refers to the T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous racemiketamine. max This ranges from approximately 65% ​​to 85%. For example, it could be approximately 65%, 70%, 75%, 80%, 85%, or any value in between.

[0213] In some embodiments, intranasal administration of racemiketamine provides higher exposure to and / or higher plasma concentrations of one or more active metabolites of ketamine compared to an equivalent dose of intravenous racemiketamine. In some embodiments, one or more active metabolites are selected from norketamine, 6-hydroxynorketamine, and combinations thereof.

[0214] In some embodiments, intranasal administration of racemiketamine provides higher exposure to and / or higher plasma concentrations of norketamine compared to an equivalent dose of intravenous racemiketamine. In some embodiments, intranasal administration of racemiketamine provides higher exposure to and / or higher plasma concentrations of 6-hydroxynorketamine compared to an equivalent dose of intravenous racemiketamine. In some embodiments, intranasal administration of racemiketamine provides higher exposure to and / or higher plasma concentrations of norketamine and 6-hydroxynorketamine compared to an equivalent dose of intravenous racemiketamine.

[0215] In some embodiments, "equivalent" doses of intranasal racemiketamine and intravenous racemiketamine and / or intravenous (S)-ketamine, or any pharmaceutically acceptable salt thereof, have an equivalent AUC. 0-inf It is determined by the value.

[0216] In some embodiments, intranasal administration of racemiketamine is performed. AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0217] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t AUC is approximately 1.7 to 2.5 times higher than 0-tThis shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t AUC is approximately 1.9 to 2.3 times higher than 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t Norketamine's AUC is at least 1.8 times higher (e.g., at least 1.9 times higher, or at least 2 times higher) than [the other value]. 0-t This indicates.

[0218] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf Norketamine's AUC is approximately 1.5 to 2.5 times higher than that of [another substance]. 0-inf This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf Norketamine's AUC is approximately 1.8 to 2.2 times higher than that of [another substance]. 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf Norketamine's AUC is at least 1.7 times higher (for example, at least 1.8 times higher, at least 1.9 times higher, or at least 2 times higher) than [the other AUC]. 0-t This indicates.

[0219] In some embodiments, intranasal administration of racemiketamine is equivalent to the C2 of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Norketamine has a C content that is approximately 2.2 to 3.5 times higher than [another substance]. max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the C of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Norketamine has a C content that is approximately 2.4 to 3.2 times higher than [another substance]. maxThis shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the C of norketamine administered by intravenous administration of an equivalent dose of racemiketamine. max Norketamine's C is at least 2.5 times higher (for example, at least 2.8 times higher, or at least 3 times higher) than [another substance]. max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the T2 dose of norketamine, as shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine's T is approximately 80% to 125% max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the T2 of norketamine, as shown by intravenous administration of an equivalent amount of racemiketamine. max Norketamine's T is approximately 90% to 110% of max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the T2 of norketamine, as shown by intravenous administration of an equivalent amount of racemiketamine. max Norketamine's T is approximately 95% to 105% max This indicates.

[0220] In some embodiments, norketamine AUC 0-t AUC 0-inf , C max , and T max One or more of these are determined after a single dose of racemiketamine. In some embodiments, the AUC of norketamine 0-t AUC 0-inf , C max , and T max One or more of these are determined after two doses of racemic ketamine. In some embodiments, the AUC of norketamine 0-t AUC 0-inf , C max , and T max One or more of these will be determined after three doses of racemiketamine.

[0221] In some embodiments, intranasal administration of racemiketamine is performed. AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-tThe AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , and Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0222] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is approximately 1.7 to 2.5 times higher than that of [another substance]. 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is approximately 1.9 to 2.3 times higher than that of [another substance]. 0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-t The AUC of hydroxynorketamine is at least 1.9 times higher (e.g., at least 2 times higher, or at least 2.1 times higher) than [the other AUC]. 0-t This indicates.

[0223] In some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf The AUC of hydroxynorketamine is approximately 1.5 to 2.5 times higher than that of [another substance]. 0-inf This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf The AUC of hydroxynorketamine is approximately 1.7 to 2.1 times higher than that of [another substance].0-t This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to the AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine. 0-inf The AUC of hydroxynorketamine is at least 1.7 times higher (for example, at least 1.8 times higher, or at least 1.9 times higher) than [the other AUC]. 0-t This indicates.

[0224] In some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine, as indicated by the equivalent dose of racemiketamine. max Hydroxynorketamine has a C content that is approximately 2.2 to 3.2 times higher than that of hydroxynorketamine. max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine, as shown by the C2 dose of racemiketamine. max Hydroxynorketamine has a C content that is approximately 2.4 to 2.8 times higher than that of hydroxynorketamine. max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine, as shown by the C2 dose of racemiketamine. max The C content of hydroxynorketamine is at least 2.4 times higher (for example, at least 2.5 times higher, or at least 2.6 times higher) than that of hydroxynorketamine. max This indicates.

[0225] In some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine by an equivalent dose of racemiketamine. max Approximately 80% to 125% of hydroxynorketamine T max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine, as shown by the equivalent dose of racemiketamine. max Approximately 90% to 110% of hydroxynorketamine T max This shows that, in some embodiments, intranasal administration of racemiketamine is equivalent to intravenous administration of hydroxynorketamine, as shown by the equivalent dose of racemiketamine. max Approximately 95% to 105% of hydroxynorketamine Tmax This indicates.

[0226] In some embodiments, the AUC of hydroxynorketamine 0-t AUC 0-inf , C max , and T max One or more of these are determined after a single dose of racemicketamine. In some embodiments, the AUC of hydroxynorketamine 0-t AUC 0-inf , C max , and T max One or more of these are determined after two doses of racemic ketamine. In some embodiments, the AUC of hydroxynorketamine 0-t AUC 0-inf , C max , and T max One or more of these will be determined after three doses of racemiketamine.

[0227] In some embodiments, the target Montgomery-Asberg Depression Rating Scale (MADRS) total score is 20 to 60 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the target MADRS total score is 30–60 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MADRS total score is reduced by at least 50% 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MADRS total score is 15 units or less 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the target MADRS total score is 12 units or less 48 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the score of the target MADRS item 10 is 4, 5, or 6 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of the target MADRS item 10 is 5 or 6 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the score of the target MADRS item 10 decreases by at least 1 unit 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the subject's clinical overall impression (CGIS-SI / B) score for the severity of suicidal ideation and behavior is 4 or 5 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is 1 or 2 units 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the Sheehan-Suicidal Tendency Tracking Scale (S-STS) Measure of Clinically Meaningful Change (CMCM) score is 15–52 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM score is 20–52 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS CMCM score is reduced by at least 50% 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS CMCM score is 1–3 units 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the subject's Sheehan-Suicidal Tendency Tracking Scale (S-STS) Measure of Clinically Meaningful Change (CMCM) suicide risk score within the next 7 days is 5–10 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM suicide risk score within the next 7 days is reduced by at least 50% 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM suicide risk score within the next 7 days is 0–2 units 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM suicide risk score within the next 7 days is 0 or 1 unit 96 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the subject's Modified Awakening / Sedation Observer Rating (MOAA / S) score is 5 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is 4 or 5 units approximately 15 minutes to approximately 6 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the Dissociative State Scale (CADSS) score administered by the clinician in question is zero units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CADSS score in question is zero units approximately 1 to 6 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the subject's C-SSRS score is 2 to 9 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's C-SSRS score is 2 to 5 units prior to intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSSR-S score is zero units 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0236] Several embodiments provide a method for treating suicidal tendencies in subjects requiring treatment, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof, wherein clinically meaningful sedation is not observed in the subject within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0237] Several embodiments provide a method for treating suicidal tendencies in subjects requiring treatment, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof, wherein clinically significant dissociation is not observed in the subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in the subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in the subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, a method for treating suicidal ideation in subjects requiring treatment of suicidal ideation is provided, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof, wherein clinically meaningful sedation is not observed in the subject within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, a method for treating suicidal ideation in subjects requiring treatment of suicidal ideation is provided, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof, wherein clinically meaningful dissociation is not observed in the subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful dissociation is not observed in the subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful dissociation is not observed in the subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0240] Several embodiments provide a method for treating major depressive disorder in subjects requiring treatment of major depressive disorder, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject, wherein clinically meaningful sedation is not observed in the subject within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in the subject within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0241] Several embodiments provide a method for treating major depressive disorder in subjects requiring treatment, comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject. Here, no clinically significant dissociation is observed in the subject within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, clinically meaningful sedation and dissociation are not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation and dissociation are not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation and dissociation are not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0243] Some embodiments are methods for treating suicidal tendencies in subjects who require treatment for suicidal tendencies, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject intranasally, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0244] Some embodiments are methods for treating suicidal ideation in subjects requiring treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-tNorketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0245] Some embodiments are methods for treating major depressive disorder in subjects requiring treatment for major depressive disorder, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. maxNorketamine C is at least twice as high max Show one or more of the following.

[0246] Some embodiments are methods for treating suicidal tendencies in subjects who require treatment for suicidal tendencies, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0247] Some embodiments are methods for treating suicidal ideation in subjects requiring treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0248] Some embodiments are methods for treating major depressive disorder in subjects requiring treatment for major depressive disorder, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t The AUC of hydroxynorketamine is at least 1.5 times higher than that of [another product]. 0-t , AUC of hydroxynorketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf The AUC of hydroxynorketamine is at least 1.2 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Hydroxynorketamine has at least twice as much C as max Show one or more of the following.

[0249] Some embodiments are methods for treating suicidal tendencies in subjects who require treatment for suicidal tendencies, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0250] A method for treating suicidal ideation in a person who requires treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as highmax Show one or more of the following.

[0251] Some embodiments are methods for treating major depressive disorder in subjects requiring treatment for major depressive disorder, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Intranasal administration of racemiketamine, AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-t Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-t , AUC of norketamine shown by intravenous administration of an equivalent dose of racemiketamine 0-inf Norketamine's AUC is at least 1.5 times higher than that of [another substance]. 0-inf , Norketamine C2 is shown by intravenous administration of an equivalent dose of racemiketamine. max Norketamine C is at least twice as high max Show one or more of the following.

[0252] Some embodiments are methods for treating suicidal tendencies in subjects who require treatment for suicidal tendencies, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) A method comprising intranasal administration of a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to a subject, Clinically meaningful sedation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0253] Some embodiments are methods for treating suicidal tendencies in subjects who require treatment for suicidal tendencies, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically significant dissociation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0254] A method for treating suicidal tendencies in a person requiring treatment for suicidal tendencies, the embodiment of which (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, no clinically significant dissociation is observed in the subjects. In some embodiments, approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation is observed in the subjects. In some embodiments, approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation is observed in the subjects.

[0255] A method for treating suicidal ideation in a person who requires treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically meaningful sedation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0256] A method for treating suicidal ideation in a person who requires treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically significant dissociation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0257] A method for treating suicidal ideation in a person who requires treatment for suicidal ideation, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically significant dissociation is not observed in subjects approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant sedation and clinically significant dissociation are not observed in subjects approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant sedation and clinically significant dissociation are not observed in subjects approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0258] Some embodiments are methods for treating major depressive disorder in subjects requiring treatment for major depressive disorder, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically meaningful sedation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically meaningful sedation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0259] Some embodiments are methods for treating major depressive disorder in subjects requiring treatment for major depressive disorder, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically significant dissociation is not observed in subjects within approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant dissociation is not observed in subjects within approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0260] A method for treating major depressive disorder in a subject requiring treatment for major depressive disorder, comprising the embodiment, (a) The subject is, (i) A total MADRS score of at least 20 units, (ii) A score of 4, 5, or 6 units of MADRS item 10, (iii) CGIS-SI / B score of 4 or 5 units, (iv) S-STS CMCM score of at least 15 units, (v) S-STS CMCM suicide risk score of at least 5 units within the next 7 days, and (vi) Determine whether the person has at least one of two C-SSRS scores, (b) administering a therapeutically effective dose of racemiketamine or a pharmaceutically acceptable salt thereof to the subject intranasally, Clinically significant dissociation is not observed in subjects approximately 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant sedation and clinically significant dissociation are not observed in subjects approximately 4 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof. In some embodiments, clinically significant sedation and clinically significant dissociation are not observed in subjects approximately 1 hour after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, one or more of the following are reduced by at least 50% 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0262] In some embodiments, one or more of the following are reduced by at least 50% 48 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0263] In some embodiments, one or more of the following are reduced by at least 50% 96 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0264] In some embodiments, one or more of the following criteria are below the threshold for remission 24 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0265] In some embodiments, one or more of the following criteria are below the remission threshold 48 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0266] In some embodiments, one or more of the following criteria are below the remission threshold 96 hours after intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof: MADRS total, MADRS item 10, CGIS-SI / B, S-STS CMCM, S-STS CMCM suicide risk within the next 7 days, and C-SSRS score.

[0267] In some embodiments, the subject has at least 20 units of MADRS total score. In some embodiments, the subject has 4, 5, or 6 units of MADRS item 10 score. In some embodiments, the subject has 4 or 5 units of CGIS-SI / B score. In some embodiments, the subject has at least 15 units of S-STS CMCM score. In some embodiments, the subject has at least 5 units of S-STS CMCM suicide risk within the next 7 days. In some embodiments, the subject has at least 2 C-SSRS score. In some embodiments, the subject has at least 20 units of MADRS total score and 4 or 5 units of CGIS-SI / B score. In some embodiments, the subject has at least 20 units of MADRS total score and at least 15 units of S-STS CMCM score. In some embodiments, the subject has at least 20 units of MADRS total score, 4 or 5 units of CGIS-SI / B score, and at least 15 units of S-STS CMCM score.

[0268] In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once a month, for example, once daily, once every other day, twice a week, or once a week. In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once every two weeks. In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once a week. In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once a week to about twice a week. In some embodiments, racemiketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice a week. In some embodiments, racemiketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally once daily, once every other day, three times a week, twice a week, or once a week. In some embodiments, racemiketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally every four days (e.g., on day 1, day 4, day 8, day 12, day 16, etc.).

[0269] Some embodiments described herein provide a comparison between intranasal administration of racemiketamine or a pharmaceutically acceptable salt thereof, intravenous administration of racemiketamine or a pharmaceutically acceptable salt thereof, and / or administration of (S)-ketamine or a pharmaceutically acceptable salt thereof (e.g., intravenous or intranasal administration).

[0270] In some embodiments, intranasal (S)-ketamine is Spravato®. In some embodiments, intranasal (S)-ketamine is essentially a solution comprising 32.3 mg of (S)-ketamine hydrochloride (equivalent to 28 mg of (S)-ketamine), citrate monohydrate, disodium edetate, sodium hydroxide, and water. In some embodiments, intranasal (S)-ketamine is a clear, colorless aqueous solution at pH 4.5. See the Spravato® ((S)-ketamine) attached document dated February 11, 2020: www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 211243s003lbl.pdf, which is incorporated herein by reference in its entirety.

[0271] Some embodiments refer to a time "prior" to the administration of intranasal racemiketamine or a pharmaceutically acceptable salt thereof. The time prior to administration may be a specific time or range of time indicated (e.g., about 30 minutes, about 1 hour, about 1 day to about 1 week, 6 months, etc.), or any time earlier than that, or any time prior to administration if no specific time or range is specified.

[0272] Combination therapy The methods of the present disclosure also envision a treatment comprising administering ketamine, or a pharmaceutically acceptable salt thereof, in combination with one or more additional treatments (such as antidepressants), as described in any embodiment of the present disclosure. Thus, as described elsewhere in this specification, ketamine, or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with one or more additional treatments. When administered in combination with one or more additional treatments, it may be administered to a separate dosage form. When administered as separate dosage forms, the one or more additional treatments may be administered concurrently with the ketamine dosage form of the present disclosure or sequentially with the ketamine dosage form of the present disclosure, in either order. In some embodiments, the intranasal ketamine dosage form and one or more additional treatments are administered sequentially on the same or different days. For example, racemic ketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally twice a week, and one or more additional treatments are administered once daily.

[0273] In some embodiments, the methods described herein further include implementing one or more additional treatments consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole.

[0274] In some embodiments, the methods described herein further include providing cognitive behavioral therapy to a subject.

[0275] In some embodiments, one or more additional therapies are standard treatments for major depressive disorder. In some embodiments, one or more additional therapies are standard treatments for suicidal tendencies. In some embodiments, one or more additional therapies are standard treatments for suicidal ideation. In some embodiments, one or more additional therapies are standard treatments for treatment-resistant depression. In some embodiments, one or more additional therapies are standard treatments for post-traumatic stress disorder.

[0276] In some embodiments, one or more additional treatments are pramipexole.

[0277] In some embodiments, one or more additional treatments are typical antipsychotics. Representative typical antipsychotics include, but are not limited to, chlorpromazine, levomepromazine, mesolidazine, periciazine, promazine, roxapine, morindone, perphenazine, thiothixen, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopentixol.

[0278] In some embodiments, one or more additional treatments are atypical antipsychotics. Representative atypical antipsychotics include, but are not limited to, aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone.

[0279] In some embodiments, one or more additional treatments are antidepressants. In some embodiments, the antidepressants are atypical antidepressants, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, or selective norepinephrine reuptake inhibitors.

[0280] In some embodiments, the antidepressant is an atypical antidepressant. Representative atypical antidepressants include, but are not limited to, mirtazapine, mianserin, bupropion, trazodone, nefazodone, thianeptine, opipramol, agomelatine, bilazodone, and vortioxetine.

[0281] In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor. Representative selective serotonin reuptake inhibitors include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0282] In some embodiments, the antidepressant is a selective serotonin-norepinephrine reuptake inhibitor. Representative selective serotonin-norepinephrine reuptake inhibitors include, but are not limited to, atomoxetine, desvenlafaxine, duloxetine, levomirunacipran, milnacipran, sibutramine, tramadol, and venlafaxine.

[0283] In some embodiments, the antidepressant is a monoamine oxidase inhibitor. Representative monoamine oxidase inhibitors include, but are not limited to, moclobemide, rasagiline, selegiline, or safinamide.

[0284] In some embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor. A representative selective norepinephrine reuptake inhibitor is, but is not limited to, reboxetine.

[0285] In some embodiments, one or more additional therapeutic agents are benzodiazepines. Representative benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clonazepam, chlorazepic acid, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

[0286] In some embodiments, one or more additional treatments are mood stabilizers. Typical mood stabilizers include, but are not limited to, lithium, valproic acid, lamotrigine, or carbamazepine. In some embodiments, one or more additional treatments are electroconvulsive therapy or transcranial magnetic stimulation.

[0287] In some embodiments, one or more additional treatments are sertraline. In some embodiments, one or more additional treatments are venlafaxine.

[0288] In some embodiments, one or more additional treatments are one additional treatment. In some embodiments, one or more additional treatments are two, three, or four additional treatments.

[0289] In some embodiments, the subjects had previously received one or more additional treatments, consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole, and the subjects had not responded to the previous one or more treatments.

[0290] In some embodiments, the subjects had previously received standard treatment for major depressive disorder and had not responded to the previous treatment. In some embodiments, the subjects had previously received standard treatment for suicidal tendencies and had not responded to the previous treatment. In some embodiments, the subjects had previously received standard treatment for suicidal ideation and had not responded to the previous treatment. In some embodiments, the subjects had previously received standard treatment for treatment-resistant depression and had not responded to the previous treatment. In some embodiments, the subjects had previously received standard treatment for post-traumatic stress disorder and had not responded to the previous treatment.

[0291] In some embodiments, the subjects had previously received one or more additional treatments, consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole, and had not responded to the prior treatments.

[0292] In some embodiments, the subjects had previously been administered pramipexole and had not responded to previous treatments.

[0293] In some embodiments, subjects had previously received one or more typical antipsychotics, such as chlorpromazine, chlorprothixen, levomepromazine, mesolidazine, periciazine, promazine, roxapine, morindone, perphenazine, thiothixen, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopentixol, and had not responded to the previous treatment.

[0294] In some embodiments, subjects had previously received one or more atypical antipsychotics, such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone, and had not responded to the previous treatment.

[0295] In some embodiments, the subjects had previously received one or more antidepressants and had not responded to the previous treatment. In some embodiments, the antidepressants were atypical antidepressants, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, or selective norepinephrine reuptake inhibitors and had not responded to the previous treatment.

[0296] In some embodiments, subjects had previously received one or more atypical antidepressants, such as mirtazapine, mianserin, bupropion, trazodone, nefazodone, thianeptine, opipramol, agomelatine, bilazodone, and vortioxetine, and had not responded to the previous treatment.

[0297] In some embodiments, subjects had previously been administered one or more selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, and had not responded to the prior treatment.

[0298] In some embodiments, subjects had previously received one or more selective serotonin-norepinephrine reuptake inhibitors, such as atomoxetine, desvenlafaxine, duloxetine, levomirunacipran, milnacipran, sibutramine, tramadol, and venlafaxine, and had not responded to the previous treatment.

[0299] In some embodiments, subjects had previously been administered one or more monoamine oxidase inhibitors, such as moclobemide, rasagiline, selegiline, or safinamide, and had not responded to the previous treatment.

[0300] In some embodiments, subjects had previously received one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and had not responded to the previous treatment.

[0301] In some embodiments, subjects had previously received one or more benzodiazepines, such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, chlorazepic acid, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam, and had not responded to the previous treatment.

[0302] In some embodiments, the subjects had previously been administered one or more mood stabilizers, such as lithium, valproic acid, lamotrigine, or carbamazepine, and had not responded to the previous treatment.

[0303] In some embodiments, one or more additional treatments were electroconvulsive therapy or transcranial magnetic stimulation, which were ineffective with the prior treatments.

[0304] In some embodiments, the subjects had been previously administered sertraline and had not responded to the previous treatment. In some embodiments, the subjects had been previously administered venlafaxine and had not responded to the previous treatment.

[0305] In some embodiments, one or more additional treatments previously administered to the subject is one additional treatment. In some embodiments, one or more additional treatments previously administered to the subject is two additional treatments. In some embodiments, one or more additional treatments previously administered to the subject is three additional treatments. In some embodiments, one or more additional treatments previously administered to the subject is four additional treatments. In some embodiments, one or more additional treatments previously administered to the subject is five, six, seven, eight, nine, or ten additional treatments.

[0306] In some embodiments, racemiketamine, or a pharmaceutically acceptable salt thereof, is administered acutely intranasally. For example, in a subject with suicidal tendencies, racemiketamine, or a pharmaceutically acceptable salt thereof, may be administered for one to four weeks, or until the suicidal tendencies subside. In some embodiments, racemiketamine, or a pharmaceutically acceptable salt thereof, is administered long-term intranasally. For example, in a subject with major depressive disorder, racemiketamine, or a pharmaceutically acceptable salt thereof, may be administered for several months to several years, or until the depression subsides.

[0307] In some embodiments described herein, (S)-ketamine is administered intravenously. In some embodiments described herein, (S)-ketamine is administered intranasally.

[0308] Some embodiments provide intranasal administration compositions comprising a therapeutically effective amount of racemiketamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0309] Some embodiments provide the use of racemiketamine or a pharmaceutically acceptable salt thereof in the preparation of an intranasal agent for treating suicidal tendencies in subjects requiring treatment for suicidal tendencies.

[0310] Some embodiments provide the use of racemiketamine or a pharmaceutically acceptable salt thereof in the preparation of an intranasal agent for treating suicidal ideation in subjects requiring treatment for suicidal ideation.

[0311] Some embodiments provide the use of racemiketamine, or a pharmaceutically acceptable salt thereof, in the preparation of an intranasal agent for treating major depressive disorder in subjects requiring treatment for major depressive disorder.

[0312] Some embodiments provide the use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of an intranasal agent for reducing one or more side effects of ketamine in subjects requiring such reduction.

[0313] intranasal delivery In some embodiments, racemiketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally. Administration can be achieved via a suitable intranasal delivery device.

[0314] In some embodiments, a device (e.g., an intranasal device) can deliver one or more doses of racemiketamine into the target nasal cavity. In some embodiments, the device is designed for the target's nostrils. In some embodiments, the device is designed to measure a specific amount or specific dose of racemiketamine. In some embodiments, the device is designed to act in response to the target's breathing. In some embodiments, the device is designed to deliver two or more doses into the target's nasal cavity. In some embodiments, the device can spray racemiketamine into the target's nostril cavity.

[0315] In some embodiments, the apparatus comprises a nozzle for providing an aerosol through a nosepiece. In some embodiments, the nozzle comprises a head coaxially positioned within the nosepiece and a delivery tube fluidly communicating with the head. In some embodiments, the nozzle can be configured to provide a jet of substance through the nosepiece. In some embodiments, the apparatus further comprises a substance supply unit for delivering a quantitative amount of racemic ketamine to the nozzle. In some embodiments, the substance supply unit comprises a mechanical delivery pump fluidly communicating with the nozzle and configured, when activated, to deliver a quantitative amount of racemic ketamine to the nozzle, causing the nozzle to generate an aerosol. The delivery pump is movable relative to the nozzle from a first non-operating position to a second operating position, delivering a quantitative amount of racemic ketamine to the nozzle and thus generating an aerosol.

[0316] ...

Claims

1. A composition comprising racemiketamine or a pharmaceutically acceptable salt thereof for reducing suicidal tendencies in a subject requiring reduction of suicidal tendencies, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with a dose of 30 mg to 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof. (a) The subject is identified as having a total Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 to 60 units, (b) Ketamine is the only therapeutic agent administered during the aforementioned 15 days, Intranasal administration of the aforementioned racemiketamine, or a pharmaceutically acceptable salt thereof, is as follows: The AUC 0-24 of norketamine on day 1, day 4, or day 8 after intranasal administration is at least 1.5 times higher than the AUC 0-24 of norketamine shown by the intravenous administration of an equivalent dose of racemiketamine on day 1, day 4, or day 8 after intravenous administration. The AUC 0-inf of norketamine on day 1, day 4, or day 8 after intranasal administration is at least 1.5 times higher than the AUC 0-inf of norketamine shown by the intravenous administration of an equivalent dose of racemiketamine on day 1, day 4, or day 8 after intravenous administration, The Cmax of norketamine on day 1, day 4, or day 8 after intranasal administration is at least twice as high as the Cmax of norketamine shown by the intravenous administration of an equivalent dose of racemiketamine on day 1, day 4, or day 8 after intravenous administration. Show one or more of the following: A composition that thereby reduces suicidal tendencies in the subject compared to the suicidal tendencies in the subject before administration of racemiketamine or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 30 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

3. The composition according to claim 1, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 60 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

4. The composition according to claim 1, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

5. The composition according to claim 1, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

6. The composition according to claim 1, wherein an equal amount of racemiketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to the subject on each day of administration.

7. The composition according to claim 1, characterized in that the composition is administered intranasally to the subject once daily on days 1, 4, 8, 11 and 15 of a 15-day cycle, with the composition comprising 30 mg to 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

8. The composition according to claim 7, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 30 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

9. The composition according to claim 7, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 60 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

10. The composition according to claim 7, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 75 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

11. The composition according to claim 7, characterized in that the composition is administered intranasally to the subject once every 3 to 4 days for 15 days, with 90 mg of racemiketamine or a pharmaceutically acceptable salt thereof.

12. The composition according to claim 7, wherein an equal amount of racemiketamine, or a pharmaceutically acceptable salt thereof, is administered intranasally to the subject on each day of administration.

13. The composition according to claim 1, wherein the total MADRS score of the subject is 20 to 60 units before intranasal administration of the composition.

14. The composition according to claim 1, wherein 24 hours after intranasal administration of the composition, the total MADRS score of the subject is reduced by at least 50%.

15. The composition according to claim 1, wherein the total MADRS score of the subject is 12 units or less 48 hours after intranasal administration of the composition.

16. The composition according to claim 1, wherein the subject has a score of 4, 5, or 6 units of the MADRS item 10 before intranasal administration of the composition.

17. The composition according to claim 1, wherein the subject has a score of MADRS item 10 that is reduced by at least 1 unit within 4 hours of administration of the composition.

18. The composition according to claim 7, wherein the total MADRS score of the subject is 20 to 60 units before intranasal administration of the composition.

19. The composition according to claim 7, wherein the total MADRS score of the subject is reduced by at least 50% 24 hours after intranasal administration of the composition.

20. The composition according to claim 7, wherein the total MADRS score of the subject is 12 units or less 48 hours after intranasal administration of the composition.

21. The composition according to claim 7, wherein the subject has a score of 4, 5, or 6 units of the MADRS item 10 before intranasal administration of the composition.

22. The composition according to claim 7, wherein the subject has a score of MADRS item 10 that is reduced by at least 1 unit 4 hours after administration of the composition.

23. The composition according to claim 1, wherein no clinically significant dissociation is observed in the subject one hour after intranasal administration of the composition.

24. The composition according to claim 1, wherein no clinically significant sedation is observed in the subject one hour after intranasal administration of the composition.

25. The composition according to claim 13, wherein no clinically significant dissociation is observed in the subject one hour after intranasal administration of the composition.

26. The composition according to claim 13, wherein no clinically significant sedation is observed in the subject one hour after intranasal administration of the composition.

27. ​​The composition according to claim 16, wherein no clinically significant dissociation is observed in the subject one hour after intranasal administration of the composition.

28. The composition according to claim 16, wherein no clinically significant sedation is observed in the subject one hour after intranasal administration of the composition.

29. The composition according to claim 1, wherein the total MADRS score 24 hours after administration is reduced by at least 50% compared to the total MADRS score before administration.

30. The composition according to claim 1, wherein the total MADRS score 24 hours after administration is less than 12 units.

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