Reducing the side effects of NMDA receptor antagonists

Abstract

The present disclosure relates to compositions comprising racemic ketamine, or a pharma- ceutically acceptable salt thereof, for use in the treatment of psychiatric disorders. Some embodiments provide a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharma- ceutically acceptable salt thereof. Some embodiments provide a method of treating treatment-resistant depression (TRD) in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharma- ceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present disclosure relates to compositions and methods for treating psychiatric disorders. [Background technology]

[0002] Mental disorders are among the most disabling of all medical disorders and a major public health problem. Many mental disorders have an onset in early childhood, can have chronic onset throughout life, and can adversely affect the prognosis of other medical diseases, such as cardiovascular and neurological conditions.

[0003] While medication and cognitive behavioral therapy are effective for people with mental disorders such as depression, up to 20% do not respond to these interventions, and many of those who respond ultimately relapse. For example, an estimated 50% of people with depression are only partially (inadequately) treated by available clinical interventions. See Al Harbi, Patient Prefer. Adherence, Vol. 6, pp. 369-388 (2012). NIMH's Sequenced Treatment Alternatives to Relieve Depression (STAR) * D) In ​​clinical trials, approximately half of patients treated with first-line antidepressant therapy reduced their symptoms to at least half of their original intensity, and only about one-third of patients achieved remission (Chan 2013). While these patients may eventually resolve, many require a trial-and-error approach to therapy, and many ultimately develop treatment-resistant depression over time. See, e.g., Sackheim, J. Clin. Psychiatry, Vol. 62, Suppl. 16, pp. 10-17 (2001). While the discovery of medications such as tricyclic antidepressants and monoamine oxidase inhibitors has revolutionized the treatment of depression, existing treatment approaches are inadequate for many other psychiatric disorders. See Smith BL, Amer. Psychol. Assoc. Monitor, Vol. 43, No. 6, p. 36 (2012). In many cases, even medications for treating psychiatric disorders take weeks to months to achieve full efficacy, and even safe doses are not effective for all subjects. For example, most antidepressants require an average of six weeks before they begin to affect depressive symptoms. Some patients do not respond to antidepressants at all, while others appear to be only partially effective in improving symptoms. Meanwhile, individuals continue to suffer from depression, are at risk of self-harm, and experience negative effects on their personal and professional lives. See, for example, Burcusa and Iacono, Clin. Psychol. Rev. Vol. 27, No. 8, pp. 959-985 (2007). Providing treatment for rapidly developing and persistent mental disorders would have a major 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] Smith BL,Amer.Psychol.Assoc.Monitor,Vol.43,No.6,p.36(2012) [Non-patent document 4] Burcusa and Iacono,Clin.Psychol.Rev.Vol.27,No.8,pp.959-985(2007) Summary of the Invention

[0005] Some embodiments provide a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments provide a method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0007] Some embodiments provide a method of treating treatment-resistant depression (TRD) in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the TRD is treatment-resistant unipolar depression. In some embodiments, the TRD is treatment-resistant bipolar depression.

[0008] Some embodiments provide a method of treating bipolar depression in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments provide a method of treating postpartum depression in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments provide a method of treating chronic pain in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments provide a method of treating neuropathic pain in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0012] Some embodiments provide a method of treating Rett syndrome in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0013] Some embodiments provide a method of treating epilepsy in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0014] Some embodiments provide a method of treating agitation associated with dementia in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0015] Some embodiments provide a method of treating agitation associated with schizophrenia in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0016] Some embodiments provide a method of treating agitation associated with bipolar disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0017] Some embodiments provide a method of treating one or more side effects of ketamine treatment in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the subject has been previously diagnosed with and / or currently suffers from post-traumatic stress disorder. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from major depressive disorder. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from treatment-resistant depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from bipolar depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from postpartum depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from postpartum depression, but is not currently breastfeeding. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from chronic pain. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from neuropathic pain. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from Rett syndrome. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from epilepsy. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from dementia-related agitation. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from schizophrenia-related agitation. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from bipolar disorder-related agitation.

[0019] Abbreviation N: number of observations; SD: standard deviation; Min: minimum value; Max: maximum value; IN: intranasal. [Brief explanation of the drawings]

[0020] [Figure 1A]1 is a table illustrating the pharmacokinetic parameters of ketamine on Day 1 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 1B] 1 is a table illustrating the pharmacokinetic parameters of ketamine on Day 1 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 1C] 1 is a table illustrating the pharmacokinetic parameters of ketamine on Day 1 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 2A] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 4 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 2B] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 4 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 2C] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 4 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 3A] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 8 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 3B] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 8 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 3C] 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 8 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 4A] 1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 1 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 4B] 1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 1 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 4C]1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 1 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 5A] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 4 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 5B] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 4 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 5C] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 4 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 6A] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 8 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 6B] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 8 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 6C] 1 is a table illustrating the pharmacokinetic parameters of norketamine on day 8 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 7A] 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on Day 1 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 7B] 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on Day 1 of Part A of the clinical trial described in Example 1 for 75 mg racemic ketamine. [Figure 7C] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on Day 1 of Part A of the clinical trial described in Example 1 for 90 mg racemic ketamine. [Figure 8A] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the trial described in Example 1 for 30 mg racemic ketamine. [Figure 8B] 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the trial described in Example 1 for 75 mg racemic ketamine. [Figure 8C] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part A of the trial described in Example 1 for 90 mg racemic ketamine. [Figure 9A] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the clinical trial described in Example 1 for 30 mg racemic ketamine. [Figure 9B] 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the trial described in Example 1 for 75 mg racemic ketamine. [Figure 9C] 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 8 of Part A of the trial described in Example 1 for 90 mg racemic ketamine. [Figure 10A] FIG. 1 is a table illustrating the pharmacokinetic parameters of ketamine on Day 1 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 10B] FIG. 1 is a table illustrating the pharmacokinetic parameters of ketamine on day 4 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 10C] FIG. 1 is a table illustrating the pharmacokinetic parameters of ketamine on Day 8 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 11A]FIG. 1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 1 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus placebo intravenous and ketamine intravenous 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus placebo intranasal. [Figure 11B] FIG. 1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 4 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 11C] FIG. 1 is a table illustrating the pharmacokinetic parameters of norketamine on Day 8 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 12A] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on Day 1 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus placebo intravenous and ketamine 0.3 mg / kg intranasal (equivalent dose to 60 mg intranasal) plus placebo intranasal. [Figure 12B] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on day 4 of Part B of the trial described in Example 1 for racemic ketamine 60 mg intranasal plus placebo intravenous and ketamine 0.3 mg / kg intranasal (equivalent dose to 60 mg intranasal) plus placebo intranasal. [Figure 12C] FIG. 1 is a table illustrating the pharmacokinetic parameters of hydroxynorketamine on Day 8 of Part B of the clinical trial described in Example 1 for racemic ketamine 60 mg intranasal plus intravenous placebo and intravenous ketamine 0.3 mg / kg racemic ketamine (equivalent dose to 60 mg intranasal) plus intranasal placebo. [Figure 13A]1 is a table illustrating the MADRS depression scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 3 of the clinical trial. [Figure 13B] 1 is a graph illustrating the MADRS depression scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 3 of the clinical trial. [Figure 14A] 1 is a table illustrating the CGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 14B] 1 is a graph illustrating the CGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 15A] 1 is a table illustrating the STS suicidality scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 15B] 1 is a graph illustrating the STS suicidality scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 16A] 1 is a table illustrating the PGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 16B] 1 is a graph illustrating the PGIS-SI / B suicidal ideation scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 17] 1 is a table illustrating the CGIC-SI / B suicidal ideation scores for Subject 1 and Subject 2 from Day 1 to Day 8 as described in Example 4 of the clinical trial. [Figure 18] 1 is a table illustrating the PGIC-SI / B scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 3 of the clinical trial. [Figure 19A] 1 is a table illustrating the MADRS item 10 scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 19B] 1 is a graph illustrating MADRS item 10 scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 20A] 1 is a table illustrating the STS-CMCM ("Current Suicide Risk") scores for Subject 1 and Subject 2 on Days 1 through 9 as described in Example 4 of the clinical trial. [Figure 20B] 1 is a graph illustrating the STS-CMCM ("Current Suicide Risk") scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 21A] 1 is a table illustrating the STS-CMCM ("Risk of Suicide Within the Next 7 Days") scores for Subject 1 and Subject 2 from Day 1 through Day 9 as described in Example 4 of the clinical trial. [Figure 21B] 1 is a graph illustrating the STS-CMCM ("Risk of Suicide in the Next 7 Days") scores for Subject 1 and Subject 2 from Day 1 to Day 9 as described in Example 4 of the clinical trial. [Figure 22] 1 is a table illustrating the MOAA / S alertness / sedation scores for Subject 1 and Subject 2 for 24 hours from pre-dose on Days 1 and 4 as described in Example 4 of the clinical trial. [Figure 23] 1 is a table illustrating the CADSS dissociation status scores for Subject 1 and Subject 2 for 24 hours from pre-dose on Days 1 and 4 as described in Example 4 of the clinical trial. [Figure 24] 1 is a table illustrating the C-SSRS scores from days 1 to 9 for subject 1 and days 1 to 4 for subject 2 described in Example 3 of the clinical trial. [Figure 25A] 1 is a table describing preliminary efficacy results for MADRS, CGIS, STS total score, and PGIS for seven subjects from Day 1 through Day 30 as described in Example 4 of the clinical trial. [Figure 25B] 1 is a graph depicting preliminary efficacy results for MADRS, CGIS, STS total score, and PGIS for seven subjects from Day 1 to Day 30 as described in Example 4 of the clinical trial. DETAILED DESCRIPTION OF THE INVENTION

[0021] definition In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly defined herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. For purposes of this disclosure, the following terms are defined:

[0023] Units, prefixes, and symbols are denoted in the format accepted by the Systeme International de Unites (SI). Numerical ranges are inclusive of the numbers defining the range. The headings provided herein do not limit the various aspects of the disclosure, which may be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0024] As used herein, the terms "a," "an," or "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 plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "cell" includes a plurality of such cells, a reference to an "agent" includes a reference to one or more agents known to those of skill in the art, and so forth.

[0025] As used herein, the term "and / or" should be interpreted as a specific disclosure of each of two particular features or components, with or without the other. Thus, when used in a phrase 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, when used in a phrase such as "A, B, and / or C," the term "and / or" is intended to encompass each of the following aspects: 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).

[0026] As used herein, the terms "about" and "approximately" generally refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 10% or 5% of a given value or range of values. Reference to "about X" specifically denotes 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 a written explanation for a claim limitation such as "0.98X." The terms "about" and "approximately," particularly with respect to a given quantity, encompass and describe the given quantity itself.

[0027] When "about" or "approximately" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "about 5 to 20%" is equivalent to "about 5% to about 20%." When "about" is applied to the first value in a set of values, it applies to every value in that set. Thus, "about 5, 10, or 15 mg" is equivalent to "about 5, about 10, or about 15 mg."

[0028] "Racemic 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.

[0029] "Equivalent dose" refers to an equivalent dose of an active agent based on bioavailability. Bioavailability-based equivalent doses can be determined, for example, by comparing the extent and rate of drug absorption of two or more dosages of an active agent (e.g., dosages formulated as an intranasal formulation and an intravenous formulation, respectively), e.g., by comparing the area under the drug blood or plasma concentration-time curve (AUC) and / or maximum concentration (C), respectively. max ) can be determined by determining the AUC and / or C. As used herein, therefore, it is understood that two dosages have AUC and / or C values ​​that are within about 80% to about 125% of each other, respectively. max where x is the dose, there is a bioavailability-based equivalent dose.

[0030] Those skilled in the art will understand that mental disorders as used herein are those described, for example, in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM 5), which is incorporated by reference in its entirety.

[0031] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting, or slowing the onset, progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease. In some embodiments, "treatment" includes elimination of a particular disorder, including reduction in one or more symptoms of the disorder and / or reduction in the severity of one or more symptoms associated with the disorder.

[0032] "Administering" or "administration" refers to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration can include oral, intranasal, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., injection or infusion (e.g., intravenous infusion). Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time. In some embodiments, administration is intranasal.

[0033] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human.

[0034] An "effective amount" or "therapeutically effective amount" of a therapeutic agent is an amount of any drug that, when used alone or in combination with one or more additional therapies, delays the onset of a psychiatric disorder or promotes regression of the disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or an improvement in functional or disability impairment due to the burden of the disease. The ability of one or more additional therapies to promote regression of the disease can be evaluated using a variety of methods known to skilled practitioners, for example, by assessing the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0035] As used herein, a measure of therapeutic effect is "clinically meaningful" based on the practical importance of the therapeutic effect. For example, whether the therapeutic effect has a true, genuine, tangible, and / or noticeable effect on the subject (e.g., a lack of a clinically meaningful effect occurs when the differences in the subject, such as before and after administration of the treatment provided herein, are small enough that they can be considered similar). Those skilled in the art will recognize whether a particular effect is "clinically meaningful." For example, a subject with a baseline score (using any of the scales described herein) indicating severe depression and / or suicidality and a post-treatment score indicating remission of severe depression and / or suicidality is a clinically meaningful effect.

[0036] As used herein, "AUC 0-t " refers to the area under the plasma concentration-time curve from time=0 to the time the last measurable concentration occurs. In some embodiments, the last measurable concentration occurs at time=32 hours (e.g., AUC 0-t =AUC 0-32 ).

[0037] " Unresponsive" subject refers to a subject that has been treated or is currently being treated with one or more therapies that do not bring about clinically meaningful changes toward desired results (for example, a non-responsive subject is resistant to a particular treatment).For example, a subject may not show measurable changes in response to treatment.An unresponsive subject may, for example, show positive changes in depression scale scores, but these changes are not clinically meaningful.

[0038] As used herein, a psychiatric assessment or side effect profile test score that is "substantially similar" or "substantially the same" as a reference score corresponds to the same score, and one of skill in the art understands that while describing a particular value, a particular test score may vary within a reasonable range (e.g., ±10%) due to, for example, experimental error, routine inter-subject evaluation, and routine statistical analysis.

[0039] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0040] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that aids in the administration of an active agent to a cell, organism, or subject. A "pharmaceutically acceptable carrier" refers to a carrier or excipient that can be included in the compositions of the present disclosure and that does not cause significant adverse toxicological effects in the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and colorings, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonicity agents, and absorption delaying agents. Carriers can also be substances that provide stability, sterility, and isotonicity to the formulation (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), prevent the action of microorganisms (e.g., antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc.), or provide edible flavors and the like to the formulation. In some cases, the carrier is an agent that facilitates delivery of the small molecule drug or antibody to the target cell or tissue. Those skilled in the art will recognize that other pharmaceutical carriers are useful in the present disclosure.

[0041] As used in the methods described herein, the term "reducing" refers to a reduction in a given parameter compared to a baseline measurement (or measurements) of the same parameter in a subject taken before the start of administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, or a reduction in a given parameter compared to a baseline measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (e.g., a subject without a psychiatric disorder described herein). In some embodiments, the same parameter is measured in comparison to another therapy (e.g., a standard of care treatment for a psychiatric disorder described herein).

[0042] Similarly, as used herein, the term "increase" refers to an increase in a given parameter compared to a baseline measurement (or measurements) of the same parameter in a subject taken before the start of administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, or an increase in a given parameter compared to a baseline measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (e.g., a subject without a psychiatric disorder described herein). In some embodiments, the same parameter is measured in comparison to another therapy (e.g., a standard of care treatment for a psychiatric disorder described herein).

[0043] The terms "synergy" or "synergistic" are used herein to mean that the combined effect of two therapeutic agents in a combination therapy is greater than the sum of the effects of each agent when administered alone. A "synergistic amount" or "synergistically effective amount" is the amount of a combination of two combination partners that results in 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 can be reliably determined by administering the combination partners at different w / w (weight / weight) ratio ranges and doses to a subject in need of treatment. However, observation of synergistic effects in in vitro or in vivo models can be predictive of effects in humans and other species, and in vitro and in vivo models exist for measuring synergistic effects, as described herein. Exemplary synergistic effects include, but are not limited to, enhanced therapeutic effect, reduced dosage at equivalent or increased levels of efficacy, reduced or delayed development of drug resistance, and simultaneous enhanced or equivalent therapeutic action (e.g., the same therapeutic effect of at least one of the therapeutic agents) and reduced undesired drug effects (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0044] For example, a synergistic ratio of two therapeutic agents can be identified by determining their synergistic effects in, for example, an art-accepted in vivo model (e.g., animal model) of depression (e.g., a mouse model of despair, reward, or anxiety).

[0045] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and fractions thereof (such as integer tenths and hundredths), where appropriate, unless otherwise indicated.

[0046] Unless otherwise specified, any reference to an amount of ketamine in this disclosure is based on the free equivalent amount of ketamine. For example, 30 mg of ketamine refers to 30 mg of ketamine in free form or an equivalent amount of ketamine in salt form (e.g., ketamine hydrochloride).

[0047] Various aspects of the disclosure are described in further detail herein.

[0048] Prologue Mental disorders are a growing public health concern, accounting for approximately 14% of the global disease burden (and growing), with at least 450 million people worldwide affected by mental disorders. See, for example, World Health Organization. WHO. Mental disorders fact sheet. Geneva 27, Switzerland; 2016. Mental disorders are the primary cause of years lived with long-term disability and dependency, including unipolar depression, schizophrenia, and bipolar disorder. See, for example, Mathers, PLoS Med. 2006;3:e442. Individuals with major mental disorders are 40–60% more likely to die prematurely than the general population. See, for example, Semahegn, et al., System. Rev., Vol. 7, No. 10 (2018). Similarly, reduced quality of life is often reported for individuals with mental disorders. For example, the majority of patients with PTSD generally have a significantly impaired quality of life (see Rapaport et al., Am. J. Psychiatry, Vol. 162, pp. 1171-1178 (2005)), and nearly 40% (compared to only 5.4% of individuals without a mental disorder) had missed at least one day of work in the previous month due to emotional problems. See, e.g., Stein, et al., Gen. Hosp. Psychiatry, Vol. 22, pp. 261-269 (2000).

[0049] Subjects with psychiatric disorders may have difficulty maintaining adherence to treatment regimens using currently approved pharmacological interventions. See, for example, Farooq et al., Neuropsychiatr Dis Treat., Vol. 10, pp. 1069-77 (2014). This non-adherence can be due to, for example, cognitive impairment caused by the psychiatric disorder or difficulties due to the significant side effects that many current treatments for psychiatric disorders eventually cause. Many current pharmacological interventions can take weeks to months to achieve full therapeutic benefit, and many subjects tolerate or become resistant to these treatments. See, for example, Kupfer, Dialogues Clin. Neurosci., Vol. 7, No. 3, pp. 191-205 (2005).

[0050] Ketamine has been used as an intravenous, short-acting anesthetic in both humans and animals. In addition to analgesia, ketamine produces a state of "dissociative anesthesia" and is also used as a recreational 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.

[0051] At low doses, ketamine causes mild sedation and euphoria, but at higher doses, individuals experience dissociative effects similar to those of phencyclidine hydrochloride (PCP). Other physical effects of ketamine include vertigo, difficulty with 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 emergencies, such as a floating sensation, vivid dreams, hallucinations, hypertonia, and delirium. These effects can last up to 24 hours after administration. See Perumal, et al., J. Res. Pharm. Pract., Vol. 4, No. 2, pp. 89-93 (2015).

[0052] 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 referred to herein as hydroxynorketamine). The structures of these (racemic) compounds are shown below. [ka]

[0053] Each of these metabolites has a unique receptor binding profile and pharmacological activity. See, e.g., Zanos, et al., Pharmacol. Rev., Vol. 70, No. 3, pp. 621-660 (2018). For example, racemic ketamine has a K of approximately 1.06 μM. i (S)-norketamine and (R)-norketamine bind to NMDA receptors with K values ​​of approximately 2.25 μM and 26.46 μM, respectively. i and (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine have K values ​​of approximately 21.19 μM and greater than 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 exhibit increased locomotion during the anesthetic recovery phase. In contrast, the same dose of 6-hydroxynorketamine does not provide anesthetic activity or locomotor 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).

[0054] This application is based, in part, on the surprising discovery that intranasal administration of racemic ketamine provides advantageous properties (e.g., at least about 95% of (R)-ketamine, or at least about 95% of (S)-ketamine) compared to intravenous administration of racemic ketamine or intranasal administration of (R)- or (S)-ketamine. Furthermore, exploiting the distinct physiological and psychological effects of each enantiomer of ketamine, and their corresponding metabolites, may provide beneficial treatments for the various psychiatric disorders described herein, including treatments with improved onset times and reduced negative side effects.

[0055] formulation Some embodiments provide a pharmaceutical composition comprising about 5% (w / v) to about 20% (w / v) racemic ketamine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is formulated for intranasal administration.

[0056] In some embodiments, the pharmaceutical composition comprises an aqueous solution of racemic ketamine or a pharmaceutically acceptable salt thereof at about 7.5% (w / v) to about 15% (w / v), e.g., 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 therebetween. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 7.5% (w / v) racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 15% (w / v) racemic ketamine or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the formulation provides about 30 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per 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 therebetween. In some embodiments, the formulation provides about 45 mg to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 60 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 30 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose.

[0058] In some embodiments, the formulation provides a total amount of about 30 mg to about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two administrations (e.g., two spray releases from an intranasal delivery device). 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, the formulation provides a total amount of about 45 mg to about 75 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two administrations. In some embodiments, the formulation provides a total amount of about 60 mg to about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, per administration. In some embodiments, the formulation provides a total amount of about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two doses. In some embodiments, the formulation provides about 60 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two doses. In some embodiments, the formulation provides about 75 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two doses. In some embodiments, the formulation provides about 90 mg of racemic ketamine, or a pharmaceutically acceptable salt thereof, over two doses.

[0059] 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, the racemic ketamine is in the form of a pharmaceutically acceptable salt, such as the hydrochloride salt. 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.

[0060] In some embodiments, the composition further comprises one or more excipients selected from the group consisting of surfactants, antioxidants, buffers, and absorption enhancers.

[0061] Exemplary surfactants include, but are not limited to, ionic, nonionic, and amphoteric surfactants, such as 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% surfactant (w / v).

[0062] 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).

[0063] 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).

[0064] 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).

[0065] In some embodiments, the pharmaceutically acceptable carrier is water or saline.

[0066] In some embodiments, the formulation is as set forth in Table 1. [Table 1]

[0067] The formulations listed in Table 1 provide a 15 mg dose per spray, a 30 mg dose in two sprays, a 60 mg dose in four sprays, and a 90 mg dose in six sprays.

[0068] In some embodiments, the formulation is as set forth in Table 2. [Table 2]

[0069] The formulations listed in Table 2 provide a 7.5 mg dose per spray, a 30 mg dose in 4 sprays, a 60 mg dose in 8 sprays, and a 90 mg dose in 12 sprays.

[0070] Treatment method Some embodiments provide a method of treating a psychiatric disorder in a subject in need thereof, comprising intranasally administering a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the psychiatric disorder is major depressive disorder, post-traumatic stress disorder, treatment-resistant depression, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder.

[0071] In some embodiments, the psychiatric disorder is post-traumatic stress disorder, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder.

[0072] In some embodiments, the subject is not currently suffering from depression. In some embodiments, the subject has not been determined to have depression. In some embodiments, the subject has been determined not to have depression. In some embodiments, the subject has not been diagnosed with depression. In some embodiments, the subject has been diagnosed as not having depression.

[0073] In some embodiments, the subject is not currently suffering from suicidal tendencies. In some embodiments, the subject has not been determined to have suicidal tendencies. In some embodiments, the subject has been determined to not have suicidal tendencies. In some embodiments, the subject has not been diagnosed with suicidal tendencies. In some embodiments, the subject has been diagnosed as not having suicidal tendencies.

[0074] In some embodiments, the subject is not currently suffering from suicidal ideation. In some embodiments, the subject has not been determined to have suicidal ideation. In some embodiments, the subject has been determined to not have suicidal ideation. In some embodiments, the subject has not been diagnosed with suicidal ideation. In some embodiments, the subject has been diagnosed as not having suicidal ideation.

[0075] Major depressive disorder Depression is characterized by depressed mood and a marked decrease in interest or pleasure in activities. Other symptoms may include significant weight loss or weight gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, and reduced ability to think or concentrate or indecisiveness. See Kennedy, Dialogues Clin. Neurosci., Vol. 10, No. 3, pp. 271-277 (2008). Various physical symptoms may also be present. While feelings of depression are common, a diagnosis of a depressive disorder is made when symptoms reach a threshold and persist for at least two weeks. The severity of depression ranges from mild to very severe. While most are temporary, it can be recurrent or chronic. More than 50% of people who suffer from a first major depressive episode will eventually experience another depressive episode.

[0076] Some embodiments provide a method of treating major depressive disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the subject meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a current diagnosis of MDD (unipolar without psychotic features), based on a preliminary examination and confirmed with the Mini International Psychiatric Interview Version 7.02 (MINI), with symptoms present for at least 4 weeks.

[0078] Post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental illness that develops after a traumatic event and is characterized by intrusive thoughts related to the event, recurrent distress / anxiety, flashbacks, and avoidance of similar situations. Symptoms usually begin as early as three months after the traumatic event, but can begin years later. PTSD is considered present if symptoms persist for more than a month and are severe enough to interfere with relationships or work. The course of the illness is variable; some people resolve within six months, while others experience longer-lasting symptoms. In some people, the condition becomes chronic and can lead to lifelong disability.

[0079] Some embodiments provide a method of treating post-traumatic stress disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the subject meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a current (i.e., in the last 6 months) diagnosis of PTSD. In some embodiments, if the subject's primary index trauma occurred in childhood and / or more than 15 years prior to screening, the current PTSD symptoms are the result of a more recent trauma that reactivates a prior traumatic response to the initial event. In some embodiments, the subject meets current MINI-confirmed criteria for PTSD-Suicidality Disorder. In some embodiments, the subject meets DSM-5 criteria for a current PTSD diagnosis, based on a prior diagnosis and confirmed with the Mini International Psychiatric Interview Version 7.02 for Suicidality Disorders (MINI). In some embodiments, the subject's PTSD and suicidality diagnoses are considered primary (i.e., the main cause of their current symptoms and impairment).

[0081] Treatment-resistant depression Treatment-resistant depression (TRD) applies to individuals with major depressive disorder (MDD) who have not responded to at least two medications (usually two antidepressants from two different drug classes). According to a 2021 clinical trial published in the Journal of Clinical Psychiatry, 30.9% of people in the United States taking medication for MDD have treatment-resistant depression. MDD can be unipolar, meaning it does not cycle back and forth between mania and depression, or bipolar, meaning it cycles back and forth between mania and depression.

[0082] Some embodiments provide a method for treating treatment-resistant depression in a subject in need thereof, comprising intranasally administering a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the TRD is treatment-resistant unipolar depression. In some embodiments, the TRD is treatment-resistant bipolar depression.

[0083] Bipolar depression Bipolar disorder, formerly known as manic depression, is a mental illness that causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). Symptoms cause unpredictable changes in mood and behavior, which can lead to significant distress and difficulty in living. In some cases, mania can lead to a disconnect from reality, i.e., psychosis.

[0084] Some embodiments provide a method of treating bipolar depression in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0085] Postpartum depression Postnatal depression is a mental illness affecting first-time mothers that is characterized by mood swings, constant crying, anxiety, irritability, difficulty concentrating, feelings of sadness, and sleep disturbances. Symptoms usually begin within a few weeks of giving birth, but can also begin earlier (during pregnancy) or up to a year after giving birth.

[0086] Some embodiments provide a method of treating postpartum depression in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0087] chronic pain Chronic pain is defined as pain that lasts for more than several months, i.e., pain that persists beyond "normal healing," typically lasting at least 3-6 months. It is estimated that over the last three months, more than 25 million U.S. adults experienced daily pain, and nearly 40 million adults experienced severe pain during the same period. Chronic pain can interfere with daily life and can lead to depression, anxiety, and other mental disorders.

[0088] Some embodiments provide a method of treating chronic pain in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0089] neuropathic pain Neuropathic pain occurs when the nervous system is damaged or malfunctions. Damaged nerve fibers send erroneous signals to pain centers. Nerve function can be altered at the site of nerve injury and in other areas of the central nervous system (central sensitization). Neuropathic pain can manifest as spontaneous pain (pain that occurs without any stimulus present), e.g., shooting, burning, stabbing, or electric shock-like pain, or as a tingling, numbing, or "pins and needles" sensation. Neuropathic pain can also manifest as evoked pain, i.e., pain elicited by a normally non-painful stimulus (allodynia), such as cold, a gentle brushing of the skin, or pressure. Elicited pain can also refer to increased pain (hyperalgesia) in response to a normally painful stimulus, such as a sting or heat. This condition often leads to sleep disturbances and emotional pain-related problems.

[0090] Some embodiments provide a method of treating neuropathic pain in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0091] Rett syndrome Rett syndrome is a neurodevelopmental disorder that affects mostly girls. It is relatively rare, occurring in approximately 1 in 10,000 to 15,000 live births in girls worldwide and across all racial and ethnic groups. A congenital disorder caused by mutations in the MECP2 gene, Rett syndrome is characterized by normal early growth and development, followed by slowed development, loss of the ability to use the hands purposefully, characteristic hand movements, delayed brain and head growth, gait disturbances, seizures, and intellectual disability. There is no cure for Rett syndrome. Treatment of the disorder focuses on managing symptoms.

[0092] Some embodiments provide a method of treating Rett syndrome in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0093] epilepsy Epilepsy is a neurological disorder in which abnormal brain activity leads to seizures and periods of abnormal behavior, sensations, and sometimes loss of consciousness. Epilepsy affects both men and women of all races, ethnic backgrounds, and ages. Symptoms range from mild, such as a blank stare for a few seconds during a seizure, to severe, such as repeated jerking of the arms and legs. Approximately half of people with epilepsy have no identifiable cause. In the other half, various factors, including genetics, head trauma, brain abnormalities, infections, prenatal injuries, and developmental disorders, contribute to these conditions. Depending on when and where they occur, epileptic seizures can be dangerous and can lead to drowning, falls, and traffic accidents. People with epilepsy are also more likely to experience psychological problems, particularly depression, anxiety, and suicidal thoughts and behaviors.

[0094] Some embodiments provide a method of treating epilepsy in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0095] Dementia-related agitation Dementia-related agitation is one of a larger group of behavioral and psychological symptoms associated with all major forms of dementia. According to some observations, the prevalence of agitation ranges from 30% to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of approximately 30%, it is the third most common neuropsychiatric symptom (NPS) in dementia, after apathy and depression, and is even more prevalent (80%) among nursing home residents. Agitation negatively impacts cognitive ability, functional status, and quality of life for patients, placing a significant burden on caregivers. Furthermore, agitation is associated with increased rates of nursing home admission, increased medication use, prolonged hospital stays, and increased mortality.

[0096] Some embodiments provide a method of treating agitation associated with dementia in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0097] Agitation associated with schizophrenia Agitation, defined as excessive motor and verbal activity, is frequently observed in psychiatric patients and impacts the treatment of schizophrenia. Individuals with schizophrenia are vulnerable to episodes of agitation, defined as excessive verbal and motor behavior, especially during exacerbations of the illness. Psychosis-related agitation is often recognized as a reason for psychiatric patients to visit the emergency department (ED) and requires immediate intervention to prevent it from escalating to a level that could endanger patients, staff, and others.

[0098] Some embodiments provide a method of treating agitation associated with schizophrenia in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0099] Agitation associated with bipolar disorder Agitation is a common symptom of bipolar disorder and can include symptoms ranging from inner tension and anxiety to violence and aggression. Agitation is common in bipolar disorder patients during acute manic episodes, when increased energy levels and decreased need for sleep can lead to patients becoming irritable and confrontational. Agitation also occurs during mixed and depressive episodes, which are characterized by fluctuating energy levels and periods of irritability.

[0100] Some embodiments provide a method of treating agitation associated with bipolar disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, subjects meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for bipolar disorder I or II for a diagnosis of a current major depressive episode (i.e., four or more mood disorder episodes in the 12 months prior to screening, without psychotic features and without a rapidly cycling illness course), based on a prior examination and confirmed with the Mini International Psychiatric Interview Version 7.02 (MINI), with symptoms present for at least four weeks.

[0102] Additional Methods and Embodiments In some embodiments, the subject has been previously diagnosed with and / or currently suffers from post-traumatic stress disorder. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from major depressive disorder. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from treatment-resistant depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from bipolar depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from post-partum depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from post-partum depression. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from post-partum depression and is not breastfeeding. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from chronic pain. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from neuropathic pain. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from Rett syndrome. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from epilepsy. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from dementia-related agitation. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from schizophrenia-related agitation. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from bipolar disorder-related agitation.

[0103] In some embodiments, the subject has not been previously diagnosed with suicidal tendencies. In some embodiments, the subject has not been previously diagnosed with suicidal ideation. In some embodiments, the subject has not previously exhibited suicidal tendencies. In some embodiments, the subject has not previously exhibited suicidal ideation. In some embodiments, the subject is not currently suffering from suicidal tendencies. In some embodiments, the subject is not currently suffering from suicidal ideation.

[0104] In some embodiments described herein, the psychiatric disorder resolves more rapidly than the resolution observed after intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject's MDD, PTSD, TRD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder resolves more rapidly.

[0105] In some embodiments, the psychotic disorder resolves from about 1.2 times faster to about 10 times faster, e.g., 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 therebetween, compared to the resolution observed following administration of an equivalent dose of intravenous racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments described herein, the psychiatric 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 agitation associated with MDD, PTSD, TRD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, dementia, schizophrenia, or bipolar disorder resolves more rapidly. In some embodiments, the psychotic disorder resolves from about 1.2 times faster to about 10 times faster, e.g., 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 therebetween, compared to the resolution observed after administration of an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments described herein, subject compliance with treatment for a psychiatric disorder is improved compared to an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments described herein, subject compliance with treatment for a psychiatric disorder is improved compared to an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, agitation associated with MDD, PTSD, TRD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, dementia, schizophrenia, or bipolar disorder is improved.

[0108] In some embodiments, the subject has a weight of about 18.0 to about 40.0 kg / m 2 have a BMI of.

[0109] In some embodiments, the subject has not undergone electroconvulsive therapy (ECT).

[0110] scale Many methods can be used to assess and / or measure the mental state of a subject as described herein. Non-limiting examples include the Mini International Psychiatric Interview Version 7.02 for Suicidality Disorders (MINI); Clinical Global Impression (CGI); Profile of Mood States (POMS) (e.g., POMS 2nd Edition); CGIS; CGIC; Patient Global Impression (PGI); PGIS; PGIC; Choice Reaction Time (CRT) Test; Columbia-Suicide Severity Rating Scale (C-SSRS); Montgomery-Asberg Depression Rating Scale (MADRS); Sheehan Suicide Tracking Scale Clinically Meaningful Change Measure (STS-CMCM, also known as S-STS CMCM) (e.g., Ghasemi et al., Health See Promot. Perspect., Vol. 5, No. 3, pp. 156-168 (2015), which is incorporated herein by reference in its entirety; Sheehan Disability Scale (SDS); QIDS-SR16 (Quick Inventory of Depressive Symptoms - Self-Report); Hamilton Depression Rating Scale (HAM-D17) total score change; Snaith-Hamilton Pleasure Scale (SHAPS) score change from baseline to 6 weeks of treatment; Patient Health Questionnaire 9-Item (PHQ-9) at week 6;Quality of Life Scale (QOLS); Hamilton Depression Rating Scale - Suicidal Ideation (HDRS-SI); Sternberg short-term memory task (SSTM); CRPS Severity Score (CSS); HDRS-28 total; Depression Score Using Goldenberg Depression Screening Test; Change in Beck Scale for Suicidal Ideation (BSSI); Quick Inventory of Depression Symptomatology (QIDS); Change from baseline in sleep disturbance using Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD); and Patient-Reported Outcomes Measurement Information System 29. Change from randomization at each study visit in the total score of the Inventory of Depressive Symptomatology-Self-Rated (IDS-SR30); Pelvic Pain and Urgency / Frequency (PUF) Patient Symptom Scale; Quality of life enjoyment and satisfaction survey (Q-LES-Q); and percentage change on the Hamilton Depression Scale.Change from baseline in anxiety symptoms measured with the Richmond Agitation-Sedation Scale (RASS); change from baseline in anxiety symptoms measured with the Hamilton Anxiety 14-Item Scale (HAM-A); change from baseline in Patient's Global Impression of Change in Suicidal Ideation and Behavior (PGIC-SI / B); change from baseline in sleep quality measured with the Pittsburgh Sleep Quality Index; quality of life on the Inventory of Depressive Symptoms (Self-Report) (IDS-SR) 10-item scale; total score on the Inventory of Depressive Symptoms (Self-Report) (IDS-SR); change on the Brief Psychotic Rating Scale (BPRS); Pain Catastrophizing Scale (PCS); and the Hamilton Anxiety Symptom Scale (Hamilton Change from baseline in the non-responder total score at week 6 on the Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) scale; Clinician Administered Dissociative States Scale (CADSS); and Change from baseline in the non-responder total score at week 6 on the Multidimensional Assessment of Fatigue (MAF) scale.Patient's Global Impression of Severity in Suicidal Ideation and Behavior (PGIS-SI / B); Beck Depression Inventory (BDI); Modified Bond-Lader Visual Analog Scale Score; Young Mania Rating Scale (YMRS); Systematic Assessment for Treatment Emergent Effects (SAFTEE); Edinburgh Postnatal Depression Scale (EPDS); Patient Global Impression Severity (PGIS); Beck Anxiety Inventory; Change in Cortisol (CRT) during the Trier Social Stress Test (TSST); and Social Functioning Based on the Postpartum Adjustment Questionnaire. Postpartum Adjustment Questionnaire; Impact of Event Scale-Revised (IES-R); Chronic Pain Acceptance Questionnaire (CPAQ); Total Pain Relief at 8 Hours (TOTPAR); Average Daily Pain Score (ADPS); Percent Change from Baseline in Numeric Pain Rating Scale (NPRS) Score for "Average Pain in the Last 24 Hours"; Pain Intensity Score using the Short-Form McGill Pain Questionnaire (SF-MPQ);The following measures were assessed: Rett Syndrome Gross Motor Scale (RSGMS); Rett Syndrome Behaviour Questionnaire (RSBQ) total score; gait speed measured with the GAITRite system; Motor Behaviour Assessment Scale (MBA); delay between seizure end point and recovery of oxygen saturation (SpO2); proportion of seizure-free patients; time to first seizure appearance; proportion of seizure-free participants for Primary Generalised Tonic Clonic (PGTC) seizures; reduction in seizure frequency; fatigue score effect; Modified Fatigue Impact Scale (M-FIS) effect; anxiety-depression; Hospital anxiety and depression scale (HAD); and quality of life in epilepsy, including seven subscores (QOLIE). 31: a global score calculated based on the mean of each subscore; the number of participants using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5); the Impact of Event Scale-Revised (IES-R); the Patient-Rated Inventory of Side Effects (PRISE); the Davidson Trauma Scale (DTS); the Connor-Davidson Resilience Scale (CD-RISC); the 36-item Short Form Health Survey (SF-36); the Pittsburgh Sleep Quality Index; and the Work Productivity and Activity Improvement Questionnaire (WPAI).These included incidence of adverse events as assessed by the 4-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS); mean change from baseline in Cohen-Mansfield Agitation Inventory (CMAI) score after 14 weeks of treatment; Mini-Mental State Examination (MMSE) score; and change from baseline in PANSS-EC. Those skilled in the art will appreciate that various scales and combinations of scales are useful for diagnosis, patient stratification, and psychiatric assessment. It will be appreciated that the present invention can be used to monitor treatment of a disorder, including, for example, using a scale for measuring depression (such as the MADRS) to assess depression in a subject with another psychiatric disorder (such as PTSD) in which depression may be an aspect of that disorder.

[0111] The Montgomery-Asberg Depression Rating Scale (MADRS) is used to assess the severity of depression in subjects diagnosed with depression. The MADRS contains 10 items and is scored after the interview using a severity scale of 0 to 6. Higher scores indicate more depressive symptoms. Ratings can be added to form a composite score (ranging from 0 to 60); no weighting is used. Cutoff points are 0-6—no symptoms, 7-19—mild depression, 20-34—moderate depression, and 35-60—severe depression.

[0112] The MADRS is a diagnostic questionnaire that can be used to measure the severity of a subject's depressive episode. In some embodiments, the MADRS can be used to measure the severity of depressive symptoms in subjects suffering from, for example, MDD, TRD, bipolar depression, and other psychiatric disorders described herein that have a depressive component. In some embodiments, the MADRS can be used to measure TRD. In some embodiments, the MADRS can be used to measure other psychiatric disorders, as described herein. For example, the MADRS includes 10 items: 1) outward sadness (e.g., expressing despondency, melancholy, or despair beyond the usual momentary low mood reflected in speech, facial expression, or posture); 2) verbal sadness (e.g., expressing verbal reports of depressed mood, whether or not expressed outwardly, including feelings of dejection, lack of energy, or helplessness or hopelessness); 3) inner tension (e.g., expressing mental tension ranging from vague discomfort, irritability, inner confusion, panic, fear, or anguish); 4) decreased sleep (e.g., experiencing a decrease in the duration or depth of sleep compared to one's own normal pattern when healthy); 5) decreased appetite (e.g., experiencing a decrease in appetite compared to when healthy). (e.g., feeling of loss of appetite due to lack of appetite), 6) difficulty concentrating (e.g., difficulty gathering one's thoughts resulting in a disruptive lack of concentration), 7) fatigue (e.g., difficulty initiating or slowness in initiating and performing daily activities), 8) inability to have emotions (e.g., subjective experience of decreased interest in one's surroundings or in activities that usually bring pleasure, accompanied by a diminished ability to respond emotionally appropriate to situations or people), 9) pessimistic thinking (e.g., thoughts of guilt, inferiority, self-blame, sinfulness, regret, and destruction), and 10) suicidal thoughts (e.g., feeling that life is meaningless, that one would be happy to die naturally at any time, suicidal thoughts, and preparations for suicide). Each item is rated from 0 to 6, with 0 indicating that the subject is not at all like the item described and 6 indicating that the subject is very similar to the item described.For example, for outward sadness, a score of 0 indicates that the subject never displays sadness, while a score of 6 indicates that the subject always appears depressed, e.g., the subject is very dejected. As another example, for suicidal thoughts, a score of 0 indicates that the subject enjoys life or accepts it as it is, a score of 2 could indicate that the subject is fed up with life and may have fleeting suicidal thoughts, a score of 4 indicates that the subject would probably prefer to die (e.g., suicidal thoughts are common and suicide is considered a possible solution, but there is no specific plan or intent), and a score of 6 indicates that the subject has a clear plan to commit suicide if the opportunity arises (e.g., the subject is actively preparing to commit suicide). Thus, after adding up the individual scores for each item, the total score would be on a scale of 0 to 60. In some embodiments, a MADRS total score of about 0 to about 6 for a subject reflects that the subject has no symptoms associated with depression, a score of about 7 to about 19 reflects that the subject is suffering from mild depression, a score of about 20 to about 34 reflects that the subject is suffering from moderate depression, and a score of about 34 to about 60 reflects that the subject is suffering from severe depression. "MADRS total score" and "total MADRS score" are used interchangeably herein.

[0113] In some embodiments, the subject's MADRS total score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 20 and 60 units.

[0114] In some embodiments, the subject's MADRS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30-60 units. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is reduced by at least 50%. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is 15 units or less. In some embodiments, 48 ​​hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is 12 units or less.

[0115] In some embodiments, the subject's MADRS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 28 units and 35 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is reduced by at least 50%. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is 8 units or less. In some embodiments, 48 ​​hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is 6 units or less.

[0116] In some embodiments, the subject's MADRS total score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 28 to 35 units, and after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject's MADRS total score is reduced by 10 to 20 units, e.g., 10 units, 15 units, or 20 units.

[0117] In some embodiments, the subject's MADRS total score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 28 to 35 units, and the subject's MADRS total score about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 to 20 units.

[0118] In some embodiments, the subject's MADRS total score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 28 to 35 units, and the subject's MADRS total score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 units to 20 units.

[0119] In some embodiments, the subject's total MADRS score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein, is between 10 and 60. For example, prior to intranasal administration of racemic ketamine as described herein, the total MADRS score is between 10 and 20, 10 and 30, 10 and 40, 10 and 50, 50 and 60, 40 and 60, 30 and 60, or 20 and 60. In some embodiments, the subject's total MADRS score prior to intranasal administration of racemic ketamine as described herein is between 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60. In some embodiments, the subject's total MADRS score prior to administration of intranasal racemic ketamine, prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between about 25 and about 35.

[0120] In some embodiments, the subject's MADRS total score is measured about 5 minutes to about 24 hours before intranasal administration of racemic ketamine 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score is measured as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the subject's MADRS total score is about 0 to about 6 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. For example, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein, the score is 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 subject's MADRS total score is 0, 1, 2, 3, 4, 5, or 6 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's MADRS total score is measured about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score is as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the subject's MADRS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is about 10 to about 60, and the subject's MADRS total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is about 0 to about 6. For example, the subject's MADRS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof described herein 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, and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof described herein is 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 subject's MADRS total score before intranasal administration of racemic ketamine described herein is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60, and the subject's MADRS total score after intranasal administration of racemic ketamine described herein is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the subject's MADRS total score is measured from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, 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 racemic ketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's MADRS total score is as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the subject's MADRS total score is reduced by about 1 to about 60 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. For example, the subject's MADRS total score may be reduced by about 1 to about 60 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, compared to before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score 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, 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score is reduced (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof) about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS total score is reduced by about 20 points to about 30 points, e.g., about 20-25 points, about 22-27 points, or about 25-30 points, 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, item 10 of the MADRS, e.g., the MADRS for suicidal ideation, can be used to measure MDD. In some embodiments, item 10 of the MADRS, e.g., the MADRS for suicidal ideation, can be used to measure TRD. In some embodiments, item 10 of the MADRS, e.g., the MADRS for suicidal ideation, can be used to measure other psychiatric disorders described herein. In some embodiments, a subject's score on item 10 of the MADRS is 0 or 1 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, a subject's score on item 10 of the MADRS is as described herein about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the score on item 10 on the MADRS for the subject is as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, a subject's MADRS item 10 score is reduced by 1 to 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's MADRS item 10 score may be reduced by about 1 to about 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS item 10 score 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS item 10 score 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, 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the score on item 10 on the MADRS for the subject is reduced (e.g., compared to before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof) about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein.

[0126] In some embodiments, the subject's MADRS Item 10 score is reduced by 4, 5, or 6 points 24 hours after intranasal administration of racemic ketamine. In some embodiments, the subject's MADRS Item 10 score is reduced by 4 points. In some embodiments, the subject's MADRS Item 10 score is reduced by 5 points. In some embodiments, the subject's MADRS Item 10 score is reduced by 6 points.

[0127] In some embodiments, a subject undergoes a MADRS prior to intranasal administration of racemic ketamine as described herein. For example, a MADRS can be administered to a subject from about 1 hour to about 6 months before intranasal administration of racemic ketamine as described herein. In some embodiments, a MADRS is administered to a 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 about 1 day to about 6 months before intranasal administration of racemic ketamine as described herein.

[0128] In some embodiments, the subject's MADRS item 10 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 4, 5, or 6 units. In some embodiments, the subject's MADRS item 10 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 5 or 6 units. In some embodiments, within 4 hours of intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject's MADRS item 10 score is reduced by at least 1 unit.

[0129] In some embodiments, the subject's MADRS item 10 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units. In some embodiments, the subject's MADRS item 10 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 1 or 2 units. In some embodiments, within about 4 hours of intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject's MADRS item 10 score is reduced by at least 1 unit.

[0130] In some embodiments, the subject's MADRS item 10 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units and is reduced by 1 to 2 units after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the subject's MADRS item 10 score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 or 3 units and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 unit to 2 units.

[0132] In some embodiments, the subject's MADRS item 10 score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units and is reduced by 1 to 2 units about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0133] The Clinician-Administered PTSD Scale (CAPS, also referred to as CAPS-5 when following DSM-5) is a structured diagnostic interview that assesses the condition and symptom severity associated with PTSD. The CAPS includes: (a) assessments of all PTSD criteria, as well as associated features such as dissociation; (b) global assessments of distress, impairment, appropriateness of responses, symptom severity, and improvement since the previous assessment; (c) both dichotomous (presence / absence) and continuous assessments of individual symptoms and overall impairment; (d) individualized assessments of symptom frequency and intensity; (e) behaviorally-oriented questions and rating scales; and (f) trauma-related assessments of individual symptoms not inherently related to the trauma (e.g., loss of interest, feelings of isolation, difficulty concentrating). See Weathers, et al., Psychol. Assess. 2018; Vol. 30, No. 3, pp. 383–95.

[0134] CAPS uses a 0-4 point scale to assess the frequency and intensity of symptoms, with 0 = no symptoms, 1 = mild / subthreshold, 2 = moderate / threshold, 3 = severe / markedly elevated, and 4 = severe / unassessable.

[0135] Frequency and intensity thresholds for two major severity ratings (2 = moderate / threshold and 3 = severe / markedly elevated) are included in the written interview for each symptom, allowing the interviewer to directly reference the rating and assign the appropriate severity rating. For example, a severity rating of 2 generally requires a minimum frequency of at least twice per month or some time (20%-30%) and an intensity that is at least clearly present. Similarly, a severity rating of 3 generally requires a minimum frequency of at least twice per week and an intensity that is at least prominent. Finally, a severity rating of 2 or higher is considered to be symptomatic and effectively constitutes a PTSD diagnosis.

[0136] In some embodiments, the subject prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, has an average CAPS of 3 or 4. In some embodiments, the subject about 24 hours after the first intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, has an average CAPS of 0 or 1.

[0137] In some embodiments, the subject's baseline CAPS-5 severity is 3. In some embodiments, the subject's baseline CAPS-5 severity is 4.

[0138] The CGIS-SI / B scale is a five-item clinician-assessed scale of the severity of symptoms specific to suicidality. Clinicians assess the most severe level of suicidality experienced by a subject during a designated look-back period (e.g., at screening, baseline, or before intranasal administration of racemic ketamine as described herein), and responses are reported on a 5-point Likert-type scale ranging from 1 (not at all suicidal) to 5 (most suicidal). Clinicians can then assess the extent to which the subject's suicidality has changed compared to baseline on a 7-point Likert-type scale ranging from 1 (very improved) to 7 (very worse). See, e.g., Meltzer et al. Arch Gen Psychiatry. 2003;60(1):82-91.

[0139] In some embodiments, the subject's Clinical Global Impression of Severity for Suicide Ideation and Behavior (CGIS-SI / B) score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or 5 units. In some embodiments, the subject's CGIS-SI / B score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is 4 or 5 about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the subject's CGIS-SI / B score is reduced by 1 to 4 (e.g., 1 to 4 units) after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is reduced by 1 to 3 (e.g., 1 to 3 units) after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is reduced by 1 to 2 (e.g., 1 to 2 units) after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is reduced by 3 or 4 units about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is reduced by 3 units. In some embodiments, the subject's CGIS-SI / B score is reduced by 4 units.

[0141] In some embodiments, the subject has a CGIS-SI / B score of 1 or 2 units 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the subject's Clinical Global Impression of Severity of Suicidal Ideation and Behavior (CGIS-SI / B) score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units. In some embodiments, the subject's CGIS-SI / B score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 1 or 2 units.

[0143] In some embodiments, the subject's Clinical Global Impression of Severity for Suicide Ideation and Behavior (CGIS-SI / B) score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units, and is reduced by 1 to 2 units after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the CGIS-SI / B score is 3 or greater (e.g., 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and is reduced by 1 to 4 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 4 or greater (e.g., 4 or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and is reduced by 1 to 4, e.g., 1, 2, 3, or 4, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 2-5 (e.g., 2, 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and is reduced by 1 to 4, e.g., 1, 2, 3, or 4, after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof, and is reduced by 1, 2, 3, or 4 about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 2, 3, 4, or 5 about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and is reduced by 1, 2, 3, or 4 about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the subject's Clinical Global Impression of Severity for Suicide Ideation and Behavior (CGIS-SI / B) score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 units, and is reduced by 1 unit to 2 units about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the CGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2 or 3, and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2. In some embodiments, the Clinical Global Impression of Severity for Suicide Ideation and Behavior (CGIS-SI / B) score about 1 to about 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 racemic ketamine or a pharmaceutically acceptable salt thereof is 2 or 3 units, and is reduced by 1 or 2 units about 1 to about 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2 or 3 and is reduced by 1 or 2 about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, a first CGIS-SI / B score is determined about 1 hour to about 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and a second CGIS-SI / B score is determined about 1 hour to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a first CGIS-SI / B score from a subject is determined about 4 hours to about 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a second CGIS-SI / B score from a subject is determined about 4 hours to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first CGIS-SI / B score and the second CGIS-SI / B score are determined at equivalent times, e.g., 4 hours, before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof. 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 racemic ketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0148] The Sheehan Suicidality Tracking Scale (Sheehan-STS, S-STS) is a promising assessment scale for tracking both treatment-emergent suicidal ideation and behavior. The Sheehan-STS is a scale consisting of 14 core items and 9 additional questions requiring confident responses that can be administered through either clinician or patient self-report. Each item on the Sheehan-STS is scored on a 5-point Likert scale (0 = not at all, 1 = not very much, 2 = somewhat, 3 = very much, and 4 = extremely).

[0149] The CMCM version of the S-STS (S-STS CMCM) includes four sections and can 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 S-STS CMCM (version 01 / 01 / 19) is a clinician-rated outcome scale that assesses suicidality / behavior using multiple patient- and clinician-rated items. It includes 13 suicidality items rated on a Likert-type scale from "not at all" (0) to "very much" (4), with a total score ranging from 0 to 52. The final six items are used only if the patient misses a visit and is unable to complete the scale. If the missed visit is due to a suicide attempt or completed suicide, the maximum possible score is 100. The CMCM also yields five different single-item global ratings: 1) subject-rated likelihood of suicide attempt, 2) subject-rated treatment needed, 3) clinician-rated overall severity of suicidal impulses, thoughts, and behaviors, 4) clinician's judgment of current suicide risk and level of management needed for suicidal ideation, and 5) clinician's judgment of the likelihood that the subject will attempt suicide or die by suicide within the next 7 days.

[0150] In some embodiments, the subject's Sheehan Suicidality Tracking Scale, Clinically Meaningful Change Measure (STS-CMCM) score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 to 52 units. In some embodiments, the subject's STS-CMCM score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 to 52 units. In some embodiments, the subject's STS-CMCM score is reduced by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 to 3 units.

[0151] In some embodiments, the subject's STS-CMCM score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by at least 1. For example, the subject's STS-CMCM score may be reduced by at least 2, at least 3, at least 4, or at least 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score 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, 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score is reduced (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof) about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject undergoes STS-CMCM before intranasal administration of racemic ketamine as described herein. For example, STS-CMCM can be administered to the subject about 1 hour to about 6 months before intranasal administration of racemic ketamine as described herein. In some embodiments, the STS-CMCM is administered to the subject 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 about 1 day to about 6 months prior to the intranasal administration of racemic ketamine described herein. In some embodiments, the subject's STS-CMCM score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 10 units and 20 units. In some embodiments, the subject's STS-CMCM score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 5 units and 10 units.In some embodiments, the subject's STS-CMCM score is reduced by at least 50% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score is reduced by 1 unit to 2 units about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the subject's STS-CMCM score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 10 units and 20 units, and is reduced by between 5 units and 10 units, e.g., 5, 6, 7, 8, 9, or 10 units, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the subject's STS-CMCM score from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 10 units to 20 units, and is reduced by 5, 6, 7, 8, or 10 units from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the subject's STS-CMCM score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 to 20 units and about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5, 6, 7, 8, 9, or 10 units.

[0155] In some embodiments, about 24 hours after intranasal administration of racemic ketamine, the subject's STS-CMCM total score is reduced by about 15 units to about 25 units, hi some embodiments, the STS-CMCM total score is reduced by about 15 units to about 20 units, about 17 units to about 22 units, or about 20 units to about 25 units.

[0156] In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 5-10 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is reduced by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 0-2 units 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 0 or 1 unit 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 3 units to 5 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is reduced by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 0 units or 1 unit 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is 0 units 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is reduced by 3 units to 5 units before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and by 2 units to 4 units, e.g., 2, 3, or 4 units, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is reduced by 3 units to 5 units about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and by 2, 3, or 4 units about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the subject's STS-CMCM suicide risk score within the next 7 days is reduced by 3 units to 5 units about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and by 2, 3, or 4 units about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0161] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation and behavior assessment scale used to measure suicidality and / or suicidal ideation in subjects, specifically assessing the severity and intensity of suicidal ideation, the type of suicidal behavior, and the lethality of suicide attempts. For example, the C-SSRS can assess the lethality of suicide attempts as well as other characteristics of suicidal ideation, such as frequency, duration, controllability, reasons for suicidal ideation, and deterrence, all of which can be highly predictive of completed suicide. See, e.g., https: / / cssrs.columbia.edu / wp-content / uploads / C-SSRS-Baseline-Screening_AU5.1_eng-USori.pdf and https: / / cssrs.columbia.edu / wp-content / uploads / C-SSRS-1-14-09-SinceLastVisit_AU5.1_eng-USori-1.pdf.

[0162] The C-SSRS provides several questions directed at suicidal ideation to which the subject responds with a "yes" or "no." Such questions are directed at wishing to die, nonspecific active suicidal thoughts, active suicidal ideation by any means (no plan) without any intention to act, active suicidal ideation with some intention to act but no specific plan, and active suicidal ideation with a specific plan or intention. Additionally, the CSSRS includes subject-rated indicators that help assess the intensity of the ideation. These symptoms include questions about frequency (e.g., less than once a week, once a week, 2–5 times a week, daily or almost daily, many times daily), duration (e.g., fleeting, less than 1 hour, 1–4 hours, 4–8 hours, 8 hours or more), controllability (e.g., can control thoughts easily, can control thoughts with little difficulty, can control thoughts with some difficulty, have very difficult thoughts, cannot control thoughts, and do not try to control thoughts), deterrence (e.g., deterrence definitely stopped you from attempting suicide, deterrence probably stopped you, uncertain deterrence stopped you, deterrence probably did not stop you, and deterrence definitely did not stop you), and reason for the ideation (e.g., completely to get attention, mainly to get attention, equal parts to get attention and to end / stop the pain, mainly to end / stop the pain, and completely to end / stop the pain). The CSSRS can also include questions about suicidal behavior and actual suicide attempts, such as asking whether a suicide attempt was made, asking whether anything was done to harm oneself, and asking whether the subject did anything dangerous where they might have died.

[0163] In some embodiments, the C-SSRS score is 0 to 2 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject answers "yes" to 0, 1, or 2 questions prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to 0 questions on the C-SSRS described herein about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine 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 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to 0 questions on the C-SSRS described herein about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the subject's C-SSRS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 2 and 9 units. In some embodiments, the subject's C-SSRS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 2 and 5 units. In some embodiments, the subject's CSSR-S score 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is zero units.

[0165] In some embodiments, the subject's C-SSRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units).

[0166] In some embodiments, a first C-SSRS score is determined about 1 hour to about 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and a second C-SSRS score is determined about 1 hour to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a first C-SSRS score from the subject is determined about 4 hours to about 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a second C-SSRS score from the subject is determined about 4 hours to about 8 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first C-SSRS score and the second C-SSRS score are determined at equivalent times, e.g., 4 hours, before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first C-SSRS score and the second C-SSRS score are determined at different times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0167] Two versions of the C-SSRS can be used: the baseline version assesses a subject's lifetime and past month and past 12-month suicidal thoughts and behaviors, and the "Since Last Visit" version assesses any suicidal thoughts or behaviors that may have occurred since the subject was administered the CCSRS. For example, if a suicide attempt occurs after the baseline version of the C-SSRS is administered, the subject only needs to answer "yes" when asked about making a suicide attempt on the "Since Last Visit" version. In some embodiments, subjects are administered the baseline version of the C-SSRS before intranasal administration of racemic ketamine, as described herein. For example, the baseline version of the C-SSRS can be administered about 1 hour to about 6 months before intranasal administration of racemic ketamine, as described herein. In some embodiments, the baseline version of the C-SSRS is administered from about 1 hour to about 6 hours, from about 1 hour to about 1 day, from about 1 hour to about 1 week, from about 1 hour to about 1 month, from about 1 hour to about 3 months, from about 3 months to about 6 months, from about 1 month to about 6 months, from about 1 week to about 5 months, or from about 1 day to about 6 months prior to the intranasal administration of racemic ketamine described herein.

[0168] In some embodiments, occurrence of post-baseline suicidal ideation is defined as answering "yes" to at least one of five suicidal ideation subcategories (i.e., wish to die, nonspecific active suicidal thoughts, active suicidal ideation by any means without intent to act, active suicidal ideation with some intent to act but no specific plan, and active suicidal ideation with a specific plan or intention) when administering a C-SSRS after the baseline C-SSRS. In some embodiments, occurrence of post-baseline suicidal behavior is defined as answering "yes" to at least one of six suicidal behavior subcategories (i.e., actual attempt, aborted attempt, thwarted attempt, and preparatory behavior or act) when administering a C-SSRS after the baseline C-SSRS. In some embodiments, the C-SSRS is completed by a trained rater based on responses from the subject.

[0169] In some embodiments, the subsequent version of the C-SSRS is administered to the subject after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the C-SSRS is administered to the subject about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, to the subject. 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 racemic ketamine, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the C-SSRS is administered to the subject 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 racemic ketamine, or a pharmaceutically acceptable salt thereof, to the subject.

[0170] In some embodiments, the C-SSRS score is about 0 to about 2 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. For example, the subject answers "yes" to 0, 1, or 2 questions on the C-SSRS after intranasal administration of racemic ketamine, as described herein. In some embodiments, the subject's C-SSRS score is as described herein about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers "yes" to 0, 1, or 2 questions on the C-SSRS about 1 hour to about 4 hours, about 2 to about 12 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 4 to about 8 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the C-SSRS is a version of the C-SSRS from the previous visit.

[0171] In some embodiments, the subject has an ideation intensity on the C-SSRS of about 0 to about 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's ideation intensity can be 0, 1, 2, 3, 4, 5, or 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's ideation intensity is as described herein about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's ideation intensity is as described herein about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, a subsequent version of the C-SSRS is administered after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein.

[0172] In some embodiments, subjects administered racemic ketamine, or a pharmaceutically acceptable salt thereof, intranasally have a C-SSRS score that is about 1 to about 2 points less than subjects administered an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof, or (S)-ketamine, or a pharmaceutically acceptable salt thereof, intravenously.

[0173] In some embodiments, the C-SSRS scores in subjects administered racemic ketamine, or a pharmaceutically acceptable salt thereof, intranasally improve at a faster rate than subjects administered an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof, or (S)-ketamine, or a pharmaceutically acceptable salt thereof, intravenously. For example, C-SSRS scores improve at a rate of 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 therebetween, faster than subjects receiving an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof, or (S)-ketamine, or a pharmaceutically acceptable salt thereof, intravenously.

[0174] The Physician Withdrawal Checklist 20-item (PWC-20) is a clinical tool designed to detect potential benzodiazepine-like withdrawal symptoms caused by non-SSRI experimental anxiolytics. Twenty subject-reported symptoms are recorded in five different categories: physical, mood, cognition, fatigue, and gastrointestinal problems. Each symptom is assigned a severity score according to 0 = not at all, 1 = not very much, 2 = somewhat, and 3 = very severe, resulting in a total score ranging from 0 to 60. Higher scores are associated with more and more severe withdrawal symptoms; lower scores are associated with fewer and less severe withdrawal symptoms.

[0175] In some embodiments, the subject's Physician Withdrawal Checklist-20 (PWC-20) score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 60 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 to 50 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 to 40 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 to 30 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 to 30 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 15 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 15 and 30 units. In some embodiments, the subject's PWC-20 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 30 and 60 units.

[0176] In some embodiments, the subject's PWC-20 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 60 and 40 units, between 40 and 20 units, between 20 and 10 units, or between 10 and 0 units, and is reduced by at least 80% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PWC-20 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 60 and 40 units, between 40 and 20 units, between 20 and 10 units, or between 10 and 0 units, and is reduced by at least 50% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PWC-20 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 60 and 40 units, between 40 and 20 units, between 20 and 10 units, or between 10 and 0 units, and is reduced by at least 25% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PWC-20 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 60 and 40 units, between 40 and 20 units, between 20 and 10 units, or between 10 and 0 units, and is reduced by at least 10% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PWC-20 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 60 to 40 units, 40 to 20, 20 to 10, or 10 to 0 units, and is reduced by 5 to 10%, or 0 to 5%, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, a subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5 units. In some embodiments, a subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 to 10 units. In some embodiments, a subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 to 20 units. In some embodiments, a subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 to 30 units. In some embodiments, a subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 to 40 units. In some embodiments, the subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 40 and 50 units. In some embodiments, the subject's PWC-20 score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 50 and 60 units.

[0178] In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by up to 5 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 5-10 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 10-20 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 20-30 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 30-40 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 40-50 units. In some embodiments, the subject's PWC-20 score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by up to 60 units.

[0179] In some embodiments, about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's PWC-20 score is reduced 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's PWC-20 score is reduced as described herein (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, prior to intranasal administration of racemic ketamine described herein, the subject completes the Physician Withdrawal Checklist-20 (PWC-20). For example, the Physician Withdrawal Checklist-20 (PWC-20) can be administered to the subject from about 1 hour to about 6 months prior to intranasal administration of racemic ketamine described herein.

[0180] In some embodiments, the Physician Withdrawal Checklist-20 (PWC-20) is administered to the subject 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine as described herein.

[0181] The European Quality of Life Group, 5-Factor, 5-Level (EQ-5D-5L) is a self-report survey measuring quality of life across five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. The EQ-5D-5L essentially consists of two parts: the EQ-5D self-report system and the EQ visual analog scale (EQ VAS). Subjects are asked to indicate their health status by checking a box corresponding to the most appropriate statement for each of the five dimensions, including 1 = no problems, 2 = some problems, 3 = moderate problems, 4 = very problems, and 5 = extremely problems. This decision results in a single-digit result indicating the selected level for that dimension. The visual analog scale (EQ VAS) provides a scale from 0 to 100, and subjects are asked to mark the scale with an "X" to indicate their health status for the day. A unique health status is defined by combining one level of each of the five dimensions. This allows for a total of 3,125 health states to be defined. Each state is represented by a five-digit unit. For example, a state of 11111 represents no problems with any of the five components, while a state of 12345 represents no problems with mobility, some problems with washing or dressing, some problems with normal everyday activities, very severe problems with pain / discomfort, and very severe problems with anxiety / depression. The EQ-5D-5L health states defined by the EQ-5D-5L descriptor system can be converted into a single index value. These index values ​​are country-specific and depend on the age and gender of the subject.

[0182] While there are many ways to compare data, one way to present the data as a health profile is to create tables listing the frequency or percentage of reported problems for each component at each level. These tables can include subgroup percentages broken down by component, such as age, before and after treatment, or treatment versus comparator or placebo. Generally, the general population in various age groups (e.g., 18-29, 30-39, 40-49, 50-59, 60-69, and over 70) has a high percentage of 1 (no problems) across all five components: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, and these percentages decrease with age. In other words, a large percentage of the general population tends to report increasing problems across all five components (increasing component health status scores) as they age.

[0183] In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 80% compared to baseline (screening). In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 70% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 60% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 50% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 40% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 30% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 20% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by at least 10% compared to baseline. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject's EQ-5D-5L index value is reduced by 5-10% or 0-5% compared to baseline.

[0184] In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, one or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, is reduced by 1 unit. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, one or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, is reduced by 2 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, one or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, is reduced by 3 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, there is a 4 unit reduction in EQ-5D-5L health status in one or more of the following five components: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, there is a 5 unit reduction in EQ-5D-5L health status in one or more of the following five components: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.

[0185] In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, two or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by one unit. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, two or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by two units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, two or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by three units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, there is a 4 unit reduction in two or more of the EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, there is a 5 unit reduction in two or more of the EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.

[0186] In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, three or more of the following five EQ-5D-5L health states are reduced by one unit: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, three or more of the following five EQ-5D-5L health states are reduced by two units: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, three or more of the following five EQ-5D-5L health states are reduced by three units: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, three or more of the following EQ-5D-5L health states are reduced by 4 units: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, three or more of the following EQ-5D-5L health states are reduced by 5 units: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.

[0187] In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, four to five of the EQ-5D-5L health states - mobility, self-care, usual activities, pain / discomfort, and anxiety / depression - are reduced by one unit. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, four to five of the EQ-5D-5L health states - mobility, self-care, usual activities, pain / discomfort, and anxiety / depression - are reduced by two units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, four to five of the EQ-5D-5L health states - mobility, self-care, usual activities, pain / discomfort, and anxiety / depression - are reduced by three units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, four to five of the EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by 4 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, four to five of the EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by 5 units.

[0188] In some embodiments, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, one or more of the five components of EQ-5D-5L health status: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression is reduced by at least 1 unit. In some embodiments, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, one or more of the five components of EQ-5D-5L health status: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression is reduced by at least 2, at least 3, at least 4, or at least 5.

[0189] In some embodiments, about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by at least 1 unit. 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the five EQ-5D-5L health states: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression, are reduced by at least 2 units, or at least 3, at least 4, or at least 5 units. 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 racemic ketamine or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the subject's EQ-5D-5L index score is reduced about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein (e.g., compared to before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof).

[0191] In some embodiments, the subject's EQ-5D-5L is administered prior to intranasal administration of racemic ketamine as described herein. For example, the subject's EQ-5D-5L can be administered about 1 hour to about 6 months prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's EQ-5D-5L is administered 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine as described herein.

[0192] The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a 9-item general patient-reported outcomes tool that assesses patient satisfaction with medication. It was adapted from the longer TSQM version 1.4 and addresses three dimensions: effectiveness, ease of use, and overall satisfaction. The tool uses domain scoring, with scores ranging from 0 to 100, with low scores indicating low satisfaction. The lookback period is "the last 2-3 weeks."

[0193] In some embodiments, the subject's TSQM-9 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is up to 100 units. In some embodiments, the subject's TSQM-9 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is up to 75 units. In some embodiments, the subject's TSQM-9 score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is up to 50 units.

[0194] In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is up to 25 units. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is up to 5, 10, 15, or 20 units.

[0195] In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, or 40 to 50, and is increased by up to 99% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, 40 to 50, or 50 to 55, and is increased by up to 80% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, or 60 to 66, and is increased by up to 50% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, or 70 to 80, and is increased by up to 25% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, or 80 to 90, and increases by up to 10% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's TSQM-9 score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, or 80 to 95, and increases by up to 5% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 100. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 to 80 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 to 70 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 to 50 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 10 units. In some embodiments, a subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 10 and 20 units. In some embodiments, a subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 20 and 30 units. In some embodiments, a subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 30 and 40 units. In some embodiments, a subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 40 and 50 units. In some embodiments, a subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is between 50 and 60 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 60 to 70 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 70 to 80 units. In some embodiments, the subject's TSQM-9 score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 80 units, up to 90 units, up to 95 units, or up to 100 units.

[0197] In some embodiments, the subject's TSQM-9 score increases about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's TSQM-9 score increases about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0198] In some embodiments, the subject is administered TSQM-9 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject is administered TSQM-9 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine, as described herein.

[0199] The Quality of Life In Depression Scale (QLDS) is a patient-reported measure of depression-specific quality of life in patients requiring antidepressant therapy, capturing the patient's perspective on the impact of depression and its treatment. The tool has a "currently" look-back period and 34 "true" / "false" response options. Scores range from 0 (good quality of life) to 34 (very poor quality of life).

[0200] In some embodiments, the subject's QLDS score for depression prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 34 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 25 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 15 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 to 10 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 5 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 to 34 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 10 to 15 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0 to 15 units. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 15 to 34 units.

[0201] In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 80% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 70% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 60% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 50% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 40% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 30% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0-5, 5-10, 10-20, 20-25, or 25-34, and is reduced by at least 20% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 10% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's QLDS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0 to 5, 5 to 10, 10 to 20, 20 to 25, or 25 to 34 and is reduced by at least 5% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the subject's QLDS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 1, at least 2, at least 3, at least 4, or at least 5 units. In some embodiments, the subject's QLDS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 10 units. In some embodiments, the subject's QLDS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 15 units. In some embodiments, the subject's QLDS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 20 units. In some embodiments, the subject's QLDS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 25 units. In some embodiments, the subject has a QLDS score of at least 34 units or less about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the subject's QLDS score is reduced about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's QLDS score is reduced about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0204] In some embodiments, the subject is administered a Quality of Life Scale for Depression (QLDS) as described herein prior to intranasal administration of racemic ketamine. In some embodiments, the subject is administered a Quality of Life Scale for Depression (QLDS) as described herein 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine.

[0205] The Healthcare Resource Use Questionnaire (HRUQ) is a tool designed to capture health care resource utilization data. The HRUQ contains information on the use of health care services, including the timing and type of services provided, allowing changes in the level and quantity of services to be considered as variables in economic models. The HRUQ is not a standard questionnaire and can be modified depending on the environment and trial design.

[0206] In some embodiments, the subject is administered an HRUQ as described herein prior to intranasal administration of racemic ketamine. In some embodiments, the subject is administered an HRUQ as described herein 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine.

[0207] In some embodiments, the HRUQ indicates the net reduction in healthcare service utilization after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, compared to the level and magnitude recorded before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the HRUQ exhibits a net reduction about 1 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, about 1 hour, about 1 to 6 hours, about 1 to 12 hours, about 1 to 18 hours, about 18 to 24 hours, about 12 to 24 hours, or about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the HRUQ exhibits a net reduction (compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof) about 1 day to about 4 days, about 1 day to about 5 days, about 5 days to about 10 days, about 10 days to about 30 days, about 1 month to 6 months, or about 6 months to 12 months after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0209] The Beck Hopelessness Scale (BHS) is a patient-reported measure assessing a subject's level of negative expectations or pessimism about the future and is therefore an important predictor of future suicide. The BHS consists of 20 true / false items assessing the respondent's attitudes over the past week by either affirming pessimistic statements or negating optimistic statements, with nine items marked as false and 11 marked as true. These items fall into three domains: (1) feelings about the future; (2) loss of motivation; and (3) future expectations. For all statements, each response is scored as either 0 or 1. The total score on the BHS is the sum of the item responses and ranges from 0 to 20, with high scores representing high levels of hopelessness. A total score of 0 to 3 is considered normal, a score of 4 to 8 indicates mild hopelessness, a score of 9 to 14 indicates moderate hopelessness, and a score above 14 indicates severe hopelessness.

[0210] In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 20 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 15 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 10 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 4, at least 5, at least 6, at least 7, at least 8, or at least 9 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 20 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 to 18 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 to 15 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 9 to 12 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 to 20 units. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 8 to 20 units.

[0211] In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 80% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 70% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 60% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 50% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 40% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 30% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 20% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by at least 10% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-10, 10-15, or 15-20, and is reduced by 5-10% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0-5, 5-10, 10-15, or 15-20, and is reduced by up to 5% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0212] In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 1, at least 2, at least 3, at least 4, or at least 5 units. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 6, at least 7, at least 8, at least 9, at least 10, or at least 11 units. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 12, at least 13, at least 14, at least 16, or at least 16 units. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is at least 17, at least 18, or at least 19 units. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 units or less. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 14 units or less. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 9 units or less. In some embodiments, the subject's BHS score about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 units or less.

[0213] In some embodiments, the subject's BHS score is reduced about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BHS score is reduced about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0214] In some embodiments, the subject is administered the Beck Hopelessness Scale (BHS) prior to intranasal administration of racemic ketamine, as described herein. In some embodiments, the subject is administered the Beck Hopelessness Scale (BHS) 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine, as described herein.

[0215] The Bladder Pain / Interstitial Cystitis Symptom Score (BPIC-SS) is a psychometrically validated, reliable questionnaire containing eight questions regarding bladder pain over the past seven days. Questions 1–5 assess urinary symptoms (frequency of urination due to pain, need to urinate again immediately after urination, pain relief after urination, intravesical pressure, and pain in the bladder) and are rated from 0 (never) to 4 (always). Questions 6 and 7 assess the impact of bladder pain (being bothered by frequent urination during the day and at night) and are rated from 0 (never) to 4 (often). Question 8 assesses maximum pain on a numeric pain scale ranging from 0 (no bladder pain) to 10 (worst possible bladder pain). The BPIC-SS total score is the sum of the individual question scores and ranges from 0–38, with higher scores indicating a worse condition. A score of 19 or greater indicates moderate / severe disease activity. A negative change indicates a reduction / improvement from baseline.

[0216] In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is up to 38 units. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 38 to 32 units. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 32 to 27 units. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 27 to 22 units. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 22 to 17 units, 17 to 13, 13 to 11, or 11 to 9 units. In some embodiments, the subject's BPIC-SS total score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is between 8 and 6 units, between 6 and 4, between 4 and 2, or between 1 and 0 units.

[0217] In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 80% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 70% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 60% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 50% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 40% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 30% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 20% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0-5, 5-15, 15-25, 25-35, or 35-38 and is reduced by at least 10% about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 0-5, 5-15, 15-25, 25-35, or 35-38, and is reduced by no more than 10-5% about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the subject's BPIC-SS total score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is at most 1-2, at most 3-4, at most 4-5, or at most 5-6 units. In some embodiments, the subject's BPIC-SS total score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is at most 7-8, at most 9-10, at most 11-12, at most 13-14, at most 15-16, or at most 17-18 units. In some embodiments, the subject's BPIC-SS total score about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is at most 19, at most 20-21, at most 22-23, at most 24-25, or at most 26-27 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject has a BPIC-SS total score of at most 28, at most 29, at most 30-31, or at most 32 units. In some embodiments, about 24 hours after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject has a BPIC-SS total score of at most 33-34, at most 35-36, or at most 36-38 units.

[0219] In some embodiments, the subject's BPIC-SS total score is reduced about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's BPIC-SS total score is reduced about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described (e.g., compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0220] In some embodiments, a BPIC-SS total is administered to a subject prior to intranasal administration of racemic ketamine as described herein. In some embodiments, a BPIC-SS total is administered to a subject 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 about 1 day to about 6 months prior to intranasal administration of racemic ketamine as described herein.

[0221] Complex regional pain syndrome (CRPS) is a chronic neurological disorder resulting from a traumatic event. The clinical diagnosis of CRPS involves a dichotomous (yes / no) categorization necessary for clinical judgment. The CRPS Severity Score (CSS) is a tool for quantifying clinical features associated with CRPS based on the presence or absence of 16 clinically relevant signs (8) and symptoms (8), with one point assigned for each. It is a continuous outcome measure that corresponds to and complements the dichotomous (yes / no) IASP diagnostic criteria for CRPS (the "Budapest criteria"). The test includes a checklist of signs and symptoms common to CRPS, including self-reported symptoms such as allodynia, bilateral temperature asymmetry, skin color asymmetry, sweat asymmetry, nutritional changes, motor changes, decreased range of motion, and asymmetric edema, as well as examiner-observed clinical signs such as pinprick sensitivity, allodynia, temperature asymmetry (palpation), skin color asymmetry, sweat asymmetry, asymmetric edema, nutritional changes, motor changes, and decreased range of motion. Higher scores indicate greater CRPS severity.

[0222] In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 14 or greater (e.g., 14, 15, or 16). In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 12 or greater. In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 8 or greater. In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 6 or greater. In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or greater. In some embodiments, the subject's CSS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 or greater.

[0223] In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 14 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 12 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 6 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 or greater.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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 16 (e.g., 1 to 16 units). In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 4 to 14 (e.g., 4 to 14 units). In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 6 to 12 (e.g., 6 to 12 units). In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 4 to 6 (e.g., 4 to 6 units). In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 4 (e.g., 2 to 4 units). In some embodiments, the subject's CSS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (eg, 1 to 2 units).

[0225] The Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) is a screening tool for monitoring the level of pain interference associated with various activities. The PROMIS-29 v2.0 profile assesses pain intensity using seven health domains (physical function, fatigue, pain interference, depression symptoms, anxiety, ability to engage in social roles and activities, and sleep interference) with one numeric rating scale ranging from 1 to 10 and four activities per domain. Each of the four activities per domain is rated from 1 to 5, with 1 = "not at all" (meaning the subject experiences no pain interference with the activity), 2 = "slightly" (meaning the subject experiences no pain interference with the activity), 3 = "somewhat" (meaning the subject experiences significant pain interference with the activity), and 5 = "extremely" (meaning the subject experiences significant pain interference with the activity). A higher PROMIS score indicates more of the condition being measured. The PROMIS sum provides the subject's raw domain score, which ranges from 4 to 20.

[0226] In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 18 or greater. In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 16 or greater. In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 12 or greater. In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 8 or greater. In some embodiments, the subject's PROMIS-29 raw score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 6 or greater. In some embodiments, the subject's PROMIS-29 raw score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 4 or greater.

[0227] In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 18 or greater. 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 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 16 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 12 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. 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 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 8 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 6 or greater. 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 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PROMIS-29 raw score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 16 (e.g., 1 to 16 units). In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 4 to 14 (e.g., 4 to 14 units). In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 6 to 12 (e.g., 6 to 12 units). In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 4 to 6 (e.g., 4 to 6 units). In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 4 (e.g., 2 to 4 units). In some embodiments, the subject's PROMIS-29 raw score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units).

[0229] The CGI-Severity (CGIS) asks clinicians one question: "Considering your overall clinical experience with this particular population, to what extent is this subject / patient mentally ill at this point?" and rates them on a 7-point scale: 1 = normal, not ill at all; 2 = borderline psychotic; 3 = mildly ill; 4 = moderately ill; 5 = moderately ill; 6 = severely ill; 7 = most severely ill subject / patient. This rating is based on observed and reported symptoms, behavior, and functioning since the last visit. The CGIS can also be measured on a 5-point scale, and the values ​​provided herein can be adjusted appropriately.

[0230] In some embodiments, the subject's CGIS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2 or greater. In some embodiments, the subject's CGIS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3, 4, or 5. In some embodiments, the subject's CGIS score is 4 or 5 about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the CGIS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5 (e.g., 1 to 5 units). In some embodiments, the CGIS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5 (e.g., 1 to 5 units). In some embodiments, the CGIS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4 (e.g., 1 to 4 units). In some embodiments, the CGIS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 3 (e.g., 1 to 3 units). In some embodiments, the CGIS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units).

[0232] In some embodiments, the CGIS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2 or greater (e.g., 3, 4, or 5), and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5. In some embodiments, the CGIS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 or greater (e.g., 3, 4, or 5), and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5, e.g., 1, 2, 3, 4, or 5. In some embodiments, the CGIS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or 5, and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4, e.g., 1, 2, 3, or 4. In some embodiments, the CGIS score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 5 and is reduced by 1 to 3, e.g., 1, 2, or 3, after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the subject's CGIS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2 or greater, e.g., 2, 3, 4, or 5, and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1, 2, 3, 4, or 5. In some embodiments, the subject's CGIS score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1, 2, 3, 4, or 5. In some embodiments, 24 hours after intranasal administration of racemic ketamine, the subject's CGIS score is reduced by 1, 2, 3, 4, or 5 points. In some embodiments, the subject's CGIS score is reduced by 2 points. In some embodiments, the subject's CGIS score is reduced by 3 points. In some embodiments, the subject's CGIS score is reduced by 4 points. In some embodiments, the subject's CGIS score is reduced by 5 points. In some embodiments, the subject's CGIS score is reduced by 6 points.

[0234] The Clinical Global Impression of Change in Suicidal Ideation and Behavior (CGIC-SI / B) and the Clinical Global Impression of Severity in Suicidal Ideation and Behavior (CGIS-SI / B) are two combined measures of: (a) change from the start of treatment, and (b) the Clinical Global Impression of Psychopathology (in this case, suicidal ideation and behavior) severity (CGI), which scales from 1 to 5. The CGI captures clinical impressions and tracks clinical progression over time. The CGI has been shown to correlate well with standard, well-known investigational drug effect scales for a wide range of psychiatric indications (e.g., Hamilton Rating Scale for Depression, Hamilton Rating Scale for Depression, Positive and Negative Syndrome Scale, Leibowitz Social Anxiety Scale, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Syndromes, etc.).

[0235] CGI-Change (CGIC) is a single-item measure of change in treatment. At each visit after a subject / patient begins taking medication, the clinician compares the subject / patient's overall clinical condition to that of the week immediately prior to starting medication (the so-called baseline visit). The CGIC is rated on a 7-point scale: "Compared to the subject / patient's condition at baseline [before starting medication], this subject / patient's condition has: 1 = much improved since starting treatment; 2 = slightly improved; 3 = slightly improved; 4 = no change from baseline (beginning of treatment); 5 = slightly worse; 6 = slightly worse; 7 = much worse since starting treatment."

[0236] In some embodiments, the subject's CGI-S score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 4. In some embodiments, the patient's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 1 (e.g., compared to their CGI-S score). In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 2. In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 3. In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 4. In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 5.

[0237] In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 (e.g., 1 unit). In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 (e.g., 2 units). In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 3 (e.g., 3 units). In some embodiments, the subject's CGIC score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5 (e.g., 5 units).

[0238] The Patient Global Impression of Suicidal Ideation and Behavior (PGIS-SI / B) is a subject-administered, 5-point rating scale assessing the subject's perception of the general severity of their illness, ranging from 1 (not at all suicidal) to 5 (very suicidal) according to a single-item Likert-type scale. The PGIS-SI / B can be administered at various time points (e.g., before intranasal administration of racemic ketamine as described herein, or after one or more doses of racemic ketamine, the latter resulting in a "change" score, as described below). See, e.g., Mohebbi et al. Eur Psychiatry. 2018;53:17-22.

[0239] The Patient Global Impression of Suicidal Ideation and Behavior (PGIS-SI / B) is a 7-point scale based on the question "How much have your suicidal impulses, thoughts, and behaviors changed compared to your state at baseline?" with the following scale: 1 Very good 2 Fairly good 3 Slightly better 4 No change 5 Slightly worse 6 Slightly worsened 7 Very worse Evaluate the effect of treatment on subject / patient impressions.

[0240] The PGIC-SI / B scale can be administered at various time points after one or more intranasal administrations of racemic ketamine, as described herein, compared to a PGIS-SI / B score determined prior to intranasal administration of racemic ketamine, as described herein. See, e.g., Mohebbi et al. Eur Psychiatry. 2018;53:17-22.

[0241] In some embodiments, the subject's PGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 or greater. In some embodiments, the subject's PGIS-SI / B score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PGIS-SI / B score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3, 4, or 5.

[0242] In some embodiments, the subject's PGIS-SI / B score (i.e., PGIC-SI / B score) after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4 (e.g., 1 to 4 units). In some embodiments, the subject's PGIS-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 3 (e.g., 1 to 3 units). In some embodiments, the subject's PGIS-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units).

[0243] In some embodiments, the PGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 or greater (e.g., 3, 4, or 5), and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 6. In some embodiments, the PGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or greater (e.g., 4 or 5), and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4, e.g., 1, 2, 3, or 4. In some embodiments, the PGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 3 to 5 (e.g., 3, 4, or 5), and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4, e.g., 1, 2, 3, or 4. In some embodiments, the subject's PGIS-SI / B score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2, 3, 4, or 5, and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1, 2, 3, or 4. In some embodiments, the subject's PGIS-SI / B score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2, 3, 4, or 5, and about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1, 2, 3, or 4. In some embodiments, 24 hours after intranasal administration of racemic ketamine, the subject's PGIS-SI / B score is reduced by 3 or 4 points. In some embodiments, the subject's PGIS-SI / B score is reduced by 3 points. In some embodiments, the subject's PGIS-SI / B score is reduced by 4 points.

[0244] In some embodiments, the PGIS-SI / B score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2 and decreases by 1 or 2 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 or 2 and decreases by 1 or 2 about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 1 or 2 about 1 to about 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 racemic ketamine or a pharmaceutically acceptable salt thereof, and is reduced by 1 or 2 about 1 to about 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 racemic ketamine or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, a first PGIS-SI / B score is determined about 1 hour to about 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof; and a second PGIS-SI / B score (i.e., a PGIC-SI / B score) is determined about 1 hour to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a first PGIS-SI / B score from a subject is determined about 4 hours to about 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a second PGIS-SI / B score from a subject is determined about 4 hours to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first PGIS-SI / B score and the second PGIS-SI / B score are taken at equal times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, e.g., 4 hours before or 4 hours after. In some embodiments, the first PGIS-SI / B score and the second PGIS-SI / B score are taken at different times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, e.g., 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof. The change in score, as described below, is the PGIC-SI / B.

[0246] In some embodiments, the subject's PGIS-SI / B score prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is greater than or equal to 1. In some embodiments, the subject's PGIC-SI / B score about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is greater than or equal to 1. 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 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PGIC-SI / B score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, about 5 minutes to 18 hours, about 18 hours to 24 hours, or about 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 2, 3, or 4. In some embodiments, the subject's PGIC-SI / B score about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours, about 5 minutes to 18 hours, about 18 hours to 24 hours, or about 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5, 6, or 7.

[0247] In some embodiments, the subject's PGIC-SI / B score is reduced by 1 to 6 (e.g., 1 to 6 units) compared to the PGIC-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PGIC-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5 (e.g., 1 to 5 units). In some embodiments, the subject's PGIC-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 4 (e.g., 1 to 4 units). In some embodiments, the subject's PGIC-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 3 (e.g., 1 to 3 units). In some embodiments, the subject's PGIC-SI / B score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units).

[0248] The Patient Global Impression of Change (PGIC) is a one-item measure of overall improvement with treatment, and participants use a 7-point scale (+3 = "markedly improved" to -3 = "markedly worse," and 0 = "no change"). The questionnaire includes the question, "What is your overall impression after taking [study drug]?"

[0249] In some embodiments, the subject's PGIS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0. In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the patient's Global Impression Change (PGIC) score (relative to the PGIS score) increases by 3 (e.g., 3 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the patient's Global Impression Change (PGIC) score increases by 2 (e.g., 2 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the patient's Global Impression Change (PGIC) score increases by 1 (e.g., 1 unit). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the patient's Global Impression Change (PGIC) score increases by 0 (i.e., no change).

[0250] The Mini-International Neuropsychiatric Interview (MINI) is a short, structured clinical interview that allows clinicians and researchers to assess the 17 most common psychiatric disorders included in DSM-III-R, DSM-IV, DSM-5, and ICD-10. The clinician or researcher asks the subject several questions about each psychiatric disorder and diagnoses the psychiatric disorder as described herein based on the number of dichotomous responses (yes / no) to these questions. For example, the MINI for Suicidality Disorder (DSM-5) is a semi-structured clinical interview administered (e.g., screening) to confirm a primary diagnosis of MDD, assess the presence or absence of current suicidal thoughts and behaviors (SI / B), and identify co-occurring neuropsychiatric disorders. When administered by qualified and experienced personnel, the MINI can provide information and complement a detailed preliminary examination. See, e.g., 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. November 2015 (available at 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 at HarmResearch.org) ISBN: 978-0-9969729-1-8).

[0251] In some embodiments, the subject does not have and / or has never been diagnosed with Impulsive-Aggressive Suicidal Disorder and / or Homicidal Suicidal Disorder, e.g., as in MINI Version 7.02 for Suicidal Disorders. In some embodiments, the subject does not have and / or has never had a determination of a score of 9 or 10 in a clinician's judgment regarding the patient's risk of suicide attempt or death by suicide on the STS-CMCM. In some embodiments, other than about 30 days prior to initiation of a treatment described herein, the subject does not have a score of about 4 or higher on item 10 of the MADRS. In some embodiments, the subject does not have a score of 2, 3, or 4 on the C-SSRS for Actual Lethality / Medical Damage.

[0252] In some embodiments, the subject has a history of chronic (>3 months) intermittent non-impulsive suicidality. In some embodiments, the subject currently has suicidal ideation intent, e.g., as determined by screening and baseline of the MINI Suicidality Module, specifically an affirmative response to question B3 regarding current symptoms and an affirmative response to questions B10 or B11 regarding symptoms within the last 24 hours. In some embodiments, the subject has a score of about 8 or less on the STS-CMCM Clinician's Assessment of Subject's Risk of Suicide Attempt or Death by Suicide.

[0253] The Antidepressant Treatment Response Questionnaire (ATRQ) is used to determine resistance in major depressive disorder (MDD). Subjects answer a number of questions related to their prior treatment experience with a broad list of antidepressants, including tricyclics, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other antidepressants. The ATRQ includes the following questions: (1) Have you received any medication treatment in the last 5 years? Please circle your answer: Yes No (2) If you answered yes, please review the list on page 2 and check the box next to the medication(s) you have taken for at least 6 weeks in the last 5 years. (3) For any medication(s) you checked on the list on page 2, please check the second box next to the medication(s) you have taken at a dose equal to or greater than the minimum dose listed for that medication. (4) For each medication you checked on the list on page 2 that you feel has helped your depression, please rate it. Compare it to when you were doing well (before the onset of your current symptoms or period of depression). Using the following scale, rate your improvement in the last column. A rating of 100% is "completely improved" and 0 is "no improvement at all." How close did this medication bring you to 100%? 1 = less than 25% improvement, 2 = between 25% and 49% improvement, 3 = between 50% and 75% improvement, 4 = more than 75% improvement.

[0254] The Sheehan Disability Scale (SDS) is a five-item self-report tool that assesses impairments in work / school, social life, and family life. The SDS is a disability or impairment scale that uses a discrete analog (discan) measure. This discrete analog measure has defined response options and simultaneously uses visuospatial, numerical, and verbal descriptive components to assess impairments or impairments across three domains: work / school, social life / leisure, activities, and family life / shared responsibilities. Each domain is scored from 0 (not at all) to 10 (severe). The scores for each of the three domains are added together to yield an overall SDS score ranging from 0 (no impairment) to 30 (severe impairment), and the three domains are combined to assess overall impairment.

[0255] In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 25-30. In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or greater. In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 or greater. In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater. In some embodiments, the subject's SDS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 or greater.

[0256] In some embodiments, the SDS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 25 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SDS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SDS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SDS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SDS score about 5 to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SDS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 1 or greater.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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 30 (e.g., 1 to 30 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 25 (e.g., 1 to 25 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 20 (e.g., 1 to 20 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 15 (e.g., 1 to 15 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 10 (e.g., 1 to 10 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5 (e.g., 1 to 5 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 15 to 25 (e.g., 15 to 25 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 to 30 (e.g., 10 to 30 units). In some embodiments, the SDS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5 to 10 (e.g., 5 to 10 units).

[0258] The Pain Self-Efficacy Questionnaire (PSEQ) is a 10-item questionnaire designed to assess people with persistent pain's confidence in performing activities despite pain. The PSEQ is applicable to all persistent pain perceptions. It addresses areas of function such as housework, social interaction, and work, as well as managing pain without medication. People are asked to rate their confidence in their ability to perform the activities listed on the questionnaire under current circumstances, despite their pain. Responses are given for each item on a 7-point Likert scale, with 0 = not at all confident and 6 = very confident. Scores for each item are added to obtain a total score ranging from 0 to 60. Higher scores reflect stronger self-efficacy beliefs.

[0259] In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 40 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 50 or less. In some embodiments, the subject's PSEQ score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 55 or less.

[0260] In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 40 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 50 or less.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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PSEQ score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 55 or less. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PSEQ score increases by 5 to 55 (e.g., 5 to 55 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PSEQ score increases by 10 to 50 (e.g., 10 to 50 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PSEQ score increases by 20 to 40 (e.g., 20 to 40 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PSEQ score increases by 25 to 35 (e.g., 5 to 10 units). In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PSEQ score increases by 5 to 10 (e.g., 1 to 10 units).

[0262] The Richmond Agitation-Sedation Scale (RASS) is a medical scale used to measure a person's level of agitation or sedation. The RASS is often used with hospitalized subjects / patients to assess the subject's level of alertness or agitation. It is a 10-point scale with four levels of anxiety or agitation (+1 to +4 [combative]), a level of 1 being calm and alert (0), and a level of 5 being sedated (-1 to -5) with eventual inability to arouse (-5). See Table A. [Table A]

[0263] In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 4. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 3. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 2. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to 1. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to -3. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to -2. In some embodiments, the subject's RASS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 0 to -1.

[0264] In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 0 to 8 (e.g., 0 to 8 units). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 0 to 6 (e.g., 0 to 6 units). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 0 to 4 (e.g., 0 to 4 units). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 0 to 2 (e.g., 0 to 2 units). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 0 to 1 (e.g., 0 to 1 unit). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 2 (e.g., 1 to 2 units). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 4 (e.g., 1 to 2 units).

[0265] In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, increases by 0 to 1 (e.g., 0 to 1 unit). In some embodiments, the RASS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, increases by 1 to 2 (e.g., 1 to 2 units). In some embodiments, if the RASS score is −3 to −4, the next intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, can be delayed until sedation subsides.

[0266] The Numeric Pain Rating Scale (NPRS) is an 11-point pain intensity measure with the following scale: 0 = no pain; 1 = very mild, barely noticeable; 2 = only slightly unpleasant; 3 = tolerable but very noticeable; 4 = very painful and severe; 5 = very severe and painful, with a stinging feeling; 6 = intense, powerful, severe, and a stinging feeling; 7 = very intense and completely takes over your senses, preventing you from thinking clearly about half the time; 8 = so intense that you cannot think clearly; 9 = extremely intense pain, you cannot tolerate the pain and require a permanent cure or surgery, regardless of any side effects or risks; and 10 = so intense that you will soon lose consciousness. The NPRS questionnaire is arranged into three bins: (1) average pain in the last 24 hours, (2) least pain in the last 24 hours, and (3) most pain in the last 24 hours, each containing the pain scale described above.

[0267] In some embodiments, about 1 minute to about 10 days prior to the start of administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject has an NPRS score of about 1 to about 6. In some embodiments, about 1 minute to about 10 days prior to the start of administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject has an NPRS score of about 6 to about 10. In some embodiments, the subject has an average daily pain intensity score of 6 or greater on the NPRS during the 7 days prior to randomization in the trial.

[0268] In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 10 (e.g., 1 to 10 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 9 (e.g., 1 to 9 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 7 (e.g., 1 to 7 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 5 (e.g., 1 to 5 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 1 to 3 (e.g., 1 to 3 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 10 (e.g., 2 to 10 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 2 to 5 (e.g., 2 to 5 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 3 to 9 (e.g., 3 to 9 units). In some embodiments, the subject's NPRS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 4 to 6 (e.g., 4 to 6 units).

[0269] The short-form McGill Pain Questionnaire (SF-MPQ) is an abbreviated version of the original MPQ and was developed to assess both the intensity and quality of pain. This pain assessment index consists of 15 pain descriptors, including 11 sensory and 4 affective descriptors. Each of these descriptors is rated on an intensity scale: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. A total pain score is calculated by adding up the intensity rank values, and the scale ranges from 0 to 45.

[0270] In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 40-45. In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 35 or greater. In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 25 or greater. In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 or greater. In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the subject's SF-MPQ total score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater.

[0271] In some embodiments, the SF-MPQ total score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 40 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SF-MPQ total score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SF-MPQ total score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SF-MPQ total score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SF-MPQ total score about 5 to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the SF-MPQ total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 5 to 45 (e.g., 5 to 45 units). In some embodiments, the SF-MPQ total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 10 to 35 (e.g., 10 to 35 units). In some embodiments, the SF-MPQ total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 15 to 25 (e.g., 15 to 25 units). In some embodiments, the SF-MPQ total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 5 to 10 (e.g., 5 to 10 units). In some embodiments, the SF-MPQ total score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1 to 5 (e.g., 1 to 5 units).

[0273] The Pain Catastrophizing Scale (PCS) is a measure of an individual's pain experience, asking how they feel and what thoughts they have when they are in pain. Compared to other measures of pain-related thoughts, this questionnaire is unique in that individuals do not need to be in pain to complete it. Pain catastrophizing is characterized by a tendency to magnify the threat value of painful stimuli and a sense of helplessness in the presence of pain, as well as a relative inability to prevent or inhibit pain-related thoughts in anticipation of, during, or after a painful event. Using a scale ranging from 0 (never) to 4 (always), participants are asked to indicate the extent to which they experience 13 different ways of thinking and feeling when experiencing pain. A total score (ranging from 0 to 52) is generated using three subscale scores, assessing repetition, magnification, and helplessness.

[0274] In some embodiments, the pain catastrophizing scale (PCS) score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 45-52. In some embodiments, the PCS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 35 or greater. In some embodiments, the PCS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 25 or greater. In some embodiments, the PCS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 or greater. In some embodiments, the PCS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the PCS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater.

[0275] In some embodiments, the PCS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 40 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PCS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 30 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PCS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PCS score about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PCS score about 5 to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater. 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the PCS score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 5 to 52 (e.g., 5 to 52 units). In some embodiments, the PCS score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 10 to 35 (e.g., 10 to 35 units). In some embodiments, the PCS score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 15 to 25 (e.g., 15 to 25 units). In some embodiments, the PCS score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 5 to 10 (e.g., 5 to 10 units). In some embodiments, the PCS score after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is reduced by 1 to 5 (e.g., 1 to 5 units).

[0277] The Pelvic Pain and Urgency / Frequency (PUF) patient symptom scale is a diagnostic tool used to screen subjects / patients for chronic pelvic pain. The PUF self-administered questionnaire includes a symptom score (measuring how often the subject / patient experiences the problem) and a distress score (indicating the extent to which the symptom bothers the subject / patient); the distress and symptom scores are added together to produce a total PUF score. There are eight questions, such as: "How many times do you go to the bathroom during the day (or night)?", "Are you bothered by pain?", and "Is urgency bothering you?" The score ranges from 0 to 35, and clinical trials have shown that a score above 12 indicates significant symptoms.

[0278] In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 25-35. In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 20 or greater. In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 15 or greater. In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 10 or greater. In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or greater. In some embodiments, the subject's PUF score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 or less.

[0279] In some embodiments, the PUF score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5 to 35 (e.g., 5 to 35 units). In some embodiments, the PUF score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 to 25 (e.g., 10 to 25 units). In some embodiments, the PUF score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 15 to 20 (e.g., 15 to 20 units). In some embodiments, the PUF score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5 to 10 (e.g., 5 to 10 units). In some embodiments, the PUF score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 5 to 0 (e.g., 1 to 0 units).

[0280] In some embodiments, within about 1 minute to about 10 days of starting administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, the subject has an NPSR score of about 6 to about 11.

[0281] Reduced side effects Some embodiments provide a method of reducing one or more side effects of ketamine treatment in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0282] Some embodiments provide a reduced side effect profile following administration of ketamine, particularly following intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein, compared to administration of (S)-ketamine, or intravenous racemic ketamine, or a pharmaceutically acceptable salt of either of these.

[0283] In some embodiments, the subject does not observe clinically significant sedation within about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not observe clinically significant sedation within about 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not observe clinically significant sedation within about 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the subject does not observe clinically meaningful dissociation within about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not observe clinically meaningful dissociation within about 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not observe clinically meaningful dissociation within about 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the subject has been previously diagnosed with and / or currently suffers from post-traumatic stress disorder. In some embodiments, the subject exhibits one or more of the following characteristics: unwanted upsetting memories, nightmares, flashbacks, mental distress after recalling the trauma, or physical reactions after recalling the trauma; and one or more trauma-related thoughts or emotions and trauma-related reminders. In some embodiments, the subject exhibits two or more of the following characteristics: inability to remember key features of the traumatic event; and excessively negative thoughts or beliefs about themselves or the world, exaggerated blaming of themselves or others for causing the traumatic event, negative emotions, decreased interest in activities, feelings of isolation, and difficulty experiencing positive emotions. In some embodiments, the subject exhibits one or more of the following characteristics: irritability or aggressiveness, dangerous or destructive behavior, increased vigilance, heightened startle response, poor concentration, and sleep disturbances. In some embodiments, these characteristics are present for about 1 month or more, result in severe anxiety and / or impaired social or occupational functioning, and are not attributable to medication or substance abuse, hi some embodiments, these characteristics are present for at least about 1 month to about 12 months.

[0286] In some embodiments, the subject has previously been diagnosed with and / or currently suffers from major depressive disorder. In some embodiments, the subject has not been diagnosed with or does not currently suffer from suicidal tendencies. In some embodiments, the subject has not been diagnosed with or does not currently suffer from suicidal ideation.

[0287] In some embodiments, the subject has previously been diagnosed with and / or currently suffers from treatment-resistant depression. In some embodiments, the treatment-resistant depression is at Stage I-Stage IV. In some embodiments, the treatment-resistant depression is at Stage V. In some embodiments, the subject has not been diagnosed with or does not currently suffer from suicidal tendencies. In some embodiments, the subject has not been diagnosed with or does not currently suffer from suicidal ideation.

[0288] In some embodiments, the subject has been previously diagnosed with and / or currently suffers from bipolar depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from postpartum depression. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from postpartum depression, but is not currently breastfeeding. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from chronic pain. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from neuropathic pain. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from Rett syndrome. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from epilepsy. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from agitation associated with dementia. In some embodiments, the subject has been previously diagnosed with and / or currently suffers from agitation associated with schizophrenia. In some embodiments, the subject has previously been diagnosed with and / or currently suffers from agitation associated with bipolar disorder.

[0289] In some embodiments, one or more side effects of intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and / or one or more additional therapies required to provide a therapeutic effect are reduced compared to the side effects of administering each agent 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 therapies are reduced. In some embodiments, one or more side effects of one or more additional therapeutic methods are reduced compared to one or more side effects observed after intranasal administration of an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, one or more side effects of one or more additional therapeutic methods are reduced compared to one or more side effects observed after intranasal administration of 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 therapeutic methods are reduced. In some embodiments, the total number of side effects is reduced. In some embodiments, the severity of one or more side effects is reduced. In some embodiments, both the total number of side effects is reduced and the magnitude of one or more remaining side effects is reduced.

[0290] In some embodiments, the one or more side effects of ketamine include cognitive impairment, movement disorders, dizziness, nausea, vomiting, sweating, elevated blood pressure, ulcerative cystitis, or interstitial cystitis. In some embodiments, the one or more side effects of ketamine consist of cognitive impairment, movement disorders, dizziness, nausea, vomiting, sweating, elevated blood pressure, ulcerative cystitis, or interstitial cystitis.

[0291] In some embodiments, the cognitive impairment comprises one or more of psychotomimetic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, auditory changes, visual changes, and hallucinations. In some embodiments, the cognitive impairment comprises one or more of psychotomimetic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, auditory changes, visual changes, and hallucinations. In some embodiments, the cognitive impairment comprises sedation. In some embodiments, the cognitive impairment is sedation. In some embodiments, the movement disorder comprises tremors, balance problems, or dystonic movements. In some embodiments, the movement disorder comprises one or more of tremors, balance problems, or dystonic movements.

[0292] Many methods can be used to assess ketamine-related side effects, including, but not limited to, the Modified Observer's 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 (CRT), the Sternberg Short-Term Memory Task (SSTM), and the Subject Rating Assessment of Intranasal Discomfort (SRAII©) (for intranasal administration of ketamine).

[0293] The modified Observer Assessment of Arousal / Sedation (MOAA / S) scale is a 6-point scale based on responsiveness to sound and touch, speech, facial expression, and eyelid ptosis. The MOAA / S scale ranges from 0 to 6, with 0 indicating the patient does not respond after painful pressure on the trapezius muscle; 1 indicating the subject responds only after painful pressure on the trapezius muscle; 2 indicating the subject responds only after a slight nod or tremble; 3 indicating the subject responds only after their name is called loudly and / or repeatedly; 4 indicating the subject responds lethargically to their name spoken in a normal tone; 5 indicating the subject responds somewhat lethargically to their name spoken in a normal tone; and 6 indicating the subject responds readily to their name spoken in a normal tone.

[0294] In some embodiments, the MOAA / S can be used to measure a subject's sedation state. 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. In some embodiments, the subject's MOAA / S score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 5 units. In some embodiments, the subject's MOAA / S score about 15 minutes to about 6 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof is 4 or 5 units.

[0295] In some embodiments, the subject's MOAA / S is 5 or 6 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's MOAA / S score is measured from about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine, 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 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the subject's MOAA / S is 5 or 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's MOAA / S score is measured about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is as described herein about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the subject's MOAA / S before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 5 or 6, and the subject's MOAA / S after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is 5 or 6. In some embodiments, the subject's MOAA / S score is measured about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is 5 or 6 about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's MOAA / S score is 5 or 6 about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours before, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the subject's MOAA / S score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's MOAA / S score is unchanged (i.e., does not increase or decrease) after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, a subject's MOAA / S score is reduced by about 1 to about 5 following intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. For example, a subject's MOAA / S score may be reduced by 1, 2, 3, 4, or 5 following 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, a subject's MOAA / S score 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, 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is as described herein about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine, 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).

[0300] 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 clinical interview consisting of 13 items that assess psychedelic effects. The VAS consists of 13 items that ask subjects to rate their current feelings. Each item is scored from 0 to 100, with a score of 0 reflecting "not at all" and a score of 100 reflecting "extremely." Lower individual and overall scores indicate less psychedelic effects. Each item in the questionnaire is described below. 1) My body or body parts seemed to change shape or position (BODY), 2) My surroundings seemed to change in size, depth, or shape (SURROUNDINGS); 3) The passage of time has been changed (TIME), 4) I had unrealistic feelings (REALITY), 5) I had difficulty controlling my thoughts. 6) Changes in color intensity (COLORS), 7) The sound intensity has changed (SOUND), 8) Hearing voices or sounds that are not real (VOICES), 9) The delusion that events, objects, or other people have special, specific meanings to the person (MEANING). 10) Suspicious thoughts and beliefs that others were against them (SUSPICIOUS) 11) I felt anxious (ANXIOUS), 12) Elevated mood (HIGH), and 13) I felt drowsy.

[0301] Items 1, 2, 3, 5, 6, and 7 are combined to assess the derived variable "subjective external perception." Items 4, 8, 9, 10, and 11 are combined to assess the derived variable "subjective internal perception." Items 12 and 13 are assessed as individual VAS items. If any item is missing, the associated score is not calculated.

[0302] In some embodiments, items 1, 2, 3, 5, 6, and 7 are combined to assess the derived variable "subjective external perception." In some embodiments, items 4, 8, 9, 10, and 11 are combined to assess the derived variable "subjective internal perception." In some embodiments, items 12 and 13 are assessed as individual VAS items.

[0303] In some embodiments, the subject's Boudle VAS is between 0 and 50 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Boudle VAS is between 25 and 75 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Boudle VAS is between 50 and 100 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Bowdle VAS is 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 prior to intranasal administration of racemic ketamine described herein. In some embodiments, the subject's Bowdle VAS is 5 to 20, 15 to 40, 10 to 50, or 20 to 60 prior to intranasal administration of racemic ketamine described herein. In some embodiments, the subject's Bowdle VAS score is measured from about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine, 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 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Bowdle VAS score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the subject's Boudle VAS is between 0 and 50 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Boudle VAS is between 25 and 75 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Boudle VAS is between 50 and 100 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's Bowdle VAS after intranasal administration of racemic ketamine described herein is 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 subject's Bowdle VAS after intranasal administration of racemic ketamine described herein is 5 to 20, 15 to 40, 10 to 50, or 20 to 60. In some embodiments, the subject's Bowdle VAS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Bowdle VAS score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the subject's Boudle VAS is 0 to 50 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's Boudle VAS is 0 to 50 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS is 25 to 75 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's Boudle VAS is 25 to 75 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS is 50 to 100 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's Boudle VAS is 50 to 100 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Bowdle VAS is measured at 0-10, 0-20, 0-30, 0-40, 0-50, 0-60, 0-70, 0-80, 0-90, 90-100, 80-100, 70-100, 60-100, 50-100, 40-100, 30-100, 20-100, or 50-100, or 40-100, or 30-100, or 20-100, or 5 ... or 10 to 100, and after intranasal administration of racemic ketamine described herein, the subject's bowdle VAS is 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 subject's bowdle VAS is 5 to 20, 15 to 40, 10 to 50, or 20 to 60 before intranasal administration of racemic ketamine described herein, and the subject's bowdle VAS is 5 to 20, 15 to 40, 10 to 50, or 20 to 60 after intranasal administration of racemic ketamine described herein. In some embodiments, the subject's bowel VAS is measured from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and the subject's bowel VAS is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's Boudle VAS score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours before, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the subject's Boudle VAS score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's Boudle VAS score changes (i.e., increases or decreases) by 0 to 10 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the subject's Boudle VAS score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS score is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, a subject's Boudl VAS score after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is reduced by 10 to 1300. For example, a subject's Boudl VAS score may be reduced by 10 to 1300 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 racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Bowdle VAS score is reduced by 10 to 100, 10 to 200, 10 to 300, 10 to 400, 10 to 500, 10 to 600, 10 to 700, 10 to 800, 10 to 900, 10 to 1000, 10 to 1100, 10 to 1200, 1200 to 1300, 1100 to 1300, 1000 to 1300, 900 to 1300, 800 to 1300, 700 to 1300, 600 to 1300, 500 to 1300, 400 to 1300, 300 to 1300, 200 to 1300, or 100 to 1300 following intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS score is reduced as described herein between 5 minutes and 24 hours after intranasal administration of racemic ketamine 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Boudle VAS score is measured between about 1 hour to 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (or administration of an equivalent dose of ketamine or a pharmaceutically acceptable salt thereof, or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0308] The CADSS is a 23-item questionnaire assessing dissociative states in subjects. See, for example, Luckenbaugh, et al., J. Affect. Disord., Vol. 159, pp. 56-61 (2014), incorporated herein by reference in its entirety. Each question is recorded on a scale of 0 to 4, with 0 = not at all, 1 = mild, 2 = moderate, 3 = severe, and 4 = extreme; questions include, "Do you see things in slow motion?", "Do you feel like you are watching things as an observer or bystander?", and "Do things seem particularly clear and real?" The total score ranges from 0 to 92, with higher scores indicating more severe dissociative states in subjects.

[0309] The CADSS assessment includes, but is not limited to, statements such as: things appearing in slow motion, things seeming unreal, feeling detached from what is happening, out-of-body experiences, feeling as a spectator or observer, feeling disconnected from the body, feeling that the body has changed, people appearing motionless / dead / mechanical, objects appearing different, feeling that colors are less intense, things appearing through a tunnel / wide-angle lens, feeling like things are taking longer, feeling like things are happening faster, feeling like unexplainable things are happening, not knowing what is happening, changes in the intensity of sounds, feeling especially clear, feeling like one is looking through a fog, and colors appearing brighter.The CADSS typically includes 23 statements that subjects rate on a scale of 0 to 4 for a score 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, and a score of 4 indicates that the subject agreed to the highest level with the question posed, e.g., 0 reflects complete disagreement, 1 reflects slight agreement, 2 reflects moderate agreement, 3 reflects strict agreement, and 4 reflects the highest level of agreement with the question posed. Thus, lower individual and overall scores indicate less dissociation. In some embodiments, a portion of the scale is completed by the subject. In some embodiments, a portion of the scale is completed by a trained observer of the subject.

[0310] In some embodiments, the subject's CADSS is 0 to 10 prior to intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, as described herein. For example, the CADSS is 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 9 to 10, 8 to 10, 7 to 10, 6 to 10, 5 to 10, 4 to 10, 3 to 10, 2 to 10, or 1 to 10 prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8 prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's CADSS score is measured from about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine, 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS scale score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the subject's CADSS is 0 to 10 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 CADSS is 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 9 to 10, 8 to 10, 7 to 10, 6 to 10, 5 to 10, 4 to 10, 3 to 10, 2 to 10, or 1 to 10. In some embodiments, the subject's CADSS is 2 to 6, 3 to 7, or 4 to 8 after intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's CADSS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS scale score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the subject's CADSS is 0 to 10 before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and the subject's CADSS is 0 to 10 after intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the nasal concentration is 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 9 to 10, 8 to 10, 7 to 10, 6 to 10, 5 to 10, 4 to 10, 3 to 10, 2 to 10, or 1 to 10 before intranasal administration of racemic ketamine described herein, and 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 9 to 10, 8 to 10, 7 to 10, 6 to 10, 5 to 10, 4 to 10, 3 to 10, 2 to 10, or 1 to 10 after intranasal administration of racemic ketamine described herein. In some embodiments, the subject's CADSS before intranasal administration of racemic ketamine described herein is 2 to 6, 3 to 7, or 4 to 8, and the subject's CADSS after intranasal administration of racemic ketamine described herein is 2 to 6, 3 to 7, or 4 to 8. In some embodiments, the subject's CADSS score is measured about 5 minutes to about 24 hours before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, and the subject's CADSS score is measured about 5 minutes to about 24 hours after intranasal administration of racemic ketamine, 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 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or 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 racemic ketamine or a pharmaceutically acceptable salt thereof.In some embodiments, the subject's CADSS scale score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's CADSS scale score is measured about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours before, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the subject's CADSS score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's CADSS score changes (i.e., increases or decreases) by about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is substantially the same about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and about 5 minutes to about 24 hours after intranasal administration of racemic ketamine 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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, about 6 hours to 24 hours, 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, a subject's CADSS score is reduced by about 1 to about 91 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, compared to the score observed following administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's CADDS score may be reduced by about 10 to about 91 following 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 racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's CADSS score is reduced by about 1 to about 90, about 1 to about 80, about 1 to about 70, about 1 to about 60, 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 80 to about 91, about 70 to about 91, about 60 to about 91, about 50 to about 91, about 40 to about 91, about 30 to about 91, about 20 to about 91, or about 10 to about 91 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, and / or after intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is reduced about 5 minutes to about 24 hours 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 and / or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof, e.g., 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 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 and / or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof.In som...

Claims

A composition for use in a method of treating a subject in need of treatment for agitation associated with MDD, TRD, PTSD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder, comprising racemic ketamine, or a pharmaceutically acceptable salt thereof, wherein the composition is administered intranasally to the subject. The composition according to claim 1, wherein the method further comprises shortening the subject's hospital stay compared to intravenous administration of an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof; or compared to intranasal administration of an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof.

3. The composition according to claim 1, which resolves agitation associated with MDD, TRD, PTSD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder in the subject more rapidly compared to intravenous administration of an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof; or compared to intranasal administration of an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof.

4. The composition according to any one of claims 1 to 3, wherein the degree of one or more side effects of intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof, is less compared to intravenous administration of an equivalent dose of racemic ketamine, or a pharmaceutically acceptable salt thereof.

5. The composition according to claim 4, wherein the one or more side effects are less compared to the one or more side effects observed after intravenous administration of an equivalent dose of (S)-ketamine, or a pharmaceutically acceptable salt thereof.

6. The composition according to claim 4, wherein the one or more side effects include cognitive impairment, movement disorder, dizziness, nausea, vomiting, sweating, increased blood pressure, ulcerative cystitis, or interstitial cystitis.

7. The composition according to claim 6, wherein the cognitive impairment includes one or more of abnormal mental effects, dizziness, abnormal taste, sedation, dissociation, a feeling of intoxication, changes in hearing, changes in vision, and hallucinations.

8. The composition according to claim 6, wherein the cognitive impairment includes sedation. The composition according to claim 1, wherein no clinically significant sedation is observed in the subject within about 24 hours after intranasal administration of the composition.

10. The composition according to claim 1, wherein no clinically significant sedation is observed in the subject about 4 hours after intranasal administration of the composition.

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

12. The composition according to claim 1, wherein no clinically significant dissociation is observed in the subject within about 24 hours after intranasal administration of the composition.

13. The composition according to claim 1, wherein no clinically significant dissociation is observed in the subject about 4 hours after intranasal administration of the composition.

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

15. Use of a therapeutically effective amount of racemic ketamine, or a pharmaceutically acceptable salt thereof, characterized by being in the manufacture of a medicament for treating a subject in need of treatment for MDD, TRD, PTSD, bipolar depression, postpartum depression, chronic pain, neuropathic pain, Rett syndrome, epilepsy, agitation associated with dementia, agitation associated with schizophrenia, or agitation associated with bipolar disorder, wherein the medicament is for intranasal administration to the subject.

Images