Reducing side effects of NMDA antagonists

Abstract

The present disclosure relates to compositions comprising racemic ketamine or a pharmaceutically acceptable salt thereof for use in the treatment of psychiatric disorders such as suicide propensity, suicide idea, major depression, anti-therapeutic depression, and post-traumatic stress disorders.

Description

Technical Field

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

[0002] Depression is one of the most disabling medical conditions and a major public health problem. It typically appears early in life, may persist chronically throughout life, and can adversely affect the prognosis of other medical conditions such as cardiovascular and neurological disorders.

[0003] While antidepressants and cognitive behavioral therapy may be effective for some individuals with depression, at most 20% do not respond to these interventions, and many of those who do respond eventually relapse. Similarly, it is estimated that 50% of individuals with depression receive only partial (inadequate) treatment with available clinical interventions. See Al Harbi, Patient Prefer. Adherence, Vol. 6, pp. 369–388 (2012). In the NIMH Sequential Treatment Alternatives for Depression (STAR*D) study, approximately half of the patients treated with first-line antidepressants experienced symptom reduction to at least half of their original intensity, and only about one-third achieved remission (Chan 2013). While these patients may eventually recover, many require a trial-and-error approach to therapy, and over time, many eventually develop treatment-resistant depression. See, for example, Sackheim, Journal of Clinical Psychiatry, Vol. 62, Supplement 16, pp. 10–17 (2001). This can lead to even more serious symptoms, such as suicidal ideation and suicidal tendencies. Suicide remains a clear, current, and growing public health problem, but this tragedy can be potentially preventable. The incidence of suicide is particularly high among individuals with undiagnosed or undertreated mental disorders.

[0004] The discovery of tricyclic antidepressants and monoamine oxidase inhibitors has revolutionized the treatment of depression. However, even recently developed medications for depression take weeks to months to reach their full effect and may not be effective for all subjects at any safe dose. For example, most antidepressants take an average of six weeks to begin acting on depressive symptoms. Some patients do not respond to antidepressants at all, and for others, only some types of medications seem to improve symptoms. Meanwhile, individuals continue to suffer from depression, are at risk of self-harm, and experience negative impacts on their personal and professional lives. See, for example, Burcusa and Iacono, *Clinical Psychology Review*, Vol. 27, No. 8, pp. 959-985 (2007). Providing rapidly acting and long-lasting antidepressant effects would have a significant impact on public health. Summary of the Invention

[0005] Details of one or more embodiments are set forth in the following description. Other features, objectives, and advantages of the invention will become apparent from the description and the claims.

[0006] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0007] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0008] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0009] Some embodiments provide a method for reducing one or more side effects of ketamine in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject.

[0010] 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. Attached Figure Description

[0011] abbreviation

[0012] N: Number of observations; SD: Standard deviation; Min: Minimum; Max: Maximum; IN: Intranasal.

[0013] Figure 1A-1C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 1A ), 75mg racemic ketamine ( Figure 1B ) or 90mg racemic ketamine ( Figure 1C (Table of pharmacokinetic parameters of ketamine on day 1).

[0014] Figure 2A-2C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 2A ), 75mg racemic ketamine ( Figure 2B ) or 90mg racemic ketamine ( Figure 2C (Table of pharmacokinetic parameters of ketamine on day 4).

[0015] Figures 3A-3C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 3A ), 75mg racemic ketamine ( Figure 3B ) or 90mg racemic ketamine ( Figure 3C (Table of pharmacokinetic parameters of ketamine on day 8).

[0016] Figures 4A-4C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 4A ), 75mg racemic ketamine ( Figure 4B ) or 90mg racemic ketamine ( Figure 4C Table of pharmacokinetic parameters of norketamine on day 1.

[0017] Figures 5A-5C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 5A ), 75mg racemic ketamine ( Figure 5B ) or 90mg racemic ketamine ( Figure 5C Table of pharmacokinetic parameters of norketamine on day 4.

[0018] Figures 6A-6C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 6A ), 75mg racemic ketamine ( Figure 6B ) or 90mg racemic ketamine ( Figure 6C Table of pharmacokinetic parameters of norketamine on day 8.

[0019] Figures 7A-7C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 7A ), 75mg racemic ketamine ( Figure 7B ) or 90mg racemic ketamine ( Figure 7C Table of pharmacokinetic parameters of hydroxynorketamine on day 1.

[0020] Figures 8A-8C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 8A ), 75mg racemic ketamine ( Figure 8B ) or 90mg racemic ketamine ( Figure 8C Table of pharmacokinetic parameters of hydroxynorketamine on day 4.

[0021] Figures 9A-9C This describes part A of the study described in Example 1 regarding 30 mg of racemic ketamine ( Figure 9A ), 75mg racemic ketamine ( Figure 9B ) or 90mg racemic ketamine ( Figure 9C Table of pharmacokinetic parameters of hydroxynorketamine on day 8.

[0022] Figures 10A-10C This describes part B of the study described in Example 1 regarding racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent to a dose of 60 mg IN) + placebo IN, on day 1 ( Figure 10A Day 4 Figure 10B ) or the 8th day ( Figure 10C Table of pharmacokinetic parameters for ketamine.

[0023] Figure 11A-11C This describes part B of the study described in Example 1 regarding racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent to a dose of 60 mg IN) + placebo IN, on day 1 ( Figure 11A Day 4 Figure 11B ) or the 8th day ( Figure 11C Table of pharmacokinetic parameters for norketamine.

[0024] Figures 12A-12C This describes part B of the study described in Example 1 regarding racemic ketamine 60 mg IN + placebo IV and ketamine IV 0.3 mg / kg racemic ketamine (equivalent to a dose of 60 mg IN) + placebo IN, on day 1 ( Figure 12A Day 4 Figure 12B ) or the 8th day ( Figure 12C Table of pharmacokinetic parameters for hydroxynorketamine.

[0025] Figures 13A-13B This is a table describing the MADRS depression scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 13A ) and charts ( Figure 13B ).

[0026] Figures 14A-14B This is a table describing the CGIS-SI / B suicidal ideation scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 14A ) and charts ( Figure 14B ).

[0027] Figures 15A-15B This is a table describing the S-STS suicidal tendency scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 15A ) and charts ( Figure 15B ).

[0028] Figures 16A-16B This is a table describing the PGIS-SI / B suicidal ideation scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 16A ) and charts ( Figure 16B ).

[0029] Figure 17 This is a table describing the CGIC-SI / B suicidal ideation scores of Subject 1 and Subject 2 from day 1 to day 8, as described in Example 3 of the study.

[0030] Figure 18 This is a table describing the PGIC-SI / B scores of Subject 1 and Subject 2 from day 1 to day 9 as described in Example 3 of the study.

[0031] Figures 19A-19B This is a table describing the MADRS item 10 scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 19A ) and charts ( Figure 19B ).

[0032] Figures 20A-20B This is a table describing the STS CMCM (“Risk of Suicide at This Time”) scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 20A ) and charts ( Figure 20B ).

[0033] Figures 21A-21BThis is a table describing the STS CMCM (“Risk of Suicide in the Next 7 Days”) scores of Subject 1 and Subject 2 from day 1 to day 9, as described in Example 3 of the study. Figure 21A ) and charts ( Figure 21B ).

[0034] Figure 22 This is a table describing the MOAA / S alertness / sedation scores of Subject 1 and Subject 2 on days 1 and 4, from before administration to 24 hours, as described in Example 3 of the study.

[0035] Figure 23 This is a table describing the CADSS separation scores of Subject 1 and Subject 2 from before administration to 24 hours on days 1 and 4, as described in Example 3 of the study.

[0036] Figure 24 This is a table describing the C-SSRS scores of Subject 1 from day 1 to day 9 and Subject 2 from day 1 to day 4, as described in Example 3 of the study. Detailed Implementation

[0037] definition

[0038] To facilitate understanding of this disclosure, certain terms are first defined. As used in this application, unless otherwise expressly stated herein, each of the following terms shall have the meaning described below. Additional definitions are set forth throughout the application.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art related to this disclosure. The following terms are defined for the purposes of this disclosure.

[0040] Units, prefixes, and symbols are represented in their International System of Units (SI) accepted form. Numerical ranges include numbers with defined ranges. The headings provided herein are not intended to limit any aspect of this disclosure, which can be obtained by referring to the entire specification. Therefore, the terms defined below immediately are defined more fully by referring to the entire specification.

[0041] As used herein, the terms “an,” “a,” or “the” include not only aspects having one member but also aspects having more than one member. For example, the singular forms “an,” “a,” and “the” include plural indicators unless the context clearly indicates otherwise. Thus, for example, a reference to “a cell” includes a plurality of such cells, a reference to “reagent” includes a reference to one or more reagents known to those skilled in the art, and so on.

[0042] The term “and / or” as used herein shall be considered a specific disclosure of each of two particular features or components having or not having the other. Therefore, the term “and / or” as used in phrases such as “A and / or B” is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover 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 (alone); B (alone); and C (alone).

[0043] As used herein, the terms “about” and “approximately” generally refer to an acceptable degree of error in a quantity measured 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. Any reference to “about X” specifically indicates at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” is intended to provide written descriptional support for the limitation of the claims, such as “0.98X”. The terms “about” and “approximately” specifically cover and describe the given quantity itself when referring to it.

[0044] When “about” is applied at the beginning of a numerical range, it applies to both ends of the range. Therefore, “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 all values ​​in the set. Therefore, “about 5 mg, 10 mg or 15 mg” is equivalent to “about 5 mg, about 10 mg or about 15 mg”.

[0045] "Raceous ketamine" refers to a 1:1 mixture of two enantiomers of ketamine: (R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone and (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone.

[0046] "Equivalent dose" refers to the equivalent dose of an active agent based on bioavailability. Equivalent doses based on bioavailability can be determined by comparing the extent and rate of drug absorption at two or more doses of the active agent (e.g., doses formulated as intranasal and intravenous preparations, respectively), for example, by determining the area under the blood or plasma concentration-time curve (AUC) and / or the maximum concentration (C). 最大 Therefore, as used herein, the equivalent dose based on bioavailability exhibits AUC and / or C at each of the two doses. 最大 They exist within approximately 80% to approximately 125% of each other.

[0047] “Suicidal ideation” refers to a mental disorder in which the subject experiences one or more of the following: desire for death, non-specific suicidal thoughts, unintentional voluntary thoughts, voluntary thoughts with a certain intention to act, and voluntary thoughts with a specific plan or intention. The presence and frequency of these thoughts and / or experiences can be assessed using several psychiatric tests known in the art, such as the Columbia Suicide Severity Rating Scale. See, for example, Ghasemi et al., Health Promot. Perspect., Vol. 5, No. 3, pp. 156-168 (2015), which is incorporated herein by reference in its entirety.

[0048] “Suicidal tendency” refers to a subject’s experience of suicidal ideation and the active steps toward suicide, including, for example, suicide attempts. See, for example, Klonsky et al., Annu. Rev. Clin. Psychol., Vol. 12, pp. 307-330 (2016), which is incorporated herein by reference in its entirety.

[0049] "Treatment" or "therapy" for a subject refers to any type of intervention or procedure performed on a subject or administration of an active agent to a subject with the aim of reversing, alleviating, improving, suppressing, or slowing the onset, progression, development, severity, or recurrence of symptoms, complications, disease, or biochemical markers associated with the disease. In some embodiments, "treatment" includes the resolution of a specific condition, including a reduction in one or more symptoms of the condition and / or a reduction in the severity of one or more symptoms associated with the condition.

[0050] "Administering" or "administration" means the physical introduction of a therapeutic agent into a subject using any of the various methods and delivery systems known to those skilled in the art. Routes of administration may include oral, intravenous, intranasal, intramuscular, subcutaneous, intraperitoneal, spinal, or other non-parenteral administration routes, such as by injection or infusion (e.g., intravenous infusion). Administration may also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0051] "Subject" can be 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.

[0052] The “effective amount” or “therapeutic effective amount” of a therapeutic agent is any amount of medicine that, when used alone or in combination with one or more additional therapies, slows the onset of a mental disorder or promotes the resolution of the disorder, as demonstrated by a reduction in the severity of symptoms, an increase in the frequency and duration of asymptomatic periods, or an improvement in impairment or disability resulting from the distress caused by the disorder. The ability of one or more additional therapies to promote the resolution of the disorder can be assessed using a variety of methods known to practitioners in the art, such as in human subjects during clinical trials, in animal model systems where efficacy in humans can be predicted, or by measuring the activity of the agent in an in vitro assay.

[0053] As used herein, a measure of therapeutic effect is “clinically significant” based on its actual importance. For example, whether the therapeutic effect has a genuine, perceptible, and / or noteworthy effect on the subject (e.g., a lack of clinically significant effect when the differences among subjects are small enough to make them appear similar, such as before and after administration of the treatment described herein). Those skilled in the art will recognize whether a particular effect is “clinically significant.” For example, the effect of a subject with a baseline score (using any scale described herein) indicative of severe depression and / or suicidal tendency and a post-treatment score indicative of remission of severe depression and / or suicidal tendency would be clinically significant.

[0054] As used in this article, "AUC" 0-t "" refers to the area under the plasma concentration-time curve from time = 0 to the point where the last measurable concentration is reached. In some embodiments, the last measurable concentration occurs at t = 32 hours (e.g., AUC). 0-t =AUC 0-32 ).

[0055] A “non-responder” subject is one who has been or is currently being treated with one or more therapies that have not provided clinically significant changes to the expected outcome (e.g., non-responder subjects include patients who are refractory to a particular treatment). For example, a subject may not show a measurable change in response to a therapy. In depression scales, non-responder subjects may also show, for example, positive changes in their scores, but these changes are not clinically significant.

[0056] As used herein, a psychiatric assessment or side effect spectrum test score that is “substantially similar” or “substantially identical” to a reference score corresponds to the same score, wherein those skilled in the art will understand that a particular test score may vary within a reasonable range (e.g., ±10%) while still describing a given value, due to factors such as experimental error, routine subject-to-subject assessment, and routine statistical analysis.

[0057] The phrase “pharmaceutically acceptable” means that a substance or composition must be chemically and / or toxicologically compatible with other ingredients, including the compound, and / or with the mammals treated with the compound.

[0058] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that facilitates the application of an active agent to cells, organisms, or subjects. "Pharmaceutically acceptable carrier" means a carrier or excipient that can be included in the compositions disclosed herein and will not cause significant adverse toxicological effects on subjects. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and colorants, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic agents, and absorption delay agents. Carriers can also be substances used to provide stability, sterility, and isotonicity to formulations (e.g., antimicrobial preservatives, antioxidants, chelating agents, and buffers), to prevent microbial action (e.g., antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc.), or to provide edible flavor to formulations. In some cases, the carrier is a reagent that facilitates the delivery of small molecule drugs or antibodies to target cells or tissues. Those skilled in the art will recognize that other drug carriers may be used in this disclosure.

[0059] As used in the methods described herein, the term "reduction" refers to a decrease in the indicated parameter relative to a baseline measurement (or multiple measurements) of the same parameter taken from a subject prior to the initiation of administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or a decrease in the indicated parameter relative to a baseline measurement (or multiple measurements) of the same parameter. In some embodiments, the same parameter is measured in healthy subjects (e.g., subjects without the mental disorders described herein). In some embodiments, the same parameter is measured relative to another treatment modality (e.g., standard of care for the mental disorders described herein).

[0060] As used herein, the term "increase" refers to an increase in the indicated parameter relative to a baseline measurement (or multiple measurements) of the same parameter taken from a subject prior to the initiation of administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or an increase in the indicated parameter relative to a baseline measurement (or multiple measurements) of the same parameter. In some embodiments, the same parameter is measured in healthy subjects (e.g., subjects without the mental disorders described herein). In some embodiments, the same parameter is measured relative to another treatment modality (e.g., standard of care for the mental disorders described herein).

[0061] The terms “synergy” or “synergism” 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. “Synergistic dose” or “synergistic effective dose” is the amount of the combination of two combination partners that produces a synergistic effect, as defined herein as “synergistic.” Determining the synergistic interaction between two combination partners, the optimal range of action, and the absolute dose range for each component can be determined by administering the combination partners to a subject requiring treatment within different w / w (weight / weight) ratio ranges and doses. However, observations of synergy in in vitro or in vivo models can predict effects in humans and other species, and in vitro or in vivo models exist as described herein to measure synergistic effects. Exemplary synergistic effects include, but are not limited to, enhanced therapeutic efficacy, reduced dose at equivalent or increased efficacy levels, reduced or delayed development of resistance, and simultaneous enhancement or equivalent therapeutic effect (e.g., the same therapeutic effect as at least one of the therapeutic agents) and undesirable pharmacological effects (e.g., side effects and adverse events) of at least one of the therapeutic agents.

[0062] For example, the synergistic ratio of two therapeutic agents can be identified by determining synergistic effects in, for example, in in vivo models of depression recognized in the art (e.g., animal models) (e.g., hopelessness-based, reward-based, or anxiety-based mouse models).

[0063] As stated herein, unless otherwise specified, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the range stated, and, where appropriate, its fractions (such as one-tenth and one-hundredth of an integer).

[0064] Unless otherwise stated, any reference to the amount of ketamine in this disclosure is based on the free equivalent of ketamine. For example, 30 mg of ketamine means 30 mg of ketamine in its free form or an equivalent amount of ketamine in its salt form (e.g., ketamine hydrochloride).

[0065] This document further details various aspects of this disclosure.

[0066] introduction

[0067] Depression is characterized by depressed mood and a significant reduction in interest in or enjoyment of activities. Other symptoms may include significant weight loss or gain, decreased or increased appetite, insomnia or somnolence, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, impaired or indecisive thinking or concentration, and recurrent thoughts of death, suicide, or suicide attempts. See Kennedy, Dialogues Clin. Neurosci., Vol. 10, No. 3, pp. 271-277 (2008). Various physical symptoms may also be present. Although depressed mood is common, a diagnosis of depression is only made when symptoms reach a threshold and persist for at least two weeks. The severity of depression can range from mild to very severe. It is most often episodic but can be recurrent or chronic. More than 50% of those who initially experience a single major depressive episode will eventually develop another form of depression. Unfortunately, current pharmacological interventions for depression take weeks to months to achieve their full therapeutic effect, and many subjects develop or become resistant to these therapies. See, for example, Kupfer, Clinical Neuroscience Dialogue, Vol. 7, No. 3, pp. 191-205 (2005).

[0068] Ketamine has been used as a short-acting intravenous anesthetic in both humans and animals. In addition to analgesia, ketamine produces a state of “dissociative anesthesia” and is also used for recreational induction of these effects. See, for example, Li and Vlisides, Frontiers in Human Neuroscience, Vol. 10, Item 612, pp. 1–15 (2016); and the article dated February 11, 2020. (S)-ketamine) packaging insert; www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 211243s003lbl.pdf The references mentioned herein are hereby incorporated in their entirety by reference.

[0069] At low doses, ketamine produces mild sedation and euphoria, while at high doses, individuals experience dissociative efficacy similar to phencyclidine hydrochloride (PCP). Other somatic effects of ketamine include dizziness, balance problems, nausea, vomiting, sweating, tremor, dystonia, respiratory depression, and sleep apnea. See Zanos et al., *Pharmacological Reviews*, Vol. 70, No. 3, pp. 621-660 (2018). The most commonly observed adverse events after ketamine administration are psychogenic phenomena such as floating sensations, vivid dreams, hallucinations, hypertonia, and delirium. These effects can persist for up to 24 hours after administration. See Perumal et al., *Journal of Pharmaceutical Practice Research*, Vol. 4, No. 2, pp. 89-93 (2015).

[0070] After application, ketamine is demethylated to form norketamine, and both ketamine and norketamine can be hydroxylated to form hydroxyphenylketamine, 6-hydroxyketamine, hydroxyphenyl norketamine, and 6-hydroxynorketamine (also referred to herein as hydroxynorketamine). The structures of these (racemic) compounds are shown below.

[0071]

[0072] Each of these metabolites possesses a unique receptor binding spectrum and pharmacological activity. See, for example, Zanos et al., *Pharmacological Reviews*, Vol. 70, No. 3, pp. 621-660 (2018). For instance, racemic ketamine at approximately 1.06 μM K... i Binding to NMDA receptors, (S)-norketamine and (R)-norketamine K i The s values ​​were approximately 2.25 μM and 26.46 μM, respectively, and the K values ​​for (2S,6S)-hydroxydemethylketamine and (2R,6R)-hydroxydemethylketamine were... iThe concentrations were approximately 21.19 μM and above 100 μM, respectively. See Moaddel et al., *European Journal of Pharmacology*, Vol. 698, pp. 228–234 (2013). Both ketamine and norketamine have anesthetic activity, and subjects given either ketamine or norketamine exhibited increased motor activity during the recovery period from anesthesia. Conversely, the same dose of 6-hydroxynorketamine did not provide anesthetic or spontaneous activity. See Leung and Baillie, *Journal of Medicinal Chemistry*, Vol. 29, pp. 2396–2399 (1986). However, like ketamine, 6-hydroxynorketamine does exhibit antidepressant properties. See Pham et al., *Biological Psychiatry*, Vol. 84, No. 1, pp. e3–e6 (2018).

[0073] This application is partly based on the surprising finding that intranasal administration of racemic ketamine offers advantageous properties compared to intravenous administration of racemic ketamine or intranasal administration of (R)- or (S)-ketamine (e.g., at least about 95% (R)-ketamine or at least about 95% (S)-ketamine). Furthermore, the different physiological and psychological effects of each enantiomer of ketamine and its corresponding metabolites can provide beneficial treatments for a variety of mental disorders, including treatments with reduced negative side effects.

[0074] Mixtures

[0075] Some embodiments provide a pharmaceutical composition comprising about 5% (w / v) to about 20% (w / v) of racemic ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; wherein the composition is formulated for intranasal administration.

[0076] In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 7.5% (w / v) to about 15% (w / v) of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 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 between these values. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 7.5% (w / v) of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 15% (w / v) of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, each dose of the formulation provides about 30 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. 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 between these values. In some embodiments, each dose of the formulation provides about 45 mg to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 60 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 30 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the formulation provides a total of about 30 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof over two doses (e.g., two sprays 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 between these values. In some embodiments, the formulation provides a total of about 45 mg to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof over two doses. In some embodiments, the formulation provides a total of about 60 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides a total 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.

[0079] 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 benzyl chloride). In some embodiments, the preservative is benzalkonium chloride. In some embodiments, racemic ketamine is in the form of a pharmaceutically acceptable salt, such as hydrochloride. In some embodiments, the composition further comprises about 0.01 mg / mL to about 0.04 mg / mL benzalkonium chloride. In some embodiments, the composition further comprises about 0.02 mg / mL benzalkonium chloride.

[0080] In some embodiments, the composition further comprises one or more excipients selected from the group consisting of surfactants, antioxidants, buffers, and absorption enhancers.

[0081] Exemplary surfactants include, but are not limited to, ionic surfactants, nonionic surfactants, and amphoteric surfactants. Examples include tweens, PEG, sorbitan esters, and ethoxylated fatty acids. In some embodiments, the composition further comprises a surfactant in an amount of about 1% to about 10% (w / v).

[0082] Exemplary antioxidants include, but are not limited to, tocopherol, butylated hydroxytoluene, sodium metabisulfite, potassium metabisulfite, and ascorbyl palmitate. In some embodiments, the composition further includes an antioxidant in an amount of about 0.001% to about 5% (w / w).

[0083] Exemplary absorption enhancers include, but are not limited to, chitosan, caprylate, and cyclopentadecanolactone. In some embodiments, the composition further includes an amount of about 1% to about 10% (w / w) of the absorption enhancer.

[0084] Exemplary buffers include, but are not limited to, buffers based on citric acid, phosphoric acid, acetic acid, lactic acid, fumaric acid, tartaric acid, malic acid, and amino acids. In some embodiments, the composition further includes a buffer in an amount of about 0.1% to about 5% (w / w).

[0085] In some embodiments, the pharmaceutically acceptable carrier is water or saline solution.

[0086] In some embodiments, the formulations are described in Table 1.

[0087] Table 1

[0088]

[0089] *1mg ketamine = 1.15mg ketamine hydrochloride

[0090] With each single spray containing 15 mg, the formulations described in Table 1 provide a dose of 30 mg with 2 sprays, a dose of 60 mg with 4 sprays, and a dose of 90 mg with 6 sprays.

[0091] In some embodiments, the formulations are described in Table 2.

[0092] Table 2

[0093]

[0094] *1mg ketamine = 1.15mg ketamine hydrochloride

[0095] With a dose of 7.5 mg per spray, the formulations described in Table 2 provide a dose of 30 mg with 4 sprays, a dose of 60 mg with 8 sprays, and a dose of 90 mg with 12 sprays.

[0096] Treatment

[0097] Some embodiments provide a method for treating a mental disorder (e.g., suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder) in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0098] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0099] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0100] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the subject's nose.

[0101] In some embodiments described herein, the regression of mental disorders is faster than that observed after administration of an equivalent dose of intravenous or intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the regression of suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder in subjects is faster. In some embodiments, the regression of mental disorders is about 1.2 × to about 10 × of the regression observed after administration of an equivalent dose of intravenous or intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, such as about 1.2 ×, 1.4 ×, 1.6 ×, 1.8 ×, 2 ×, 2.5 ×, 3 ×, 3.5 ×, 4 ×, 4.5 ×, 5 ×, 5.5 ×, 6 ×, 6.5 ×, 7 ×, 7.5 ×, 8 ×, 8.5 ×, 9 ×, 9.5 ×, 10 ×, or any value between these values.

[0102] In some embodiments described herein, the regression of mental disorders is faster than that 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 regression of suicidal tendencies, suicidal ideation, major depressive disorder, anti-treatment depressive disorder, or post-traumatic stress disorder in subjects is faster. In some embodiments, the regression of mental disorders is about 1.2 × to about 10 × of the regression observed after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, such as about 1.2 ×, 1.4 ×, 1.6 ×, 1.8 ×, 2 ×, 2.5 ×, 3 ×, 3.5 ×, 4 ×, 4.5 ×, 5 ×, 5.5 ×, 6 ×, 6.5 ×, 7 ×, 7.5 ×, 8 ×, 8.5 ×, 9 ×, 9.5 ×, 10 ×, or any value between these values.

[0103] In some of the embodiments described herein, subject adherence to treatment of mental disorders was improved relative to equivalent doses of intravenous or intravenous racemic ketamine or pharmaceutically acceptable salts thereof. For example, subject adherence to treatment for suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder was improved.

[0104] Many methods can be used to measure a subject's suicidal tendencies and / or suicidal ideation. Non-limiting examples include the Mini International Psychiatric Interview Version 7.02 for Suicidal Disorders (MINI), Clinical Global Impression (CGI), Patient Global Impression (PGI), the Columbia-Suicide Severity Rating Scale (CSSRS), and the Montgomery-Asperger's Depression Rating Scale. The Depression Rating Scale (MADRS) and the Sheehan Suicide Tracking Scale Clinically Meaningful Change Measure (STS-CMCM). See, for example, Ghasemi et al., Health Promotion Perspectives, Vol. 5, No. 3, pp. 156–168 (2015), which is incorporated herein by reference in its entirety.

[0105] The DSM-5 Mini-Indication on Suicidal Ideation Disorders (MINI) can be administered (e.g., during screening) to confirm a preliminary diagnosis of MDD, to assess current suicidal ideation and behavior (SI / B), and to evaluate comorbid neuropsychiatric disorders during a semi-structured clinical interview. The MINI can inform and complement a full psychiatric intake assessment when administered by qualified and trained personnel. See, for example, Sheehan et al., *Journal of Clinical Psychiatry*, 1998; 59(Supplement 20): 22-33; Sheehan and Giddens (2015), *Suicidality: A Roadmap for Assessment and Treatment* (1st ed.), Tampa, FL: Harm Research Press, November 2015 (Source: HarmResearch.org) ISBN: 978-0-9969729-0-1; and Sheehan and Giddens (2016), *Suicidality Assessment and Documentation for Healthcare Providers: A Brief, Practical Guide*. Guide. (1st Edition), Tampa, Florida: Harm Research Press, April 2016 (Source: HarmResearch.org) ISBN: 978-0-9969729-1-8).

[0106] The S-STS CMCM (version 01 / 01 / 19) is a measure of clinician assessment of SI / B outcomes using a standard 22-item scale and multiple patient and clinician-rated items. The first 16 items are assessed using a Likert-type scale ranging from “never” (0) to “extremely” (4), where a selection score (i.e., scoring four specific items based on the highest scores of two of these items) yields an overall score ranging from 0 to 52. The last six items are used only if the patient misses a visit and is unable to complete the scale; if the missed visit was due to a suicide attempt or completed suicide, the highest possible score is 100. The CMCM also received five different individual overall assessments: 1) the subject's assessment of the likelihood of a suicide attempt; 2) the subject's assessment of the treatment needed; 3) the clinician's overall severity of suicidal impulses, thoughts, and behaviors; 4) the clinician's assessment of the level of management required for the current suicide risk and suicidal tendencies; and 5) the clinician's assessment of the likelihood of the subject attempting suicide or dying by suicide in the next 7 days.

[0107] In some embodiments, 24 hours after intranasal administration of racemic ketamine, the subject's overall S-STS CMCM score decreased by approximately 15 to approximately 25 points. In some embodiments, the overall S-STS CMCM score decreased by approximately 15 to approximately 20 points, approximately 17 to approximately 22 points, or approximately 20 to approximately 25 points.

[0108] The CGIS-SI / B scale is a five-item clinically assessed measure of the severity of suicidal tendencies. Clinicians assess the most severe level of suicidal tendencies experienced by the subject during a specific recall period (e.g., at screening, at baseline, or before intranasal administration of racemic ketamine as described herein), with responses reported on a 5-point Likert scale ranging from 1 (no suicidal tendencies) to 5 (one of the most extreme suicidal tendencies). Clinicians can then assess how much the subject's suicidal tendencies have changed compared to their baseline symptoms on a 5-point Likert scale ranging from 1 (significantly improved) to 5 (very poor). See, for example, Meltzer et al., *Archives of General Psychiatry*, 2003; 60(1):82-91.

[0109] In some embodiments, the subject's CGIS-SI / B score is 4 or higher prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI / B score is 4 or higher approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score is 4, 5, 6, or 7 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CGIS-SI / B score decreases by 1 to 4 (e.g., a decrease of 1 to 4 units). In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CGIS-SI / B score decreases by 1 to 3 (e.g., a decrease of 1 to 3 units). In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CGIS-SI / B score decreases by 1 to 2 (e.g., a decrease of 1 to 2 units). In some embodiments, the subject's CGIS-SI / B score decreases by 3 or 4 points 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI / B score decreases by 3 points. In some embodiments, the subject's CGIS-SI / B score decreases by 4 points.

[0111] In some embodiments, the CGIS-SI / B score is 3 or higher (e.g., 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases 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 higher (e.g., 4 or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, a decrease of 1, 2, 3, or 4. In some embodiments, the CGIS-SI / B score is 2 to 5 (e.g., 2, 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, a decrease of 1, 2, 3, or 4. In some embodiments, the subject's CGIS-SI / B score was 2, 3, 4, or 5 approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and decreased by 1, 2, 3, or 4 approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, the subject's CGIS-SI / B score was 2, 3, 4, or 5 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and decreased by 1, 2, 3, or 4 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0112] In some embodiments, a first CGIS-SI / B score is determined approximately 1 hour to approximately 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof; and a second CGIS-SI / B score is determined approximately 1 hour to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, a first CGIS-SI / B score from the subject is determined approximately 4 hours to approximately 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, a second CGIS-SI / B score from the subject is determined approximately 4 hours to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, the first and second CGIS-SI / B scores are determined at equal time points before and after administration of racemic ketamine or a pharmaceutically acceptable saponin thereof, such as 4 hours. In some embodiments, a first CGIS-SI / B score and a second CGIS-SI / B score are determined at different times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0113] The PGIS-SI / B is a 5-point subject-rating scale used to assess a subject's perception of the overall severity of their illness. The scale is a single-item Likert scale ranging from 1 (no suicidal tendencies) to 5 (extreme suicidal tendencies). The PGIS-SI / B and PGIC-SI / B scales can be administered at various time points (e.g., before intranasal administration of racemic ketamine as described herein, or after one or more administrations of racemic ketamine). See, for example, Mohebbi et al., *European Journal of Psychiatry*, 2018;53:17-22.

[0114] In some embodiments, the subject's PGIS-SI / B score is 3 or higher prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 3 or higher approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PGIS-SI / B score is 3, 4, or 5 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PGIS-SI / B score decreases by 1 to 4 (e.g., a decrease of 1 to 4 units). In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PGIS-SI / B score decreases by 1 to 3 (e.g., a decrease of 1 to 3 units). In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the PGIS-SI / B score decreases by 1 to 2 (e.g., a decrease of 1 to 2 units).

[0116] In some embodiments, the PGIS-SI / B score is 3 or higher (e.g., 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI / B score is 4 or higher (e.g., 4 or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, a decrease of 1, 2, 3, or 4. In some embodiments, the PGIS-SI / B score is 3 to 5 (e.g., 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 4 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, a decrease of 1, 2, 3, or 4. In some embodiments, the subject's PGIS-SI / B score was 2, 3, 4, or 5 approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable saponins, and decreased by 1, 2, 3, or 4 approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable saponins. In some embodiments, the subject's PGIS-SI / B score was 2, 3, 4, or 5 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable saponins, and decreased by 1, 2, 3, or 4 approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable saponins. In some embodiments, the subject's PGIS-SI / B score decreased by 3 or 4 points 24 hours after intranasal administration of racemic ketamine. In some embodiments, the subject's PGIS-SI / B score decreased by 3 points. In some embodiments, the subject's PGIS-SI / B score decreased by 4 points.

[0117] In some embodiments, a first PGIS-SI / B score is determined approximately 1 hour to approximately 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof; and a second PGIS-SI / B score is determined approximately 1 hour to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, a first PGIS-SI / B score from the subject is determined approximately 4 hours to approximately 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, a second PGIS-SI / B score from the subject is determined approximately 4 hours to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, the first and second PGIS-SI / B scores are determined at equal time points before and after administration of racemic ketamine or a pharmaceutically acceptable saponin thereof, such as 4 hours. In some embodiments, a first PGIS-SI / B score and a second PGIS-SI / B score are determined at different times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the CSSRS is used to measure a subject's suicidal tendencies and / or suicidal ideation. The CSSRS can assess a subject's suicidal behavior and ideation. For example, the CSSRS can assess the lethality of suicide attempts and other characteristics of suicidal ideation, such as frequency, duration, controllability, motives, and deterrent power, all of which can significantly predict a completed suicide. See, for example, www.med.upenn.edu / cbti / assets / user-content / documents / Columbia-Suicide%20Severity%20Rating%20Scales%20(C-SSRS).pdf. In some embodiments, the CSSRS can be used to provide a summary of a subject's suicidal ideation and behavior.

[0119] The CSSRS provides several questions related to suicidal ideation, to which participants answer "yes" or "no." These questions cover: a desire to die; non-specific, active suicidal thoughts; active suicidal ideation without intention to act in any way (unplanned); active suicidal ideation with some intention to act; no specific plan; and active suicidal ideation with specific plan and intention. In addition, the CSSRS includes features rated by participants to help assess the intensity of the ideation. These characteristics include inquiries about the following: frequency (e.g., less than once a week, once a week, 2–5 times a week, daily or almost daily, and multiple times a day); duration (e.g., brief, less than one hour, 1–4 hours, 4–8 hours, and more than 8 hours); controllability (e.g., able to easily control thoughts, able to control thoughts with little difficulty, able to control thoughts with some difficulty, able to control thoughts with much difficulty, unable to control thoughts, and not attempting to control thoughts); deterrence (e.g., deterrence did prevent you from attempting suicide, deterrence likely prevented you, it is uncertain whether deterrence prevented you, deterrence likely did not prevent you, and deterrence definitely did not prevent you); and the reason for the intention (e.g., solely for attention, primarily for attention, equally for attention and to end / stop pain, primarily for end / stop pain, and solely for end / stop pain). CSSRS may also include questions relating to suicidal behavior and actual suicide attempts, such as inquiring about whether there has been an attempt; asking if anything has been done that has caused harm to oneself; and asking if the subject has done anything that could have resulted in his or her death.

[0120] In some embodiments, the CSSRS score is 3 or higher prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, subjects answered "yes" to 3, 4, 5, 6, or 7 questions on the CSSRS as described herein, approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 to approximately 4 hours, approximately 1.5 to approximately 5 hours, approximately 2 to approximately 6 hours, or approximately 5 to approximately 10 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject answers “yes” to 3, 4, 5, 6, or 7 questions on the CSSRS as described herein.

[0121] In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CSSRS score decreases by 1 to 7 (e.g., a decrease of 1 to 7 units). For example, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions. In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CSSRS decreases by 1 to 5 (e.g., 1 to 5 units). In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the CSSRS decreases by 1 to 3 (e.g., 1 to 3 units).

[0122] In some embodiments, the CSSRS score is 3 or higher (e.g., 3, 4, 5, 6, or 7) before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and decreases by 1 to 7 after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. For example, the subject answers "yes" to 3, 4, 5, 6, or 7 questions before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and answers "yes" to at least 1, 2, 3, 4, 5, 6, or 7 questions after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, the CSSRS score is 6 or higher (e.g., 6 or 7) before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and decreases by 1 to 7 after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, for example, a decrease of 1, 2, 3, 4, 5, 6, or 7. In some embodiments, the CSSRS score is 3 to 5 (e.g., 3, 4, or 5) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and decreases by 1 to 5 (e.g., a decrease of 1, 2, 3, 4, or 5) after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, subjects answer “yes” to 3, 4, 5, 6, or 7 questions on the CSSRS as described herein approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and answer “yes” to at least 1, 2, 3, 4, 5, 6, or 7 questions after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, subjects answered “yes” to 3, 4, 5, 6, or 7 questions on the CSSRS approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and answered “yes” to at least 1, 2, 3, 4, 5, 6, or 7 questions approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, subjects answered “yes” to 3, 4, 5, 6, or 7 questions on the CSSRS described herein approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and answered “yes” to at least 1, 2, 3, 4, 5, 6, or 7 questions approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, a first CSSRS score is determined approximately 1 hour to approximately 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof; and a second CSSRS score is determined approximately 1 hour to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, a first CSSRS score from the subject is determined approximately 4 hours to approximately 8 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, a second CSSRS score from the subject is determined approximately 4 hours to approximately 8 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the first and second CSSRS scores are determined at equal time points before and after administration of racemic ketamine or a pharmaceutically acceptable saline thereof, such as 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable saline thereof.

[0124] Two versions of the CSSRS can be used: a baseline version that assesses a subject's suicidal ideation and behavior over a lifetime and twelve months, and a "since last visit" version that assesses suicidal thoughts or behaviors the subject may have had since the last administration of the CSSRS. For example, in the "since last visit" version, if the attempt was made after the administration of the baseline version of the CSSRS, the subject should only answer "yes" to questions about the suicide attempt. In some embodiments, the baseline version of the CSSRS is administered to the subject before intranasal administration of racemic ketamine as described herein. For example, the baseline version of the CSSRS may be administered approximately 1 hour to approximately 6 months before intranasal administration of racemic ketamine as described herein. In some embodiments, the baseline version of the CSSRS is administered approximately 1 hour to approximately 6 hours, approximately 1 hour to approximately 1 day, approximately 1 hour to approximately 1 week, approximately 1 hour to approximately 1 month, approximately 1 hour to approximately 3 months, approximately 3 months to approximately 6 months, approximately 1 month to approximately 6 months, approximately 1 week to approximately 5 months, or approximately 1 day to approximately 6 months before intranasal administration of racemic ketamine as described herein.

[0125] In some embodiments, post-baseline suicidal ideation is defined as responding "yes" to at least one of the five suicidal ideation subcategories (i.e., desire to die; non-specific suicidal thoughts; voluntary suicidal ideation without action in any way; voluntary suicidal ideation with some action intent; and voluntary suicidal ideation with a specific plan and intention) when the CSSRS is applied after the baseline CSSRS. In some embodiments, post-baseline suicidal behavior is defined as responding "yes" to at least one of the four suicidal behavior subcategories (i.e., actual attempt, interrupted attempt, aborted attempt, and preparation for action or behavior) when the CSSRS is applied after the baseline CSSRS. In some embodiments, a trained rater completes the CSSRS based on responses from the subject.

[0126] In some embodiments, a version of the CSSRS since the last visit is administered to the subject after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS is administered to the subject approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS is administered to the subject approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the CSSRS score is about 0 to about 2 following intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof. For example, after intranasal administration of racemic ketamine as described herein, the subject answers “yes” to 0, 1, or 2 questions on the CSSRS. In some embodiments, the subject’s CSSRS score is as described herein from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, from 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, approximately 1 hour to approximately 4 hours, approximately 2 hours to approximately 12 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 4 hours to approximately 8 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject answers “yes” to 0, 1, or 2 questions on the CSSRS. In some embodiments, the CSSRS is a version of the CSSRS since the last visit.

[0128] In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's intention intensity on the CSSRS is about 0 to about 5. For example, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's intention intensity may be 0, 1, 2, 3, 4, or 5. In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, from about 5 minutes to about 24 hours, the subject's intention intensity is as described herein. For example, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, from about 5 minutes to 1 hour, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 hours to 24 hours, from about 12 hours to 24 hours, or from about 6 hours to 24 hours. In some embodiments, the subject’s intention strength is as described herein for approximately 1 to approximately 4 hours, approximately 1.5 to approximately 5 hours, approximately 2 to approximately 6 hours, or approximately 5 to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a version of the CSSRS since its last administration is given after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the CSSRS score decreases by about 1 to about 7 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject may answer "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions on the CSSRS compared to the number of "yes" answers given by the subject before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject answers "yes" to 1, 2, 3, 4, 5, 6, or 7 fewer questions on the CSSRS described herein. For example, from about 5 minutes to 1 hour, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 hours to 24 hours, from about 12 hours to 24 hours, or from about 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 to approximately 4 hours, approximately 1.5 to approximately 5 hours, approximately 2 to approximately 6 hours, or approximately 5 to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject answers “yes” to at least 1, 2, 3, 4, 5, 6, or 7 questions on the CSSRS described herein (e.g., relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the CSSRS administered since the last administration following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the baseline version of the CSSRS administered prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the intensity of intention on the CSSRS of a subject is lower after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the intensity of intention in a subject may decrease by about 1 to about 25 relative to the intensity of intention before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of intention in a subject may decrease by about 1 to about 5, about 1 to about 10, about 1 to about 15, about 1 to about 20, about 20 to about 25, about 15 to about 25, about 10 to about 25, or about 5 to about 25 relative to the intensity of intention before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of intention in a subject decreases as described herein from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's intention intensity is reduced as described herein (e.g., relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, a version of the CSSRS since the last administration is given after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a baseline version of the CSSRS given before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, subjects who received intranasal or intranasal racemic ketamine or a pharmaceutically acceptable salt thereof had CSSRS scores that were approximately 1 to approximately 7 points lower than subjects who received equivalent doses of intravenous or intranasal racemic ketamine or a pharmaceutically acceptable salt thereof, or (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the CSSRS score of subjects receiving intranasal or intravenous racemic ketamine or a pharmaceutically acceptable salt thereof improves at a faster rate than that of subjects receiving an equivalent dose of intravenous or intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, or (S)-ketamine or a pharmaceutically acceptable salt thereof. For example, compared to subjects receiving an equivalent dose of intravenous or intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, or (S)-ketamine or a pharmaceutically acceptable salt thereof, the CSSRS score improves 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 between these values.

[0133] The Montgomery-Asperger's Depression Rating Scale (MADRS) is a diagnostic questionnaire that can be used to measure the severity of a subject's depressive episodes. In some embodiments, the MADRS can be used to measure suicidal ideation. For example, the MADRS includes 10 items that relate to the following: 1) marked sadness (e.g., expressing depression, melancholy, and hopelessness, not just a general, transient low mood reflected in speech, facial expressions, and posture); 2) reported sadness (e.g., expressing a report of depressed mood, whether or not it is reflected outwardly and may include feelings of low mood, melancholy, or helplessness and hopelessness); 3) inner tension (e.g., expressing feelings of vague discomfort, irritability, inner turmoil, escalating into panic, fear, or distress); 4) reduced sleep (e.g., expressing a reduced experience of duration or depth of sleep compared to a subject's normal sleep pattern when well); 5) decreased appetite (e.g., expressing... 6) Loss of appetite compared to when one is in good health; 7) Difficulty concentrating (e.g., expressing difficulty concentrating to the point of incapacitated lack of concentration); 8) Burnout (e.g., expressing difficulty in starting daily activities or slowness in initiating and performing daily activities); 9) Feelings of inadequacy (e.g., expressing a subjective experience of decreased interest in one's surroundings or activities that would normally bring pleasure, and a reduced ability to respond emotionally to one's environment or people); 10) Pessimistic thoughts (e.g., expressing feelings of guilt, inferiority, self-blame, remorse, and destructive thoughts); and 11) Suicidal thoughts (e.g., expressing feelings that life is not worth living, that natural death would be welcome, suicidal thoughts, and feelings of being prepared to commit suicide). Each item is rated from 0 to 6, where 0 reflects that the subject did not show any sadness at all, and 6 reflects that the subject is extremely similar to the description given by the item. For example, for apparent sadness, a score of 0 may indicate that the subject did not show any sadness, while a score of 6 may indicate that the subject appeared to be in constant distress, such as extreme depression. As another example, for suicidal thoughts, a score of 0 may indicate that the subject enjoys life or is resigned to it; a score of 2 may indicate that the subject is bored with life and may have brief suicidal thoughts; a score of 4 may indicate that the subject feels that he or she might be better off dead (e.g., the suicidal ideation is normal and suicide is seen as a possible solution, but there is no specific plan or intention); and a score of 6 may indicate that the subject has a clear plan for suicide when given the opportunity (e.g., the subject has made active preparations for suicide). Therefore, the overall score, after summing each score for each item, ranges from 0 to 60. In some embodiments, a subject's overall MADRS score of approximately 0 to approximately 6 reflects that the subject does not have symptoms associated with depression; a score of approximately 7 to approximately 9 reflects that the subject has mild depression; a score of approximately 20 to approximately 34 reflects that the subject has moderate depression; and a score of approximately 34 to approximately 60 reflects that the subject has severe depression.

[0134] In some embodiments, the overall MADRS score of the subject is about 10 to about 60 prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof. For example, it 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 prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the overall MADRS score of the subject is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the overall MADRS score of the subject 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, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's overall MADRS score is as described herein.

[0135] In some embodiments, after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's overall MADRS score is about 0 to about 6. For example, after intranasal administration of racemic ketamine as described herein, the scores are about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 5 to about 6, about 4 to about 6, about 3 to about 6, about 2 to about 6, or about 1 to about 6. In some embodiments, after intranasal administration of racemic ketamine as described herein, the subject's overall MADRS score is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the subject's overall MADRS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine as described herein. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's overall MADRS score is as described herein.

[0136] In some embodiments, the subject’s overall MADRS score is about 10 to about 60 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and about 0 to about 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, it 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 before intranasal administration of racemic ketamine as described herein, and 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 after intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's overall MADRS score is about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 before intranasal administration of racemic ketamine as described herein, and the subject's overall MADRS score is 0, 1, 2, 3, 4, 5, or 6 after intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's overall MADRS 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, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, the overall MADRS score of the subject is as described herein, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the overall MADRS score of a subject decreases by about 1 to about 60. For example, the overall MADRS score of a subject may decrease 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, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the overall MADRS score of a subject decreases 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. In some embodiments, the overall MADRS score of a subject decreases as described herein from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's overall MADRS score decreased as described herein (e.g., relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof). In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's overall MADRS score decreased by approximately 20 to approximately 30 points, such as approximately 20-25 points, approximately 22-27 points, or approximately 25-30 points.

[0138] In some embodiments, item 10 of the MADRS, such as suicidal ideation, may be used to measure suicidal ideation. In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof as described herein, the subject's score for item 10 of the MADRS is 0 or 1. In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, from approximately 5 minutes to approximately 24 hours, the subject's score for item 10 of the MADRS is as described herein. For example, after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, from approximately 5 minutes to 1 hour, from approximately 5 minutes to 6 hours, from approximately 5 minutes to 12 hours, from approximately 5 minutes to 18 hours, from approximately 18 hours to 24 hours, from approximately 12 hours to 24 hours, or from approximately 6 hours to 24 hours. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject’s MADRS score is as described herein.

[0139] In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS score on item 10 decreased by 1 to 6. For example, the subject's MADRS score on item 10 may decrease by 1 to 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, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS score on item 10 decreased 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. In some embodiments, from approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS score on item 10 decreased as described herein. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS score on item 10 decreased as described herein (e.g., relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0140] In some embodiments, 24 hours after intranasal administration of racemic ketamine, the subject's MADRS item 10 score decreased by 4, 5, or 6 points. In some embodiments, the subject's MADRS item 10 score decreased by 4 points. In some embodiments, the subject's MADRS item 10 score decreased by 5 points. In some embodiments, the subject's MADRS item 10 score decreased by 6 points.

[0141] In some embodiments, MADRS is administered to the subject before intranasal administration of racemic ketamine as described herein. For example, MADRS may be administered to the subject approximately 1 hour to approximately 6 months before intranasal administration of racemic ketamine as described herein. In some embodiments, MADRS may be administered to the subject approximately 1 hour to approximately 6 hours, approximately 1 hour to approximately 1 day, approximately 1 hour to approximately 1 week, approximately 1 hour to approximately 1 month, approximately 1 hour to approximately 3 months, approximately 3 months to approximately 6 months, approximately 1 month to approximately 6 months, approximately 1 week to approximately 5 months, or approximately 1 day to approximately 6 months before intranasal administration of racemic ketamine as described herein.

[0142] STS-CMCM is a diagnostic questionnaire that can be used to measure changes in suicidal ideation and behavior in subjects. STS-CMCM also provides a comprehensive description of suicidal ideation and behavior. See, for example, Sheehan et al., *Innovation in Clinical Neuroscience*, Vol. 11, Nos. 9-10, pp. 93-140 (2014). STS-CMCM consists of four parts. The first part may contain a 16-item scale that assesses the severity of suicidal tendencies on a 0-4 scale, ranging from "none" (0) to "extremely" (4). The second part presents the subject with a series of additional items for assessment, including: 1) a series of risk or protective items that may be significant aggravating or mitigating factors in the subject's suicidal ideation and behavior; 2) a series of 11-point (0-10) discrete visual analog scales (DISCAN); and 3) items related to the overall severity of the assessment of suicidal impulses, thoughts, and behaviors, as well as the subject's opportunity to provide a self-assessment of their need for treatment. The DISCAN scale may include assessments by the subject of the following: their ability and willingness to cope with suicidal ideation, their ability and willingness to "stay safe," the degree to which their suicidal ideation is intentional, the degree to which it is impulsive, the extent to which it has affected their quality of life, and the extent to which it has impaired their work, social, or family life. Part III includes assessments from the clinician regarding their judgment of the subject's suicide risk and the level of management required for the subject's suicidal ideation and behavior. Part III may also include an overall assessment of suicidal ideation based on all information collected in earlier sections of the scale, plus any additional probing questions from other individuals and the clinician that they deem necessary to complete the assessment. If the subject misses a follow-up appointment and is unavailable, Part IV may be completed by the clinician, allowing for the completion of the scale.

[0143] In some embodiments, the subject's STS-CMCM score decreases by at least 2 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's STS-CMCM score may decrease by at least 2, at least 3, at least 4, or at least 5 compared to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS-CMCM score decreases as described herein from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, from about 5 minutes to 1 hour, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 hours to 24 hours, from about 12 hours to 24 hours, or from 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 decreases as described herein (e.g., relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof) approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is given STS-CMCM before intranasal administration of racemic ketamine as described herein. For example, the subject may be given STS-CMCM approximately 1 hour to approximately 6 months before intranasal administration of racemic ketamine as described herein. In some embodiments, the subject may be given STS-CMCM approximately 1 hour to approximately 6 hours, approximately 1 hour to approximately 1 day, approximately 1 hour to approximately 1 week, approximately 1 hour to approximately 1 month, approximately 1 hour to approximately 3 months, approximately 3 months to approximately 6 months, approximately 1 month to approximately 6 months, approximately 1 week to approximately 5 months, or approximately 1 day to approximately 6 months before intranasal administration of racemic ketamine as described herein.

[0144] In some of the embodiments described herein, when subjects are given one or more additional therapies, they do not experience clinically significant weight gain compared to the administration of one or more additional therapies in the absence of intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. Clinically significant weight gain is defined as an increase in body mass of at least about 5% during treatment, such as about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or any value in between.

[0145] In some embodiments, the methods described herein provide one or more synergistic effects when racemic ketamine or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapies.

[0146] In some embodiments, the efficacy of intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts, combined with one or more additional therapies, is greater than the sum of the efficacies of each individual agent when administered alone. For example, in some embodiments, the change in CSSRS score after administration of intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts compared to before administration is greater than the change in CSSRS score after administration of intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts, combined with one or more additional therapies compared to before administration of intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts, combined with one or more additional therapies. In some embodiments, the efficacy of ketamine or its pharmaceutically acceptable salts is increased. In some embodiments, the efficacy of one or more additional therapies is increased. In some embodiments, the efficacy of both intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts and one or more additional therapies is increased. In some embodiments, the efficacy of one or more additional therapies with intranasal / extranasal racemic ketamine or its pharmaceutically acceptable salts is increased relative to the efficacy observed after administration of an equivalent dose of intravenous / extranasal racemic ketamine or its pharmaceutically acceptable salts. In some embodiments, the efficacy of one or more additional therapies involving intranasal and extranasal racemic ketamine or a pharmaceutically acceptable salt thereof is increased relative to the efficacy observed after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the dose of intranasal or extranasal racemic ketamine or its pharmaceutically acceptable salt and / or one or more additional therapies required to provide a therapeutic effect is reduced relative to the dose of each individual agent when administered alone. In some embodiments, the dose of one or more additional therapies required to provide a therapeutic effect is reduced relative to the dose of an equivalent dose of intravenous or extranasal racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, the dose of one or more additional therapies required to provide a therapeutic effect is reduced relative to the dose of an equivalent dose of (S)-ketamine or its pharmaceutically acceptable salt. In some embodiments, the dose of ketamine or its pharmaceutically acceptable salt is reduced. In some embodiments, the dose of one or more additional therapies is reduced. In some embodiments, the dose of both intranasal and extranasal racemic ketamine or its pharmaceutically acceptable salt and one or more additional therapies is reduced. For example, the dosage of intranasal or extranasal racemic ketamine or its pharmaceutically acceptable salts may be reduced by about 5% to about 95% or any value between therewith, such as about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%. Similarly, the dosage of one or more additional therapies may be reduced by about 5% to about 95% or any value between therewith, such as about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.

[0148] In some embodiments, the onset of resistance to treatment with intranasal or extranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies is delayed, relative to the onset of resistance to treatment with each individual agent administered alone. In some embodiments, the onset of resistance to treatment with one or more additional therapies is delayed, relative to the onset of resistance to treatment with intravenous or extranasal racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the onset of resistance to treatment with one or more additional therapies is delayed, relative to the onset of resistance to treatment with (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the number of one or more side effects of intranasal or extranasal racemic ketamine or its pharmaceutically acceptable salts and / or one or more additional therapies required to provide a therapeutic effect is reduced relative to the side effects of each individual agent when administered alone. In some embodiments, the number of one or more side effects of ketamine or its pharmaceutically acceptable salts is reduced. In some embodiments, the number of one or more side effects of one or more additional therapies is reduced. In some embodiments, the number of one or more side effects of one or more additional therapies is reduced relative to one or more side effects observed after administration of an equivalent dose of intravenous or extranasal racemic ketamine or its pharmaceutically acceptable salts. In some embodiments, the number of one or more side effects of one or more additional therapies is reduced relative to one or more side effects observed after administration of an equivalent dose of (S)-ketamine or its pharmaceutically acceptable salts. In some embodiments, the number of one or more side effects of both ketamine or its pharmaceutically acceptable salts and one or more additional therapies is reduced. In some embodiments, the total number of side effects is reduced. In some embodiments, the magnitude of one or more side effects is reduced. In some embodiments, the total number of side effects is reduced, and the magnitude of one or more remaining side effects is also reduced.

[0150] In some embodiments, one or more side effects of ketamine include cognitive impairment, motor dysfunction, dizziness, nausea, vomiting, sweating, increased blood pressure, ulcerative cystitis, or interstitial cystitis. In some embodiments, one or more side effects of ketamine consist of: cognitive impairment, motor dysfunction, dizziness, nausea, vomiting, sweating, increased blood pressure, ulcerative cystitis, or interstitial cystitis.

[0151] In some embodiments, cognitive impairment includes one or more of the following: psychotic effects, dizziness, taste disturbance, sedation, dissociation, euphoria, auditory changes, visual changes, and hallucinations. In some embodiments, cognitive impairment comprises one or more of the following: psychotic effects, dizziness, taste disturbance, sedation, dissociation, euphoria, auditory changes, visual changes, and hallucinations. In some embodiments, cognitive impairment includes sedation. In some embodiments, cognitive impairment is sedation. In some embodiments, motor impairment includes tremor, balance problems, or dystonia. In some embodiments, motor impairment comprises one or more of the following: tremor, balance problems, or dystonia.

[0152] Many methods can be used to assess ketamine-related side effects. Non-limiting examples of such methods include the Modified Observer's Assessment of Alertness / Sedation Scale (MOAA / S), the Bowdle Visual Analog Scale (VAS), the Clinician Administered Dissociative States Scale (CADSS), the Profile of Mood States (POMS), the Choice Reaction Time Test, the Sternberg Short-Term Memory Task, and the Subject-Rated Assessment of Intranasal Irritation. (For intranasal administration of ketamine).

[0153] In some embodiments, the MOAA / S can be used to measure sedation in a subject. See, for example, Kim et al., *British Journal of Anesthesiology*, Vol. 115, No. 4, pp. 569–577 (2015), which is incorporated herein by reference in its entirety. The MOAA / S is a scale from 0 to 5, where 0 indicates no response after painful trapezius contraction; 1 indicates a response only after painful trapezius contraction; 2 indicates a response only after gentle poking or shaking; 3 indicates a response only after the name is called loudly and / or repeatedly; 4 indicates a sluggish response to a name spoken in a normal tone; and 5 indicates a rapid response to a name spoken in a normal tone.

[0154] 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 approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein.

[0155] In some embodiments, the subject's MOAA / S is 5 or 6 following 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 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, from about 5 minutes to 1 hour, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 hours to 24 hours, from about 12 hours to 24 hours, or from 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 from about 1 hour to about 4 hours, from about 1.5 hours to about 5 hours, from about 2 hours to about 6 hours, from about 5 hours to about 10 hours, or from about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the subject's MOAA / S is 5 or 6 before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the subject's MOAA / S score is measured approximately 5 minutes to approximately 24 hours before and approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. 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, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the MOAA / S score of the subjects was substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the MOAA / S score of the subjects was not changed (i.e., neither increased nor decreased) after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the MOAA / S score of the subjects was substantially the same from approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof as it was from approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0158] In some embodiments, the MOAA / S score of a subject decreases by about 1 to about 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the MOAA / S score of a subject may decrease by 1, 2, 3, 4, or 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, relative to administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof and / or intravenous administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the MOAA / S score of a subject decreases as described herein from about 5 minutes to about 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the decrease may occur from 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 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the MOAA / S score of the subject is as described herein (e.g., relative to the administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, and / or the administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof) approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0159] In some embodiments, the Bowdle Visual Analogue Scale (VAS) can be used to measure the psychedelic effects of a subject. See, for example, Bowdle et al., *Anesthesiology*, Vol. 88, No. 1, pp. 82-88 (1998), which is incorporated herein by reference in its entirety. The Bowdle VAS is a questionnaire that asks the subject to rate his or her current feelings. For example, for the subject to be rated, the questionnaire may include the following: 1) My body or body parts seem to have changed in shape and position; 2) The size, depth, or shape of my surroundings seems to have changed; 3) The passage of time is altered; 4) I have unreal feelings; 5) I have difficulty controlling my thoughts; 6) The intensity of colors has changed; 7) The intensity of sounds has changed; 8) I hear unreal sounds or noises; 9) I think events, objects, or other people have a particular meaning to me; 10) I have doubts or opinions about others that are contrary to my own; 11) I feel anxious; 12) I feel elated; and 13) I feel drowsy. Each item was rated by the subject from 0 to 100, with an overall score of up to 1300, indicating that the subject experienced significant side effects. A score of 0 reflects that the subject felt none of the side effects described in the item (i.e., very few side effects), while a score of 100 reflects that the subject felt extremely like the item. Therefore, lower individual and overall scores indicate less psychedelic effects.

[0160] In some embodiments, items 1, 2, 3, 5, 6, and 7 are combined to evaluate the derived variable “subjective external perception”. In some embodiments, items 4, 8, 9, 10, and 11 are combined to evaluate the derived variable “subjective internal perception”. In some embodiments, items 12 and 13 are combined as separate VAS items.

[0161] In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 0 to about 50. In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 25 to about 75. In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 50 to about 100. In some embodiments, prior to intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS was about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100. In some embodiments, prior to intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS was about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60. In some embodiments, the subject's Baudelaire VAS score is measured approximately 5 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the subject's Baudelaire VAS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof.

[0162] In some embodiments, following intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 0 to about 50. In some embodiments, following intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 25 to about 75. In some embodiments, following intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 50 to about 100. In some embodiments, following intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS was about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100. In some embodiments, following intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS was about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60. In some embodiments, the Baudelaire VAS score of the subject is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, from 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 saline thereof. In some embodiments, the Baudelaire VAS score of the subject is measured from 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 saline thereof.

[0163] In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 0 to about 50, and after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 0 to about 50. In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 25 to about 75, and after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 25 to about 75. In some embodiments, prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 50 to about 100, and after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS was about 50 to about 100. In some embodiments, the subject's Baudelaire VAS prior to intranasal administration of racemic ketamine as described herein was about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100, and after intranasal administration of racemic ketamine as described herein, about 0 to about 10, about 0 to about 20, about 0 to about 30, about 0 to about 40, about 0 to about 50, about 0 to about 60, about 0 to about 70, about 0 to about 80, about 0 to about 90, about 90 to about 100, about 80 to about 100, about 70 to about 100, about 60 to about 100, about 50 to about 100, about 40 to about 100, about 30 to about 100, about 20 to about 100, or about 10 to about 100. In some embodiments, prior to intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS score was about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60, and after intranasal administration of racemic ketamine as described herein, the subject's Baudelaire VAS score was about 5 to about 20, about 15 to about 40, about 10 to about 50, or about 20 to about 60. In some embodiments, the subject's Baudelaire VAS score was 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, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or its pharmaceutically acceptable salt, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt. In some embodiments, the subject’s Baudelaire 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 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.

[0164] In some embodiments, the subject's Baudelaire 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 Baudelaire VAS score changes (i.e., increases or decreases) by about 0 to about 10 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof relative to the subject's score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Baudelaire VAS score is substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof as it is from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0165] In some embodiments, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, a subject's Baudelaire VAS score decreased by approximately 10 to approximately 1300. For example, compared to scores 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, a subject's Baudelaire VAS score may decrease by approximately 10 to approximately 1300 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS score decreased by approximately 10 to approximately 100, approximately 10 to approximately 200, approximately 10 to approximately 300, approximately 10 to approximately 400, approximately 10 to approximately 500, approximately 10 to approximately 600, approximately 10 to approximately 700, approximately 10 to approximately 800, approximately 10 to approximately 900, approximately 10 to approximately 1000, or approximately 10 to approximately 1100. Approximately 10 to approximately 1200, approximately 1200 to approximately 1300, approximately 1100 to approximately 1300, approximately 1000 to approximately 1300, approximately 900 to approximately 1300, approximately 800 to approximately 1300, approximately 700 to approximately 1300, approximately 600 to approximately 1300, approximately 500 to approximately 1300, approximately 400 to approximately 1300, approximately 300 to approximately 1300, approximately 200 to approximately 1300, or approximately 100 to approximately 1300. In some embodiments, approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's Baudelaire VAS score decreased as described herein. For example, the subject's Baudelaire VAS score is measured approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's Baudelaire VAS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (or after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, or after intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0166] In some embodiments, the dissociation status of a subject can be measured using a clinician-administered Dissociation Status Scale (CADSS). See, for example, Luckenbaugh et al., *Journal of Affective Disorders*, Vol. 159, pp. 56-61 (2014), which is incorporated herein by reference in its entirety. CADSS assessments include, but are not limited to, statements such as things moving in slow motion, things appearing unreal, feeling dissociated from what is happening, detached experience, feeling like a bystander or observer, feeling disconnected from the body, altered bodily sensations, people appearing motionless / dead / mechanical, objects appearing different, decreased color intensity, seeing things as if in a tunnel / wide-angle lens, things taking longer, things happening very quickly, unexplained events, deviating from the trajectory of events, altered sound intensity, unusual clarity, a feeling of seeing through a fog, and colors appearing brighter. Typically, the CADSS will contain 23 statements, which subjects rate on a scale of 0 to 4, with scores ranging from 0 (no dissociation) to 92 (extreme dissociation). A score of 0 reflects that the subject felt no agreement whatsoever with the item described, while a score of 4 reflects the subject's maximum level of agreement with the issue raised. For example, 0 reflects no agreement at all, 1 reflects mild agreement, 2 reflects moderate agreement, 3 reflects strong agreement, and 4 reflects the maximum level of agreement indicated by the issue. Therefore, 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.

[0167] In some embodiments, the subject's CADSS is about 0 to about 10 prior to intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof. For example, the scores prior to intranasal administration of racemic ketamine as described herein are about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. In some embodiments, the 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 about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine as described herein. For example, the subject's CADSS score is measured approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's CADSS is about 0 to about 10. For example, after intranasal administration of racemic ketamine as described herein, the scores are about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. In some embodiments, after intranasal administration of racemic ketamine as described herein, the subject's CADSS is about 2 to about 6, about 3 to about 7, or about 4 to about 8. In some embodiments, the subject's CADSS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine as described herein. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the subject's CADSS was about 0 to about 10 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, prior to intranasal administration of racemic ketamine as described herein, the CADSS was about 0 to about 2, about 0 to about 3, about 0 to about 4, about 0 to about 5, about 0 to about 6, about 0 to about 7, about 0 to about 8, about 0 to about 9, about 9 to about 10, about 8 to about 10, about 7 to about 10, about 6 to about 10, about 5 to about 10, about 4 to about 10, about 3 to about 10, about 2 to about 10, or about 1 to about 10. Approximately 10, and after intranasal administration of racemic ketamine, approximately 0 to approximately 2, approximately 0 to approximately 3, approximately 0 to approximately 4, approximately 0 to approximately 5, approximately 0 to approximately 6, approximately 0 to approximately 7, approximately 0 to approximately 8, approximately 0 to approximately 9, approximately 9 to approximately 10, approximately 8 to approximately 10, approximately 7 to approximately 10, approximately 6 to approximately 10, approximately 5 to approximately 10, approximately 4 to approximately 10, approximately 3 to approximately 10, approximately 2 to approximately 10, or approximately 1 to approximately 10. In some embodiments, prior to intranasal administration of racemic ketamine as described herein, the subject's CADSS is approximately 2 to approximately 6, approximately 3 to approximately 7, or approximately 4 to approximately 8, and after intranasal administration of racemic ketamine as described herein, the subject's CADSS is approximately 2 to approximately 6, approximately 3 to approximately 7, or approximately 4 to approximately 8. In some embodiments, the subject's CADSS score is measured approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, and approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, and approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the subject's CADSS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, approximately 5 hours to approximately 10 hours, or approximately 45 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the subject's CADSS score was substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, the subject's CADSS score changed (i.e. increased or decreased) by about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the subject's CADSS score was substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof as it was from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0171] In some embodiments, the CADSS score of a subject decreased by about 1 to about 92 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the CADDS score of a subject may decrease by about 10 to about 92 following 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 some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's CADSS score decreased by approximately 1 to approximately 90, approximately 1 to approximately 80, approximately 1 to approximately 70, approximately 1 to approximately 60, approximately 1 to approximately 50, approximately 1 to approximately 40, approximately 1 to approximately 30, approximately 1 to approximately 20, approximately 1 to approximately 10, approximately 80 to approximately 92, approximately 70 to approximately 92, approximately 60 to approximately 92, approximately 50 to approximately 92, approximately 40 to approximately 92, approximately 30 to approximately 92, approximately 20 to approximately 92, or approximately 10 to approximately 92. In some embodiments, following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's CADSS score decreased from approximately 5 minutes to approximately 24 hours. For example, the subject's CADDS score is measured approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADDS score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (or after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof, or after intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof).

[0172] In some embodiments, a mood state profile (POMS) (e.g., POMS version 2) can be used to measure a subject's transient feelings and emotions. See, for example, Lin et al., Journal of Pharmaceutical Analysis (JPA), Vol. 32, No. 3, pp. 273-277 (2014), which is incorporated herein by reference in its entirety. A mood state profile may include items for monitoring changes in a subject's mood.

[0173] In some embodiments, the subject's mood profile scores were substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the subject's mood profile scores were substantially the same from approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof as they were from approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0174] In some embodiments, the choice reaction time (CRT) test can be used to measure the psychomotor performance of a subject. See, for example, Hindmarch et al., *Br. J. Clin. Pharmcol.*, Vol. 49, No. 2, pp. 118-125 (2000), which is incorporated herein by reference in its entirety. The choice reaction time test is administered using a computer on which a screen equivalent of a numeric keypad is presented to the subject. When a key on the screen illuminates, the subject presses the corresponding button on a separate keypad. For a given test, four to eight numbered squares on the computer screen will illuminate, spatially corresponding to keys on the keypad. The order in which the keys illuminate can be random. In some embodiments, the order in which the keys illuminate follows a pattern of alternation between the central button and any buttons that are part of a stimulus group. In some embodiments, the stimulus group size increases from 4 to 6 to 8 during the test. In each cycle, the number of alternating choices may increase with the number of response blocks. The CRT test can include three outcome variables: discrimination reaction time (RRT), which is the time it takes for the subject to notice the light (e.g., the time between stimulus initiation and the subject lifting his or her finger from the start button); motor reaction time (MRT), which is the time between the subject lifting his or her finger from the start button and touching the response button; and total reaction time (TRT), which is the sum of RRT and MRT. The accuracy of the response can also be recorded.

[0175] In some embodiments, the CRT test scores of subjects were substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. In some embodiments, the CRT test scores of subjects were substantially the same from approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof as they were from approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0176] In some embodiments, the Sternberg Short-Term Memory Task (SSTM) can be used to measure a subject's immediate memory. See, for example, Sternberg, Science, Vol. 153, No. 3736, pp. 652-654 (1966), which is incorporated herein by reference in its entirety. The SSTM may consist of requiring the subject to remember a series of numbers rapidly presented on a computer screen. For example, the SSTM may consist of target lists of 2, 4, and 6 stimulus numbers being rapidly presented (e.g., at 1.2 seconds / number), and a series of 24 probe numbers being presented two seconds after each list. The subject identifies as quickly as possible whether each probe appears in the target list by pressing a button on a response box corresponding to "yes" or "no". Probes appearing in the target list can be referred to as "positive", while probes not appearing in the target list can be referred to as "negative". The SSTM may consist of three trials with digit order size lengths of 2, 4, and 6. Performance can be evaluated by measures of response delay and accuracy.

[0177] In some embodiments, the subject's SSTM score was substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SSTM score was substantially the same from approximately 5 minutes to approximately 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof as it was from approximately 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0178] In some embodiments, the Subject-Rated Intranasal Irritation Assessment (SRAII) can be used to determine intranasal irritation in subjects administering intranasal ketamine (e.g., racemic ketamine or (S)-ketamine) or a pharmaceutically acceptable saline thereof. For example, the SRAII can be used to assess the subjective effects of intranasal administration of ketamine or a pharmaceutically acceptable saline thereof as described herein. The SRAII comprises five categories for which subjects are asked to provide assessments. For example, the categories may include: 1) burning sensation; 2) need to blow the nose / sneeze; 3) runny nose and / or nasal discharge; 4) facial pressure or pain; and 5) nasal congestion. In some embodiments, each item is scored on a 6-point scale. For example, 0 indicates no difficulty at all; 1 indicates very mild difficulty; 2 indicates mild / slight difficulty; 3 indicates moderate difficulty; 4 indicates severe difficulty; and 5 indicates very severe difficulty, e.g., the worst possible outcome.

[0179] In some embodiments, after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's SRAII score is about 0 to about 5. For example, after intranasal administration of racemic ketamine as described herein, the score is about 0 to about 1, about 0 to about 2, about 0 to about 3, about 0 to about 4, about 4 to about 5, about 3 to about 5, or about 2 to about 5. In some embodiments, after administration of ketamine as described herein or a pharmaceutically acceptable salt thereof, the subject's SRAII score is about 1, about 2, about 3, about 4, or about 5. In some embodiments, the subject's SRAII score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine as described herein or a pharmaceutically acceptable salt thereof. For example, after intranasal administration of racemic ketamine as described herein, the score is measured from 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. In some embodiments, the subject’s SRAII 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.

[0180] In some embodiments, the subject's SRAII score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's SRAII 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 relative to before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SRAII score is substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof as it is from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, approximately 6 hours to 24 hours, 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours before or after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

[0181] In some embodiments, the SRAII score of a subject decreases by about 5 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, relative to intranasal administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. For example, the SRAII score of a subject decreases by about 5 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, relative to the score observed after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SRAII score of a subject decreases by about 5 to about 20, about 5 to about 15, about 5 to about 10, about 20 to about 25, about 15 to about 25, or about 10 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the SRAII score of a subject decreases as described herein from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject's SRAII score is measured approximately 5 minutes to 1 hour, approximately 5 minutes to 6 hours, approximately 5 minutes to 12 hours, approximately 5 minutes to 18 hours, approximately 18 hours to 24 hours, approximately 12 hours to 24 hours, or approximately 6 hours to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SRAII score is measured approximately 1 hour to approximately 4 hours, approximately 1.5 hours to approximately 5 hours, approximately 2 hours to approximately 6 hours, or approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (or after administration of an equivalent dose of (S)-ketamine or a pharmaceutically acceptable salt thereof).

[0182] In some embodiments, no clinically significant sedation was observed in subjects approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, no clinically significant sedation was observed in subjects approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, no clinically significant sedation was observed in subjects approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof.

[0183] In some embodiments, no clinically significant separation was observed in subjects within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in subjects within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in subjects within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments where the subject exhibited suicidal ideation, the subject had previously been diagnosed with one or more of the following: suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some embodiments where the subject exhibited suicidal ideation, the subject currently suffered from one or more of the following: suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

[0185] In some instances where the subject exhibited suicidal tendencies, the subject had previously been diagnosed with one or more of the following: suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some instances where the subject exhibited suicidal tendencies, the subject currently suffered from one or more of the following: suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

[0186] In some embodiments, anti-therapeutic depression is stage I through IV. In some embodiments, anti-therapeutic depression is stage V. In some embodiments, the subject exhibits one or more of the following characteristics: unwanted and distressing memories, nightmares, recurring hallucinations, emotional distress following exposure to traumatic reminders, or physical reactivity following exposure to traumatic reminders; and one or more of trauma-related thoughts or feelings and trauma-related external reminders.

[0187] In some embodiments, the subject exhibits two or more of the following characteristics: inability to recall key features of the traumatic event, excessively negative thoughts and assumptions about themselves or the world, excessive blame towards themselves or others who caused 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 aggression, dangerous or destructive behavior, hypervigilance, heightened startle response, difficulty concentrating, and difficulty falling asleep. In some embodiments, the characteristics persist for more than about one month, causing distress and / or dysfunction in social or occupational situations and are not due to substance or drug abuse. In some embodiments, the characteristics persist for at least about one month and at most about 12 months.

[0188] In some embodiments, about 30 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally to the subject. For example, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, or any value between these values. In some embodiments, about 30 mg to about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally to the subject. In some embodiments, about 45 mg to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally to the subject. In some embodiments, about 60 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally to the subject. In some embodiments, about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally to the subject. In some embodiments, each dose of the formulation provides about 30 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, each dose of the formulation provides about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0189] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject, wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0190] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0191] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0192] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0193] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject, wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0194] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0195] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0196] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0197] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0198] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0199] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0200] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0201] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-t Approximately 1.7 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-tThe AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-t Approximately 1.9 to approximately 2.3 times that of norketamine. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-t Approximately 2.0 times that.

[0202] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-无穷大 The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 Approximately 1.5 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-无穷大 The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 Approximately 1.8 to approximately 2.2 times that of norketamine. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-无穷大 The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 Approximately 2.0 times that.

[0203] In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of norketamine. 最大 The C-value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.2 to 3.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of norketamine. 最大 The C-value of noreketamine was approximately 2.4 to approximately 3.2 times that of the equivalent dose of racemic ketamine administered intravenously. In some embodiments, intranasal administration of racemic ketamine showed a C-value of noreketamine. 最大 The C-value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 It is about 2.9 times that of the previous year.

[0204] In some embodiments, intranasal administration of racemic ketamine exhibits the T-activity of norketamine. 最大 The T value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 80% to approximately 125%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of norketamine. 最大 The T value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 90% to approximately 110%.

[0205] In some embodiments, the AUC of norketamine is determined after a single dose of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of norketamine is determined after two administrations of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of norketamine is determined after three doses of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them.

[0206] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject, wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0207] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0208] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0209] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0210] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject, wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0211] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0212] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0213] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0214] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject, wherein intranasal administration of the racemic ketamine exhibits one or more of the following:

[0215] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0216] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0217] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0218] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t Approximately 1.7 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t Approximately 1.9 to approximately 2.3 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t It is about 2.1 times that.

[0219] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 Approximately 1.5 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 Approximately 1.7 to approximately 2.1 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 It is about 1.9 times that of the previous year.

[0220] In some embodiments, intranasal administration of racemic ketamine exhibits the C-type properties of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.2 to 3.2 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C60-like effect of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.4 to 2.8 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 It is about 2.6 times that of the previous year.

[0221] In some embodiments, intranasal administration of racemic ketamine exhibits the T-type effect of hydroxynorketamine. 最大 The T-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 80% to approximately 125%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of hydroxynorketamine. 最大 The T-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 90% to approximately 110%.

[0222] In some embodiments, the relative ratios and percentages described herein are measured from about 15 minutes to about 8 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the ratios described herein are measured at about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or any value between these. In some embodiments, the relative ratios and percentages described herein are measured from about 24 hours to about 1 month. In some embodiments, the relative ratios and percentages described herein are measured from about 24 hours to about 2 weeks. For example, approximately 24 hours, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, approximately 10 days, approximately 11 days, approximately 12 days, approximately 13 days, approximately 2 weeks, or any value between these. In some embodiments, racemic ketamine or its pharmaceutically acceptable saline solution is administered intranasally twice daily, once daily, every other day, every three days, every four days, every five days, every six days, or once a week, or combinations thereof, for a continuous measurement period (e.g., from approximately 24 hours to approximately 1 month).

[0223] In some embodiments, ketamine's T 最大 Approximately 20 to approximately 120 minutes after intranasal administration of racemic ketamine, such as approximately 20 minutes, approximately 30 minutes, approximately 40 minutes, approximately 50 minutes, approximately 60 minutes, approximately 70 minutes, approximately 80 minutes, approximately 90 minutes, approximately 100 minutes, approximately 110 minutes, approximately 120 minutes, or any value between these times. In some embodiments, the T of ketamine... 最大 Approximately 20 to approximately 90 minutes after intranasal administration of racemic ketamine, such as approximately 20 minutes, approximately 30 minutes, approximately 40 minutes, approximately 50 minutes, approximately 60 minutes, approximately 70 minutes, approximately 80 minutes, approximately 90 minutes, or any value between these times. In some embodiments, the T of ketamine... 最大 Approximately 30 to 90 minutes after intranasal administration of racemic ketamine.

[0224] In some embodiments, the T of norketamine 最大Approximately 45 to approximately 360 minutes after intranasal administration of racemic ketamine, for example, approximately 45 minutes, approximately 60 minutes, approximately 75 minutes, approximately 90 minutes, approximately 105 minutes, approximately 120 minutes, approximately 135 minutes, approximately 150 minutes, approximately 165 minutes, approximately 180 minutes, approximately 195 minutes, approximately 210 minutes, approximately 225 minutes, approximately 240 minutes, approximately 255 minutes, approximately 270 minutes, approximately 285 minutes, approximately 300 minutes, approximately 315 minutes, approximately 315 minutes, approximately 330 minutes, approximately 345 minutes, approximately 360 minutes, or any value between these intervals. In some embodiments, the T of norketamine... 最大 Approximately 100 to 250 minutes after intranasal administration of racemic ketamine.

[0225] In some embodiments, the T of 6-hydroxynorketamine 最大 Following intranasal administration of racemic ketamine, approximately 45 minutes to approximately 8 hours, for example, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, approximately 9 hours, approximately 10 hours, or any value between these times. In some embodiments, the T of 6-hydroxydemethylketamine... 最大 Approximately 2 to 4 hours after intranasal administration of racemic ketamine, for example, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, approximately 3.5 hours, approximately 4 hours, or any value between these times. In some embodiments, the T of 6-hydroxynorketamine... 最大 Approximately 3 to 4 hours after intranasal administration of racemic ketamine.

[0226] In some embodiments, following intranasal administration of racemic ketamine, the C of ketamine... 最大 The concentration is any value between approximately 15 ng / mL and approximately 225 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C60 of ketamine is... 最大 The concentration is from about 25 ng / mL to about 225 ng / mL, for example, about 25 ng / mL, about 35 ng / mL, about 45 ng / mL, about 55 ng / mL, about 65 ng / mL, about 75 ng / mL, about 85 ng / mL, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL, about 155 ng / mL, about 165 ng / mL, about 175 ng / mL, about 185 ng / mL, about 195 ng / mL, about 205 ng / mL, about 215 ng / mL, about 225 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of ketamine... 最大The concentration is from about 70 ng / mL to about 205 ng / mL, for example, about 85 ng / mL, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL, about 155 ng / mL, about 165 ng / mL, about 175 ng / mL, about 185 ng / mL, about 195 ng / mL, about 205 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of ketamine... 最大 The concentration is from about 75 ng / mL to about 175 ng / mL, for example, about 75 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of ketamine... 最大 It ranges from about 95 ng / mL to about 145 ng / mL, for example, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL or any value in between.

[0227] In some embodiments, following intranasal administration of racemic ketamine, the C of norketamine... 最大 The concentration is any value between approximately 40 ng / mL and approximately 375 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 The concentration is from about 50 ng / mL to about 275 ng / mL, for example, about 50 ng / mL, about 75 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 275 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最 The concentration is approximately 90 ng / mL to approximately 180 ng / mL, for example, approximately 90 ng / mL, approximately 100 ng / mL, approximately 110 ng / mL, approximately 120 ng / mL, approximately 130 ng / mL, approximately 140 ng / mL, approximately 150 ng / mL, approximately 160 ng / mL, approximately 170 ng / mL, approximately 180 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最 The concentration is approximately 70 ng / mL to approximately 85 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 The concentration is approximately 90 ng / mL to approximately 130 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is...最大 The concentration is approximately 120 ng / mL to approximately 150 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 The concentration is approximately 160 ng / mL to approximately 195 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 The concentration is approximately 140 ng / mL to approximately 180 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 It ranges from approximately 215 ng / mL to approximately 225 ng / mL.

[0228] In some embodiments, following intranasal administration of racemic ketamine, the C of 6-hydroxynorketamine... 最大 The concentration is any value between about 15 ng / mL and about 275 ng / mL. In some embodiments, after intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最大 The concentration is approximately 40 ng / mL to approximately 275 ng / mL or any value between therewith. In some embodiments, following intranasal administration of racemic ketamine, the C60 of 6-hydroxynorketamine is... 最大 The concentration is from about 55 ng / mL to about 245 ng / mL, for example, about 55 ng / mL, about 65 ng / mL, about 75 ng / mL, about 85 ng / mL, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL, about 155 ng / mL, about 165 ng / mL, about 175 ng / mL, about 185 ng / mL, about 195 ng / mL, about 205 ng / mL, about 215 ng / mL, about 225 ng / mL, about 235 ng / mL, about 245 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of 6-hydroxydemethylketamine... 最大 The concentration is approximately 55 ng / mL to approximately 100 ng / mL. In some embodiments, following intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最大 The concentration is approximately 95 ng / mL to approximately 135 ng / mL. In some embodiments, following intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最大 The concentration is approximately 130 ng / mL to approximately 155 ng / mL. In some embodiments, following intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最大 The concentration is approximately 150 ng / mL to approximately 185 ng / mL. In some embodiments, following intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最大The concentration is approximately 175 ng / mL to approximately 215 ng / mL. In some embodiments, following intranasal administration of racemic ketamine, the C6-hydroxynorketamine... 最 The levels range from approximately 210 ng / mL to approximately 245 ng / mL.

[0229] In some embodiments, the t1 / 2 of ketamine is approximately 2 to approximately 9 hours after intranasal administration of racemic ketamine, for example, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, approximately 3.5 hours, approximately 4 hours, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, or any value between these times. In some embodiments, the t1 / 2 of ketamine is approximately 4 to approximately 7 hours after intranasal administration of racemic ketamine, for example, approximately 4 hours, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, or any value between these times.

[0230] In some embodiments, the t1 / 2 of norketamine is approximately 4.5 hours to approximately 12.5 hours after intranasal administration of racemic ketamine, for example, approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 9.5 hours, approximately 10 hours, approximately 10.5 hours, approximately 11 hours, approximately 11.5 hours, approximately 12 hours, approximately 12.5 hours, or any value between these times. In some embodiments, the t1 / 2 of norketamine is approximately 5 hours to approximately 10 hours after intranasal administration of racemic ketamine, for example, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 0.5 hours, approximately 10 hours, or any value between these times. In some embodiments, the t1 / 2 of norketamine is approximately 7 to approximately 8 hours after intranasal administration of racemic ketamine.

[0231] In some embodiments, t1 / 2 of 6-hydroxydemethylketamine is approximately 5.5 hours to approximately 22.5 hours after intranasal administration of racemic ketamine, for example, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 9.5 hours, approximately 10 hours, approximately 10.5 hours, approximately 11 hours, approximately 11.5 hours, approximately 12 hours, approximately 12.5 hours, approximately 13 hours, approximately 13.5 hours, approximately 14 hours, approximately 14.5 hours, approximately 15 hours, approximately 15.5 hours, approximately 16 hours, approximately 16.5 hours, approximately 17 hours, approximately 18.5 hours, approximately 19 hours, approximately 19.5 hours, approximately 20 hours, approximately 20.5 hours, approximately 21 hours, approximately 21.5 hours, approximately 22 hours, approximately 22.5 hours, or any value between these times. In some embodiments, the t1 / 2 of 6-hydroxydemethylketamine is approximately 8 hours and approximately 15 hours after intranasal administration of racemic ketamine, for example, approximately 8 hours, approximately 8.5 hours, approximately 9 hours, approximately 9.5 hours, approximately 10 hours, approximately 10.5 hours, approximately 11 hours, approximately 11.5 hours, approximately 12 hours, approximately 12.5 hours, approximately 13 hours, approximately 13.5 hours, approximately 14 hours, approximately 14.5 hours, approximately 15 hours, or any value between these times. In some embodiments, the t1 / 2 of 6-hydroxydemethylketamine is approximately 10 hours and approximately 12 hours after intranasal administration of racemic ketamine.

[0232] In some embodiments, after intranasal administration of racemic ketamine, the apparent clearance of ketamine is about 150 liters / hour to about 350 liters / hour, for example, about 150 liters / hour, about 175 liters / hour, about 200 liters / hour, about 225 liters / hour, about 250 liters / hour, about 275 liters / hour, about 300 liters / hour, about 325 liters / hour, about 350 liters / hour, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the apparent clearance of ketamine is about 200 liters / hour to about 300 liters / hour, for example, about 200 liters / hour, about 225 liters / hour, about 250 liters / hour, about 275 liters / hour, about 300 liters / hour, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the apparent clearance of ketamine is about 195 liters per hour to about 245 liters per hour, for example, about 195 liters per hour, about 200 liters per hour, about 225 liters per hour, about 230 liters per hour, about 235 liters per hour, about 240 liters per hour, about 245 liters per hour, or any value between these values.

[0233] In some embodiments, following intranasal administration of racemic ketamine, the apparent V of ketamine... d / F is any value from about 2.5 L / kg to about 6 L / kg or between. In some embodiments, after intranasal administration of racemic ketamine, the apparent V of ketamine is... d / F is from about 1,000 L to about 2,500 L, for example, about 1,000 L, about 1,250 L, about 1,500 L, about 1,750 L, about 2,000 L, about 2,250 L, about 2,500 L, or any value between these. In some embodiments, after intranasal administration of racemic ketamine, the apparent V of ketamine is... d / F is approximately 1,250L to approximately 1,750L, for example, approximately 1,250L, approximately 1,300L, approximately 1,350L, approximately 1,400L, approximately 1,450L, approximately 1,500L, approximately 1,550L, approximately 1,600L, approximately 1,650L, approximately 1,700L, approximately 1,750L or any value in between.

[0234] In some embodiments, after intranasal administration of racemic ketamine, the elimination rate constant (K) of ketamine is... el (1 / hour or hour-) 1 It takes about 0.1 hours. 1 Approximately 0.25 hours - 1 For example, about 0.1 hours - 1 Approximately 0.15 hours - 1 Approximately 0.2 hours - 1 Approximately 0.25 hours - 1 or any value in between.

[0235] In some embodiments, after intranasal administration of racemic ketamine, the elimination rate constant (K) of norketamine is... el (1 / hour or hour-) 1 It takes approximately 0.05 hours. 1 Approximately 0.15 hours - 1 For example, approximately 0.05 hours - 1 Approximately 0.1 hours 1 Approximately 0.15 hours - 1 Or any value between them. In some embodiments, the elimination rate constant (K) of norketamine after intranasal administration of racemic ketamine. el (1 / hour or hour-) 1 It takes approximately 0.09 hours. 1 To approximately 0.1 hours - 1 .

[0236] In some embodiments, following intranasal administration of racemic ketamine, the elimination rate constant (K) of 6-hydroxydemethylketamine is... el (1 / hour or hour-) 1 It takes approximately 0.05 hours.1 Approximately 0.15 hours - 1 For example, approximately 0.05 hours - 1 Approximately 0.1 hours 1 Approximately 0.15 hours - 1 Or any value between them. In some embodiments, the elimination rate constant (K) of 6-hydroxynorketamine after intranasal administration of racemic ketamine. el (1 / hour or hour-) 1 It takes approximately 0.09 hours. 1 To approximately 0.1 hours - 1 .

[0237] In some embodiments, the AUC of ketamine after intranasal administration of racemic ketamine is... 0-t From approximately 70 nanograms per hour (Ng*h / mL) to approximately 675 Ng*h / mL, for example, approximately 70 Ng*h / mL, approximately 100 Ng*h / mL, approximately 125 Ng*h / mL, approximately 150 Ng*h / mL, approximately 175 Ng*h / mL, approximately 200 Ng*h / mL, approximately 225 Ng*h / mL, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, or any value between these values. In some embodiments, the AUC of ketamine after intranasal administration of racemic ketamine. 0-t The AUC of ketamine is approximately 70 ng / h / mL to approximately 250 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration is approximately 200 ng / h / mL to approximately 450 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of ketamine is approximately 400 ng / h / mL to approximately 675 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t It ranges from approximately 600 nanograms per hour to approximately 675 nanograms per hour per milliliter.

[0238] In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 70 nanograms per hour (Ng*h / mL) to approximately 350 Ng*h / mL, for example, approximately 70 Ng*h / mL, approximately 100 Ng*h / mL, approximately 125 Ng*h / mL, approximately 150 Ng*h / mL, approximately 175 Ng*h / mL, approximately 200 Ng*h / mL, approximately 225 Ng*h / mL, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL, or any value between these values. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 70 nanograms per hour / mL to approximately 150 nanograms per hour / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 100 nanograms per hour / mL to approximately 250 nanograms per hour / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 200 nanograms per hour / mL to approximately 350 nanograms per hour / mL.

[0239] In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 225 ng*h / mL to approximately 525 ng*h / mL, for example, approximately 225 ng*h / mL, approximately 250 ng*h / mL, approximately 275 ng*h / mL, approximately 300 ng*h / mL, approximately 325 ng*h / mL, approximately 350 ng*h / mL, approximately 375 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, or any value between these values. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of ketamine... 0-t Approximately 225 ng*h / mL to approximately 325 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 300 ng*h / mL to approximately 425 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 400 nanograms per hour / mL to approximately 525 nanograms per hour / mL.

[0240] In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 220 nanograms per hour (Ng*h / mL) to approximately 675 Ng*h / mL, for example, approximately 220 Ng*h / mL, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL, approximately 375 Ng*h / mL, approximately 400 Ng*h / mL, approximately 425 Ng*h / mL, approximately 450 Ng*h / mL, approximately 475 Ng*h / mL, approximately 500 Ng*h / mL, approximately 525 Ng*h / mL, approximately 550 Ng*h / mL, approximately 575 Ng*h / mL, approximately 600 Ng*h / mL, approximately 625 Ng*h / mL, approximately 650 Ng*h / mL, approximately 675 Ng*h / mL, or any value between these values. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 220 ng*h / mL to approximately 375 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 350 ng*h / mL to approximately 525 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of ketamine is... 0-t Approximately 500 nanograms per hour / mL to approximately 675 nanograms per hour / mL.

[0241] In some embodiments, the AUC of norketamine after intranasal administration of racemic ketamine 0-t From approximately 250 nanograms per hour / mL to approximately 2,200 nanograms per hour / mL, for example, approximately 250 nanograms per hour / mL, approximately 350 nanograms per hour / mL, approximately 450 nanograms per hour / mL, approximately 550 nanograms per hour / mL, approximately 650 nanograms per hour / mL, approximately 750 nanograms per hour / mL, approximately 850 nanograms per hour / mL, approximately 950 nanograms per hour / mL, approximately 1,050 nanograms per hour / mL, approximately 1,150 nanograms per hour / mL. The values ​​are approximately 1,250 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,450 ng*h / mL, approximately 1,550 ng*h / mL, approximately 1,650 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,850 ng*h / mL, approximately 1,950 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, or any value between these values. In some embodiments, the AUC of desmethylketamine is measured after intranasal administration of racemic ketamine. 0-tThe concentration ranges from approximately 250 ng / h / mL to approximately 950 ng / h / mL. In some embodiments, the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration ranges from approximately 900 ng / h / mL to approximately 1,550 ng / h / mL. In some embodiments, the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 1,500 nanograms per hour / mL to approximately 2,200 nanograms per hour / mL.

[0242] In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration is from about 250 ng*h / mL to about 725 ng*h / mL, for example, about 250 ng*h / mL, about 300 ng*h / mL, about 350 ng*h / mL, about 400 ng*h / mL, about 450 ng*h / mL, about 500 ng*h / mL, about 550 ng*h / mL, about 600 ng*h / mL, about 650 ng*h / mL, about 700 ng*h / mL, about 725 ng*h / mL, or any value between these values. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t The concentration is approximately 250 ng / h / mL to approximately 400 ng / h / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t Approximately 375 ng*h / mL to approximately 550 ng*h / mL. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t Approximately 500 nanograms per hour / mL to approximately 725 nanograms per hour / mL.

[0243] In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-tThe values ​​range from approximately 675 ng*h / mL to approximately 1,800 ng*h / mL, for example, approximately 675 ng*h / mL, approximately 800 ng*h / mL, approximately 900 ng*h / mL, approximately 1,000 ng*h / mL, approximately 1,100 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,300 ng*h / mL, approximately 1,400 ng*h / mL, approximately 1,500 ng*h / mL, approximately 1,600 ng*h / mL, approximately 1,700 ng*h / mL, approximately 1,800 ng*h / mL, or any value between these values. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t The concentration ranges from approximately 675 ng*h / mL to approximately 1,050 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t Approximately 1,000 ng*h / mL to approximately 1,450 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t From approximately 1,400 nanograms per hour / mL to approximately 1,800 nanograms per hour / mL.

[0244] In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration is from about 850 ng*h / mL to about 2,200 ng*h / mL, for example, about 850 ng*h / mL, about 950 ng*h / mL, about 1,050 ng*h / mL, about 1,150 ng*h / mL, about 1,250 ng*h / mL, about 1,350 ng*h / mL, about 1,450 ng*h / mL, about 1,550 ng*h / mL, about 1,650 ng*h / mL, about 1,750 ng*h / mL, about 1,850 ng*h / mL, about 1,950 ng*h / mL, about 2,050 ng*h / mL, about 2,200 ng*h / mL, or any value between these values. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t The concentration ranges from approximately 850 ng*h / mL to approximately 1,350 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-t Approximately 1,300 ng*h / mL to approximately 1,850 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of norketamine is... 0-tFrom approximately 1,800 nanograms per hour / mL to approximately 2,200 nanograms per hour / mL.

[0245] In some embodiments, the AUC of 6-hydroxynorketamine following intranasal administration of racemic ketamine 0-t From approximately 300 nanograms per hour / mL to approximately 3,100 nanograms per hour / mL, for example, approximately 300 nanograms per hour / mL, approximately 450 nanograms per hour / mL, approximately 600 nanograms per hour / mL, approximately 750 nanograms per hour / mL, approximately 900 nanograms per hour / mL, approximately 1,050 nanograms per hour / mL, approximately 1,200 nanograms per hour / mL, approximately 1,350 nanograms per hour / mL, and approximately 1,500 nanograms per hour / mL. Approximately 1,750 nanograms per hour / mL, approximately 1,900 nanograms per hour / mL, approximately 2,050 nanograms per hour / mL, approximately 2,200 nanograms per hour / mL, approximately 2,450 nanograms per hour / mL, approximately 2,600 nanograms per hour / mL, approximately 2,750 nanograms per hour / mL, approximately 2,900 nanograms per hour / mL, approximately 3,100 nanograms per hour / mL, or any value between these values. In some embodiments, the AUC of 6-hydroxydemethylketamine after intranasal administration of racemic ketamine is... 0-t The concentration is approximately 300 ng / h / mL to approximately 700 ng / h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0- The t value is approximately 700 ng*h / mL to approximately 900 ng*h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of 6-hydroxynorketamine is approximately 850 ng / h / mL to approximately 950 ng / h / mL. In some embodiments, the AUC of 6-hydroxynorketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of 6-hydroxynorketamine is approximately 900 ng / h / mL to approximately 1,100 ng / h / mL. In some embodiments, the AUC of 6-hydroxynorketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of 6-hydroxydemethylketamine is approximately 1,100 ng / h / mL to approximately 1,300 ng / h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of 6-hydroxydemethylketamine is approximately 1,300 ng*h / mL to approximately 1,700 ng*h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The AUC of 6-hydroxydemethylketamine is approximately 1,700 ng / h / mL to approximately 2,400 ng / h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-tFrom approximately 2,400 nanograms per hour / mL to approximately 3,100 nanograms per hour / mL.

[0246] In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The value is approximately 300 ng / h / mL to approximately 825 ng / h / mL, for example, approximately 300 ng / h / mL, approximately 400 ng / h / mL, approximately 500 ng / h / mL, approximately 600 ng / h / mL, approximately 700 ng / h / mL, approximately 800 ng / h / mL, approximately 825 ng / h / mL, or any value between these values. In some embodiments, approximately 30 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration was approximately 300 ng / h / mL to approximately 450 ng / h / mL. In some embodiments, approximately 30 mg of racemic ketamine was administered intranasally, and the AUC of 6-hydroxydemethylketamine was measured after intranasal administration of racemic ketamine. 0-t The concentration was approximately 400 ng / h / mL to approximately 550 ng / h / mL. In some embodiments, approximately 30 mg of racemic ketamine was administered intranasally, and the AUC of 6-hydroxydemethylketamine was measured after intranasal administration of racemic ketamine. 0-t From approximately 500 nanograms per hour / mL to approximately 825 nanograms per hour / mL.

[0247] In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration is from about 650 ng*h / mL to about 1,900 ng*h / mL, for example, about 650 ng*h / mL, about 750 ng*h / mL, about 850 ng*h / mL, about 950 ng*h / mL, about 1,050 ng*h / mL, about 1,150 ng*h / mL, about 1,250 ng*h / mL, about 1,350 ng*h / mL, about 1,450 ng*h / mL, about 1,550 ng*h / mL, about 1,650 ng*h / mL, about 1,750 ng*h / mL, about 1,900 ng*h / mL, or any value between these values. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration was approximately 450 ng*h / mL to approximately 950 ng*h / mL. In some embodiments, approximately 75 mg of racemic ketamine was administered intranasally, and the AUC of 6-hydroxydemethylketamine was measured after intranasal administration of racemic ketamine.0-t The concentration ranges from approximately 900 ng / h / mL to approximately 1,400 ng / h / mL. In some embodiments, approximately 75 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 1,350 nanograms per hour / mL to approximately 1,900 nanograms per hour / mL.

[0248] In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The values ​​range from approximately 1,050 ng*h / mL to approximately 3,100 ng*h / mL, for example, approximately 1,050 ng*h / mL, approximately 1,200 ng*h / mL, approximately 1,350 ng*h / mL, approximately 1,500 ng*h / mL, approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value between these values. In some embodiments, approximately 90 mg of racemic ketamine is administered intranasally, and the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-t The concentration was approximately 1,050 ng*h / mL to approximately 1,850 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine was administered intranasally, and the AUC of 6-hydroxydemethylketamine was measured after intranasal administration of racemic ketamine. 0-t The concentration was approximately 1,800 ng*h / mL to approximately 2,600 ng*h / mL. In some embodiments, approximately 90 mg of racemic ketamine was administered intranasally, and the AUC of 6-hydroxydemethylketamine was measured after intranasal administration of racemic ketamine. 0-t From approximately 2,550 nanograms per hour / mL to approximately 3,100 nanograms per hour / mL.

[0249] In some embodiments, the AUC of ketamine after intranasal administration of racemic ketamine is... 0-tFrom approximately 70 nanograms per hour (Ng*h / mL) to approximately 675 Ng*h / mL, for example, approximately 70 Ng*h / mL, approximately 100 Ng*h / mL, approximately 125 Ng*h / mL, approximately 150 Ng*h / mL, approximately 175 Ng*h / mL, approximately 200 Ng*h / mL, approximately 225 Ng*h / mL, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL, approximately 375 Ng*h / mL. 5 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, and after intranasal administration of racemic ketamine, the C of ketamine... 最大 The value is any value from about 15 ng / mL to about 225 ng / mL or between. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t From approximately 70 nanograms per hour (Ng*h / mL) to approximately 675 Ng*h / mL, for example, approximately 70 Ng*h / mL, approximately 100 Ng*h / mL, approximately 125 Ng*h / mL, approximately 150 Ng*h / mL, approximately 175 Ng*h / mL, approximately 200 Ng*h / mL, approximately 225 Ng*h / mL, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL, approximately 375 Ng*h / mL. 5 ng*h / mL, approximately 400 ng*h / mL, approximately 425 ng*h / mL, approximately 450 ng*h / mL, approximately 475 ng*h / mL, approximately 500 ng*h / mL, approximately 525 ng*h / mL, approximately 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, and after intranasal administration of racemic ketamine, the C of ketamine... 最大The concentration is from about 70 ng / mL to about 205 ng / mL, for example, about 70 ng / mL, about 85 ng / mL, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL, about 155 ng / mL, about 165 ng / mL, about 185 ng / mL, about 205 ng / mL, or any value between these values. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-t The concentrations were approximately 70 ng / h / mL to approximately 250 ng / h / mL, approximately 200 ng / h / mL to approximately 450 ng / h / mL, approximately 400 ng / h / mL to approximately 675 ng / h / mL, and approximately 600 ng / h / mL to approximately 675 ng / h / mL, and after intranasal administration of racemic ketamine, the C of ketamine... 最大 It ranges from about 75 ng / mL to about 1755 ng / mL, for example, about 75 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL or any value in between.

[0250] In some embodiments, the AUC of norketamine after intranasal administration of racemic ketamine 0-t From approximately 250 nanograms per hour / mL to approximately 2,200 nanograms per hour / mL, for example, approximately 250 nanograms per hour / mL, approximately 350 nanograms per hour / mL, approximately 450 nanograms per hour / mL, approximately 550 nanograms per hour / mL, approximately 650 nanograms per hour / mL, approximately 750 nanograms per hour / mL, approximately 850 nanograms per hour / mL, approximately 950 nanograms per hour / mL, approximately 1,050 nanograms per hour / mL, approximately 1,150 nanograms per hour / mL, approximately 1,250 nanograms per hour / mL. Nanograms per hour / mL, approximately 1,350 nanograms per hour / mL, approximately 1,450 nanograms per hour / mL, approximately 1,550 nanograms per hour / mL, approximately 1,650 nanograms per hour / mL, approximately 1,750 nanograms per hour / mL, approximately 1,850 nanograms per hour / mL, approximately 1,950 nanograms per hour / mL, approximately 2,050 nanograms per hour / mL, approximately 2,200 nanograms per hour / mL, or any value between these values, and after intranasal administration of racemic ketamine, the C of norketamine... 最大 The value is any value between approximately 40 ng / mL and approximately 375 ng / mL. In some embodiments, the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-tFrom approximately 250 nanograms per hour (Ng*h / mL) to approximately 2,200 Ng*h / mL, for example, approximately 250 Ng*h / mL, approximately 350 Ng*h / mL, approximately 450 Ng*h / mL, approximately 550 Ng*h / mL, approximately 650 Ng*h / mL, approximately 750 Ng*h / mL, approximately 850 Ng*h / mL, approximately 950 Ng*h / mL, approximately 1,050 Ng*h / mL, approximately 1,150 Ng*h / mL, and approximately 1,250 Ng*h / mL. The concentrations of ketamine at 1,350 ng / h / mL, approximately 1,450 ng / h / mL, approximately 1,550 ng / h / mL, approximately 1,650 ng / h / mL, approximately 1,750 ng / h / mL, approximately 1,850 ng / h / mL, approximately 1,950 ng / h / mL, approximately 2,050 ng / h / mL, approximately 2,200 ng / h / mL, or any value between these values, and the C of ketamine after intranasal administration of racemic ketamine, are as follows: 最大 The concentration is from about 50 ng / mL to about 275 ng / mL, for example, about 50 ng / mL, about 75 ng / mL, about 100 ng / mL, about 125 ng / mL, about 150 ng / mL, about 175 ng / mL, about 200 ng / mL, about 225 ng / mL, about 250 ng / mL, about 275 ng / mL, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the C of norketamine is... 最大 The concentrations were approximately 50 ng / mL to approximately 135 ng / mL, approximately 130 ng / mL to approximately 15 ng / mL, approximately 210 ng / mL to approximately 245 ng / mL, and approximately 240 ng / mL to approximately 275 ng / mL, and the AUC of norketamine after intranasal administration of racemic ketamine was... 0-t The values ​​are approximately 250 ng*h / mL to approximately 950 ng*h / mL, approximately 900 ng*h / mL to approximately 1,550 ng*h / mL, or approximately 1,500 ng*h / mL to approximately 2,200 ng*h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-tFrom approximately 300 nanograms per hour / mL to approximately 3,100 nanograms per hour / mL, for example, approximately 300 nanograms per hour / mL, approximately 450 nanograms per hour / mL, approximately 600 nanograms per hour / mL, approximately 750 nanograms per hour / mL, approximately 900 nanograms per hour / mL, approximately 1,050 nanograms per hour / mL, approximately 1,200 nanograms per hour / mL, approximately 1,350 nanograms per hour / mL, approximately 1,500 nanograms per hour / mL, approximately 1,750 nanograms per hour / mL, approximately 1,750 nanograms per hour / mL, approximately 1,350 nanograms per hour / mL, approximately 1,500 nanograms per hour / mL, approximately 1,750 nanograms per hour / mL, approximately 1,100 nanograms per hour / mL, approximately 1,100 nanograms per hour / mL, approximately 1,200 nanograms per hour / mL, approximately 1,350 nanograms per hour / mL, approximately 1,500 nanograms per hour / mL, approximately 1,750 nanograms per hour / mL, approximately 1,10 ... 0 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value between these values, and following intranasal administration of racemic ketamine, the C of 6-hydroxydemethylketamine... 最大 The value is any value from about 15 ng / mL to about 275 ng / mL or between. In some embodiments, the AUC of 6-hydroxynorketamine is measured after intranasal administration of racemic ketamine. 0-t The values ​​range from approximately 300 nanograms per hour (Ng*h / mL) to approximately 3,100 Ng*h / mL, for example, after intranasal administration of racemic ketamine, approximately 300 Ng*h / mL, approximately 450 Ng*h / mL, approximately 600 Ng*h / mL, approximately 750 Ng*h / mL, approximately 900 Ng*h / mL, approximately 1,050 Ng*h / mL, approximately 1,200 Ng*h / mL, approximately 1,350 Ng*h / mL, and approximately 1,500 Ng*h / mL. Approximately 1,750 ng*h / mL, approximately 1,900 ng*h / mL, approximately 2,050 ng*h / mL, approximately 2,200 ng*h / mL, approximately 2,450 ng*h / mL, approximately 2,600 ng*h / mL, approximately 2,750 ng*h / mL, approximately 2,900 ng*h / mL, approximately 3,100 ng*h / mL, or any value between these values, and following intranasal administration of racemic ketamine, the C60 of 6-hydroxydemethylketamine... 最大The concentration is from about 55 ng / mL to about 245 ng / mL, for example, about 55 ng / mL, about 65 ng / mL, about 75 ng / mL, about 85 ng / mL, about 95 ng / mL, about 105 ng / mL, about 115 ng / mL, about 125 ng / mL, about 135 ng / mL, about 145 ng / mL, about 155 ng / mL, about 165 ng / mL, about 175 ng / mL, about 185 ng / mL, about 195 ng / mL, about 205 ng / mL, about 215 ng / mL, about 225 ng / mL, about 235 ng / mL, about 245 ng / mL, or any value between these values. In some embodiments, the AUC of 6-hydroxydemethylketamine after intranasal administration of racemic ketamine is... 0-t The concentrations were approximately 700 ng / h / mL to approximately 1,550 ng / h / mL, approximately 1,500 ng / h / mL to approximately 2,050 ng / h / mL, approximately 2,000 ng / h / mL to approximately 2,550 ng / h / mL, and approximately 2,500 ng / h / mL to approximately 3,100 ng / h / mL, and after intranasal administration of racemic ketamine, the C of 6-hydroxydemethylketamine... 最大 The values ​​range from approximately 55 ng / mL to approximately 125 ng / mL, approximately 120 ng / mL to approximately 180 ng / mL, or approximately 175 ng / mL to approximately 245 ng / mL.

[0251] In some embodiments, the AUC of ketamine after intranasal administration of racemic ketamine is... 0-无穷大 The value ranges from approximately 80 nanograms per hour (Ng*h / mL) to approximately 675 Ng*h / mL, for example, approximately 80 Ng*h / mL, approximately 125 Ng*h / mL, approximately 175 Ng*h / mL, approximately 225 Ng*h / mL, approximately 275 Ng*h / mL, approximately 325 Ng*h / mL, approximately 475 Ng*h / mL, approximately 525 Ng*h / mL, approximately 575 Ng*h / mL, approximately 625 Ng*h / mL, approximately 675 Ng*h / mL, or any value between these values. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of ketamine is approximately 80 ng / h / mL to approximately 175 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of ketamine is approximately 150 ng / h / mL to approximately 275 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of ketamine is approximately 250 ng / h / mL to approximately 375 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大The concentration ranges from approximately 350 ng*h / mL to approximately 475 ng*h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of ketamine is approximately 450 ng / h / mL to approximately 575 ng / h / mL. In some embodiments, the AUC of ketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 It ranges from approximately 550 nanograms per hour to approximately 675 nanograms per hour per milliliter.

[0252] In some embodiments, the AUC of norketamine after intranasal administration of racemic ketamine 0-无穷大 From approximately 250 nanograms per hour (Ng*h / mL) to approximately 875 Ng*h / mL, for example, approximately 250 Ng*h / mL, approximately 275 Ng*h / mL, approximately 300 Ng*h / mL, approximately 325 Ng*h / mL, approximately 350 Ng*h / mL, approximately 375 Ng*h / mL, approximately 400 Ng*h / mL, approximately 425 Ng*h / mL, approximately 450 Ng*h / mL, approximately 475 Ng*h / mL, approximately 500 Ng*h / mL, approximately 525 Ng*h / mL, approximately... 550 ng*h / mL, approximately 575 ng*h / mL, approximately 600 ng*h / mL, approximately 625 ng*h / mL, approximately 650 ng*h / mL, approximately 675 ng*h / mL, approximately 700 ng*h / mL, approximately 725 ng*h / mL, approximately 750 ng*h / mL, approximately 775 ng*h / mL, approximately 800 ng*h / mL, approximately 825 ng*h / mL, approximately 850 ng*h / mL, approximately 875 ng*h / mL, or any value between these values. In some embodiments, the AUC of desmethylketamine after intranasal administration of racemic ketamine. 0-无穷大 The concentration ranges from approximately 250 ng*h / mL to approximately 475 ng*h / mL. In some embodiments, the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The concentration ranges from approximately 450 ng*h / mL to approximately 675 ng*h / mL. In some embodiments, the AUC of norketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 It ranges from approximately 650 nanograms per hour to approximately 875 nanograms per hour per milliliter.

[0253] In some embodiments, the AUC of 6-hydroxynorketamine following intranasal administration of racemic ketamine 0-无穷大The values ​​range from approximately 375 nanograms per hour (Ng*h / mL) to approximately 3,700 Ng*h / mL, for example, approximately 375 Ng*h / mL, approximately 500 Ng*h / mL, approximately 650 Ng*h / mL, approximately 900 Ng*h / mL, approximately 1,050 Ng*h / mL, approximately 1,200 Ng*h / mL, approximately 1,350 Ng*h / mL, approximately 1,500 Ng*h / mL, approximately 1,650 Ng*h / mL, approximately 1,800 Ng*h / mL, and approximately 1,950 Ng*h / mL. Approximately 2,100 ng*h / mL, approximately 2,250 ng*h / mL, approximately 2,400 ng*h / mL, approximately 2,550 ng*h / mL, approximately 2,700 ng*h / mL, approximately 2,850 ng*h / mL, approximately 3,000 ng*h / mL, approximately 3,150 ng*h / mL, approximately 3,300 ng*h / mL, approximately 3,450 ng*h / mL, approximately 3,600 ng*h / mL, approximately 3,700 ng*h / mL, or any value between these values. In some embodiments, the AUC of 6-hydroxydemethylketamine after intranasal administration of racemic ketamine is... 0-无穷大 The AUC of 6-hydroxydemethylketamine is approximately 375 ng*h / mL to approximately 1,250 ng*h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of 6-hydroxydemethylketamine is approximately 1,200 ng / h / mL to approximately 1,400 ng / h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 The AUC of 6-hydroxydemethylketamine is approximately 1,350 ng*h / mL to approximately 2,700 ng*h / mL. In some embodiments, the AUC of 6-hydroxydemethylketamine is measured after intranasal administration of racemic ketamine. 0-无穷大 From approximately 2,600 nanograms per hour / mL to approximately 3,700 nanograms per hour / mL.

[0254] In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​ketamine is from about 2.5% to about 8%, for example, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​ketamine is from about 2.5% to about 5%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​ketamine is from about 4% to about 6%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​ketamine is from about 5% to about 8%.

[0255] In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​norketamine is about 6% to about 15%, such as about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​norketamine is about 2.5% to about 5%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​norketamine is about 4% to about 6%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​norketamine is about 5% to about 8%.

[0256] In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​6-hydroxydemethylketamine is about 16% to about 34%, such as about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or any value between these values. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​6-hydroxydemethylketamine is about 16% to about 24%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​6-hydroxydemethylketamine is about 20% to about 30%. In some embodiments, after intranasal administration of racemic ketamine, the residual area of ​​6-hydroxydemethylketamine is about 26% to about 34%.

[0257] In some embodiments, the AUC of racemic ketamine inside and outside the nose 0-t AUC of equivalent intravenous and intravenous racemic ketamine 0-t Approximately 80% to approximately 125%. For example, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, approximately 105%, approximately 110%, approximately 115%, approximately 120%, approximately 125%, or any value between these. In some embodiments, the AUC of racemic ketamine inside and outside the nose... 0-t AUC of equivalent intravenous and intravenous racemic ketamine 0-t Approximately 80% to approximately 95%. In some embodiments, the AUC of intranasal and extranasal racemic ketamine... 0-无穷大 AUC of equivalent intravenous and intravenous racemic ketamine 0-无穷大Approximately 80% to approximately 125%. For example, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, approximately 105%, approximately 110%, approximately 115%, approximately 120%, approximately 125%, or any value between these. In some embodiments, intranasal and extranasal racemic ketamine... AUC0-无穷大 AUC of equivalent intravenous and intravenous racemic ketamine 0-无穷大 Approximately 80% to approximately 95%.

[0258] In some embodiments, the AUC of demethylketamine after intranasal and extranasal racemic ketamine administration 0-t The AUC of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine. 0-t Approximately 1.1 to approximately 4.0 times higher. In some embodiments, the AUC of demethylketamine is measured after intranasal and extranasal administration of racemic ketamine. 0-无穷大 The AUC of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine. 0-无穷大 Approximately 1.1 times to approximately 4.0 times. For example, approximately 1.1 times, approximately 1.2 times, approximately 1.3 times, approximately 1.4 times, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, approximately 3.6 times, approximately 3.7 times, approximately 3.8 times, approximately 3.9 times, or approximately 4.0 times, or any value between these.

[0259] In some embodiments, the AUC of 6-hydroxydemethylketamine after intranasal and extranasal racemic ketamine administration 0-t The AUC of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine. 0-t Approximately 1.3 to approximately 3.6 times. For example, approximately 1.3 times, approximately 1.4 times, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, or approximately 3.6 times, or any value between these values. In some embodiments, the AUC of 6-hydroxydemethylketamine after intranasal and extranasal administration of racemic ketamine. 0-无穷大 The AUC of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine. 0-无穷大Approximately 1.1 times to approximately 3.1 times. For example, approximately 1.1 times, approximately 1.2 times, approximately 1.3 times, approximately 1.4 times, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, or approximately 3.1 times, or any value in between.

[0260] In some embodiments, the C-type of racemic ketamine inside and outside the nose 最大 C10 of equivalent intravenous and intravenous racemic ketamine 最大 Approximately 25% to approximately 125%. For example, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100%, approximately 105%, approximately 110%, approximately 115%, approximately 120%, approximately 125%, or any value between these values. In some embodiments, the C of intranasal and extranasal racemic ketamine... 最大 C10 of equivalent intravenous and intravenous racemic ketamine 最大 Approximately 25% to approximately 100%. In some embodiments, the C of intranasal and extranasal racemic ketamine... 最大 C10 of equivalent intravenous and intravenous racemic ketamine 最大 Approximately 30% to approximately 75%. In some embodiments, the C of intranasal and extranasal racemic ketamine... 最大 C10 of equivalent intravenous and intravenous racemic ketamine 最大 Approximately 50% to approximately 70%.

[0261] In some embodiments, the C-type of norketamine following intranasal and extranasal racemic ketamine administration 最大 C-value of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大 Approximately 1.5 to 6.0 times. For example, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, approximately 3.6 times, approximately 3.7 times, approximately 3... Approximately 3.9 times, approximately 4.0 times, approximately 4.1 times, approximately 4.2 times, approximately 4.3 times, approximately 4.4 times, approximately 4.5 times, approximately 4.6 times, approximately 4.7 times, approximately 4.8 times, approximately 4.9 times, approximately 5.0 times, approximately 5.1 times, approximately 5.2 times, approximately 5.3 times, approximately 5.4 times, approximately 5.5 times, approximately 5.6 times, approximately 5.7 times, approximately 5.8 times, approximately 5.9 times, or approximately 6.0 times, or any value between these values.

[0262] In some embodiments, C6-hydroxynorketamine C6 is obtained after intranasal and extranasal administration of racemic ketamine. 最大 To determine the C-value of 6-hydroxynorketamine after administration of an equivalent dose of intravenous or intra-racial racemic ketamine. 最大 Approximately 1.4 to approximately 5.0 times. For example, approximately 1.4 times, approximately 1.5 times, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, approximately 3.6 times, approximately 3.7 times, approximately 3.8 times, approximately 3.9 times, approximately 4.0 times, approximately 4.1 times, approximately 4.2 times, approximately 4.3 times, approximately 4.4 times, approximately 4.5 times, approximately 4.6 times, approximately 4.7 times, approximately 4.8 times, approximately 4.9 times, or approximately 5.0 times, or any value between these values.

[0263] In some embodiments, T-type intranasal and extranasal racemic ketamine 最大 T is the equivalent dose of intravenous and intravenous racemic ketamine. 最大 Approximately 1.6 to 6.0 times. For example, approximately 1.6 times, approximately 1.7 times, approximately 1.8 times, approximately 1.9 times, approximately 2.0 times, approximately 2.1 times, approximately 2.2 times, approximately 2.3 times, approximately 2.4 times, approximately 2.5 times, approximately 2.6 times, approximately 2.7 times, approximately 2.8 times, approximately 2.9 times, approximately 3.0 times, approximately 3.1 times, approximately 3.2 times, approximately 3.3 times, approximately 3.4 times, approximately 3.5 times, approximately 3.6 times, approximately 3.7 times, and approximately 3.8 times. Approximately 3.9 times, approximately 4.0 times, approximately 4.1 times, approximately 4.2 times, approximately 4.3 times, approximately 4.4 times, approximately 4.5 times, approximately 4.6 times, approximately 4.7 times, approximately 4.8 times, approximately 4.9 times, approximately 5.0 times, approximately 5.1 times, approximately 5.2 times, approximately 5.3 times, approximately 5.4 times, approximately 5.5 times, approximately 5.6 times, approximately 5.7 times, approximately 5.8 times, approximately 5.9 times, or approximately 6.0 times, or any value between these values.

[0264] In some embodiments, T-type ketamine following intranasal and extranasal administration of racemic ketamine 最大 T of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大Approximately 30% to approximately 550%. For example, approximately 30%, approximately 45%, approximately 60%, approximately 75%, approximately 90%, approximately 105%, approximately 120%, approximately 140%, approximately 155%, approximately 170%, approximately 185%, approximately 200%, approximately 215%, approximately 230%, approximately 245%, approximately 260%, approximately 275%, approximately 290%, approximately 305%, approximately 320%, approximately 340%, approximately 355%, approximately 370%, approximately 385%, approximately 400%, approximately 415%, approximately 430%, approximately 445%, approximately 460%, approximately 475%, approximately 490%, approximately 505%, approximately 520%, approximately 540%, approximately 550%, or any value between these values. In some embodiments, after intranasal and extranasal administration of racemic ketamine, T of demethylketamine is... 最大 T of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大 Approximately 80% to approximately 240%. For example, approximately 80%, approximately 100%, approximately 120%, approximately 140%, approximately 160%, approximately 180%, approximately 200%, approximately 220%, approximately 240%, or any value between these. In some embodiments, after intranasal and extranasal administration of racemic ketamine, T of demethylketamine is... 最大 T of norketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大 Approximately 90% to approximately 180%. For example, approximately 90%, approximately 100%, approximately 110%, approximately 120%, approximately 130%, approximately 140%, approximately 150%, approximately 160%, approximately 170%, approximately 180%, or any value in between.

[0265] In some embodiments, 6-hydroxynorketamine T following intranasal and extranasal racemic ketamine administration 最大 T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大 Approximately 20% to approximately 200%. For example, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 110%, approximately 120%, approximately 130%, approximately 140%, approximately 150%, approximately 160%, approximately 170%, approximately 180%, approximately 190%, approximately 200%, or any value between these. In some embodiments, 6-hydroxydemethylketamine is administered intranasally and extranasally after racemic ketamine. 最大 T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine 最大 Approximately 50% to approximately 100%. For example, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, or any value between these. In some embodiments, 6-hydroxynorketamine is administered intranasally and intranasally after T... 最大 T of 6-hydroxynorketamine after administration of an equivalent dose of intravenous or intravenous racemic ketamine最大 Approximately 65% ​​to approximately 85%. For example, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, or any value in between.

[0266] In some embodiments, intranasal and intranasal administration of racemic ketamine provides higher exposure and / or higher plasma concentrations of one or more active metabolites of ketamine, relative to an equivalent dose of intravenous or intranasal racemic ketamine. In some embodiments, one or more active metabolites are selected from norketamine, 6-hydroxynorketamine, and combinations thereof.

[0267] In some embodiments, intranasal and extranasal racemic ketamine administration provides higher exposure and / or higher plasma concentrations of norketamine compared to equivalent doses of intravenous and extranasal racemic ketamine. In some embodiments, intranasal and extranasal racemic ketamine administration provides higher exposure and / or higher plasma concentrations of 6-hydroxynorketamine compared to equivalent doses of intravenous and extranasal racemic ketamine. In some embodiments, intranasal and extranasal racemic ketamine administration provides higher exposure and / or higher plasma concentrations of both norketamine and 6-hydroxynorketamine compared to equivalent doses of intravenous and extranasal racemic ketamine.

[0268] In some embodiments, via AUC 0-无穷大 The equivalent value is determined to be an “equivalent” dose of intranasal and intravenous racemic ketamine and intravenous racemic ketamine and / or intravenous (S)-ketamine or any of the aforementioned pharmaceutically acceptable salts.

[0269] In some embodiments, intranasal administration of racemic ketamine exhibits one or more of the following:

[0270] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0271] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0272] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0273] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-tApproximately 1.7 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-t Approximately 1.9 to approximately 2.3 times that of norketamine. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-t At least 1.8 times (e.g., at least 1.9 times or at least 2 times).

[0274] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-无穷大 The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 Approximately 1.5 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 Approximately 1.8 to approximately 2.2 times that of norketamine. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of norketamine. 0-t The AUC of noreketamine as a result of intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 At least 1.7 times (e.g., at least 1.8 times, at least 1.9 times, or at least 2 times).

[0275] In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of norketamine. 最大 The C-value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.2 to 3.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of norketamine. 最大 The C-value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.4 to 3.2 times that of norketamine. In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of norketamine. 最大 The C-value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 At least 2.5 times (e.g., at least 2.8 times or at least 3 times). In some embodiments, intranasal administration of racemic ketamine exhibits the T of norketamine. 最大 The T value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大Approximately 80% to approximately 125%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of norketamine. 最大 The T value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 90% to approximately 110%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of norketamine. 最大 The T value of noreketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 95% to approximately 105%.

[0276] In some embodiments, the AUC of norketamine is determined after a single dose of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of norketamine is determined after two administrations of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of norketamine is determined after three doses of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them.

[0277] In some embodiments, intranasal administration of racemic ketamine exhibits one or more of the following:

[0278] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0279] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0280] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0281] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-tThe AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t Approximately 1.7 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t Approximately 1.9 to approximately 2.3 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.9 times (e.g., at least 2 times or at least 2.1 times).

[0282] In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 Approximately 1.5 to 2.5 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 Approximately 1.7 to approximately 2.1 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the AUC of hydroxynorketamine. 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.7 times (e.g., at least 1.8 times or at least 1.9 times).

[0283] In some embodiments, intranasal administration of racemic ketamine exhibits the C-type properties of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.2 to 3.2 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C60-like effect of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 2.4 to 2.8 times higher. In some embodiments, intranasal administration of racemic ketamine exhibits the C-value of hydroxynorketamine. 最大 The C-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 At least 2.4 times (e.g., at least 2.5 times or at least 2.6 times).

[0284] In some embodiments, intranasal administration of racemic ketamine exhibits the T-type effect of hydroxynorketamine. 最大 The T-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 80% to approximately 125%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of hydroxynorketamine. 最大 The T-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 90% to approximately 110%. In some embodiments, intranasal administration of racemic ketamine exhibits the T-value of hydroxynorketamine. 最大 The T-value of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 最大 Approximately 95% to approximately 105%.

[0285] In some embodiments, the AUC of hydroxynorketamine is determined after a single dose of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of hydroxynorketamine is determined after two administrations of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them. In some embodiments, the AUC of hydroxynorketamine is determined after three doses of racemic ketamine. 0-t AUC 0-无穷大 C 最大 and T 最大 One or more of them.

[0286] In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's overall score on the Montgomery-Asperger's Depression Rating Scale (MADRS) was 20–60 units.

[0287] In some embodiments, the subject's overall MADRS score is 30-60 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, the subject's overall MADRS score decreases by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, the subject's overall MADRS score is less than or equal to 15 units 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof. In some embodiments, the subject's overall MADRS score is less than or equal to 12 units 48 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saponin thereof.

[0288] In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS item 10 score was 4, 5, or 6 units. In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's MADRS item 10 score was 5 or 6 units. In some embodiments, administration of racemic ketamine or a pharmaceutically acceptable salt thereof 4 hours later resulted in a decrease of at least 1 unit in the subject's MADRS item 10 score.

[0289] In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's Clinical Global Impression of Suicidal Ideation and Behavior (CGIS-SI / B) score was 4 or 5 units. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, the subject's CGIS-SI / B score was 1 or 2 units.

[0290] In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's Clinically Significant Measure of Change (CMCM) score on the Sheehan's Suicide Proneness Tracking Scale (S-STS) was 15-52 units. In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM score was 20-52 units. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM score decreased by at least 50%. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM score was 1-3 units.

[0291] In some embodiments, prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's clinically significant measure of change (CMCM) on the Sheehan's Suicide Proneness Tracking Scale (S-STS) indicates a suicide risk score of 5 to 10 units over the next 7 days. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM indicates a suicide risk score of at least 50% over the next 7 days. In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM indicates a suicide risk score of 0 to 2 units over the next 7 days. In some embodiments, 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable saline thereof, the subject's S-STS CMCM indicates a suicide risk score of 0 or 1 unit over the next 7 days.

[0292] In some embodiments, the subject's Improved Alertness / Sedation Observer Assessment (MOAA / S) score is 5 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA / S score is 4 or 5 units 15 minutes to 6 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the subject's clinician-administered Dissociation Status Scale (CADSS) score was zero before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score was zero 1 hour to 6 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the subject's C-SSRS score was 2 to 9 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's C-SSRS score was 2 to 5 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CSSR-S score was zero units 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0295] Some embodiments provide a method for treating suicidal tendencies in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant sedation is observed in the subject within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0296] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant dissociation is observed in the subject within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0297] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant sedation is observed in the subject within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0298] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant dissociation is observed in the subject within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0299] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant sedation is observed in the subject for approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject for approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation is observed in the subject for approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0300] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising administering a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof intranasally to the subject; wherein no clinically significant dissociation is observed in the subject within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant dissociation is observed in the subject within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, no clinically significant sedation or dissociation was observed in subjects within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation or dissociation was observed in subjects within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation or dissociation was observed in subjects within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0302] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0303] (a) Determine whether the subject has one or more of the following:

[0304] (i) At least 20 units of MADRS overall score;

[0305] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0306] (iii) CGIS-SI / B score of 4 or 5 units;

[0307] (iv) At least 15 units of S-STS CMCM scores;

[0308] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0309] (vi) A C-SSRS score of at least 2; and

[0310] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0311] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0312] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0313] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0314] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0315] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0316] (a) Determine whether the subject has one or more of the following:

[0317] (i) At least 20 units of MADRS overall score;

[0318] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0319] (iii) CGIS-SI / B score of 4 or 5 units;

[0320] (iv) At least 15 units of S-STS CMCM scores;

[0321] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0322] (vi) A C-SSRS score of at least 2; and

[0323] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0324] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0325] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0326] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0327] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0328] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0329] (a) Determine whether the subject has one or more of the following:

[0330] (i) At least 20 units of MADRS overall score;

[0331] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0332] (iii) CGIS-SI / B score of 4 or 5 units;

[0333] (iv) At least 15 units of S-STS CMCM scores;

[0334] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0335] (vi) A C-SSRS score of at least 2; and

[0336] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0337] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0338] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0339] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0340] C of norketamine 最大The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0341] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0342] (a) Determine whether the subject has one or more of the following:

[0343] (i) At least 20 units of MADRS overall score;

[0344] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0345] (iii) CGIS-SI / B score of 4 or 5 units;

[0346] (iv) At least 15 units of S-STS CMCM scores;

[0347] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0348] (vi) A C-SSRS score of at least 2; and

[0349] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0350] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0351] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0352] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0353] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0354] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0355] (a) Determine whether the subject has one or more of the following:

[0356] (i) At least 20 units of MADRS overall score;

[0357] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0358] (iii) CGIS-SI / B score of 4 or 5 units;

[0359] (iv) At least 15 units of S-STS CMCM scores;

[0360] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0361] (vi) A C-SSRS score of at least 2; and

[0362] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0363] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0364] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0365] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0366] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0367] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0368] (a) Determine whether the subject has one or more of the following:

[0369] (i) At least 20 units of MADRS overall score;

[0370] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0371] (iii) CGIS-SI / B score of 4 or 5 units;

[0372] (iv) At least 15 units of S-STS CMCM scores;

[0373] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0374] (vi) A C-SSRS score of at least 2; and

[0375] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0376] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0377] AUC of hydroxynorketamine 0-t The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0378] AUC of hydroxynorketamine 0-无穷大 The AUC of hydroxynorketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.2 times; and

[0379] C of hydroxynorketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0380] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0381] (a) Determine whether the subject has one or more of the following:

[0382] (i) At least 20 units of MADRS overall score;

[0383] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0384] (iii) CGIS-SI / B score of 4 or 5 units;

[0385] (iv) At least 15 units of S-STS CMCM scores;

[0386] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0387] (vi) A C-SSRS score of at least 2; and

[0388] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0389] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0390] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0391] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0392] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0393] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0394] (a) Determine whether the subject has one or more of the following:

[0395] (i) At least 20 units of MADRS overall score;

[0396] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0397] (iii) CGIS-SI / B score of 4 or 5 units;

[0398] (iv) At least 15 units of S-STS CMCM scores;

[0399] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0400] (vi) A C-SSRS score of at least 2; and

[0401] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0402] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0403] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-t At least 1.5 times;

[0404] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0405] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0406] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0407] (a) Determine whether the subject has one or more of the following:

[0408] (i) At least 20 units of MADRS overall score;

[0409] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0410] (iii) CGIS-SI / B score of 4 or 5 units;

[0411] (iv) At least 15 units of S-STS CMCM scores;

[0412] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0413] (vi) A C-SSRS score of at least 2; and

[0414] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0415] Intranasal administration of the racemic ketamine exhibits one or more of the following:

[0416] AUC of norketamine 0-t The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-tAt least 1.5 times;

[0417] AUC of norketamine 0-无穷大 The AUC of norketamine as expressed by an equivalent dose of racemic ketamine administered intravenously. 0-无穷大 At least 1.5 times; and

[0418] C of norketamine 最大 The C of noreketamine as expressed by intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much.

[0419] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0420] (a) Determine whether the subject has one or more of the following:

[0421] (i) At least 20 units of MADRS overall score;

[0422] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0423] (iii) CGIS-SI / B score of 4 or 5 units;

[0424] (iv) At least 15 units of S-STS CMCM scores;

[0425] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0426] (vi) A C-SSRS score of at least 2; and

[0427] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0428] No clinically significant sedation was observed in the subjects approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0429] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0430] (a) Determine whether the subject has one or more of the following:

[0431] (i) At least 20 units of MADRS overall score;

[0432] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0433] (iii) CGIS-SI / B score of 4 or 5 units;

[0434] (iv) At least 15 units of S-STS CMCM scores;

[0435] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0436] (vi) A C-SSRS score of at least 2; and

[0437] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0438] No clinically significant separation was observed in the subjects within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0439] Some embodiments provide a method for treating suicidal tendencies in a subject in need, the method comprising:

[0440] (a) Determine whether the subject has one or more of the following:

[0441] (i) At least 20 units of MADRS overall score;

[0442] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0443] (iii) CGIS-SI / B score of 4 or 5 units;

[0444] (iv) At least 15 units of S-STS CMCM scores;

[0445] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0446] (vi) A C-SSRS score of at least 2; and

[0447] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0448] Within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects.

[0449] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0450] (a) Determine whether the subject has one or more of the following:

[0451] (i) At least 20 units of MADRS overall score;

[0452] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0453] (iii) CGIS-SI / B score of 4 or 5 units;

[0454] (iv) At least 15 units of S-STS CMCM scores;

[0455] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0456] (vi) A C-SSRS score of at least 2; and

[0457] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0458] No clinically significant sedation was observed in the subjects approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0459] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0460] (a) Determine whether the subject has one or more of the following:

[0461] (i) At least 20 units of MADRS overall score;

[0462] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0463] (iii) CGIS-SI / B score of 4 or 5 units;

[0464] (iv) At least 15 units of S-STS CMCM scores;

[0465] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0466] (vi) A C-SSRS score of at least 2; and

[0467] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0468] No clinically significant separation was observed in the subjects within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0469] Some embodiments provide a method for treating suicidal ideation in a subject in need, the method comprising:

[0470] (a) Determine whether the subject has one or more of the following:

[0471] (i) At least 20 units of MADRS overall score;

[0472] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0473] (iii) CGIS-SI / B score of 4 or 5 units;

[0474] (iv) At least 15 units of S-STS CMCM scores;

[0475] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0476] (vi) A C-SSRS score of at least 2; and

[0477] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0478] Within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects.

[0479] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0480] (a) Determine whether the subject has one or more of the following:

[0481] (i) At least 20 units of MADRS overall score;

[0482] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0483] (iii) CGIS-SI / B score of 4 or 5 units;

[0484] (iv) At least 15 units of S-STS CMCM scores;

[0485] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0486] (vi) A C-SSRS score of at least 2; and

[0487] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0488] No clinically significant sedation was observed in the subjects approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant sedation was observed in the subjects approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0489] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0490] (a) Determine whether the subject has one or more of the following:

[0491] (i) At least 20 units of MADRS overall score;

[0492] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0493] (iii) CGIS-SI / B score of 4 or 5 units;

[0494] (iv) At least 15 units of S-STS CMCM scores;

[0495] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0496] (vi) A C-SSRS score of at least 2; and

[0497] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0498] No clinically significant separation was observed in the subjects within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, no clinically significant separation was observed in the subjects within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

[0499] Some embodiments provide a method for treating major depressive disorder in a subject of need, the method comprising:

[0500] (a) Determine whether the subject has one or more of the following:

[0501] (i) At least 20 units of MADRS overall score;

[0502] (ii) MADRS item 10 score of 4, 5 or 6 units;

[0503] (iii) CGIS-SI / B score of 4 or 5 units;

[0504] (iv) At least 15 units of S-STS CMCM scores;

[0505] (v) A suicide risk score of at least 5 units of the S-STS CMCM over the next 7 days; and

[0506] (vi) A C-SSRS score of at least 2; and

[0507] (b) Administer a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof into the nasal cavity of the subject;

[0508] Within approximately 24 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 4 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects. In some embodiments, within approximately 1 hour following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, no clinically significant sedation or dissociation was observed in the subjects.

[0509] In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are reduced by at least 50%: MADRS overall score, MADRS Item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0510] In some embodiments, 48 ​​hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are reduced by at least 50%: MADRS overall score, MADRS Item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0511] In some embodiments, 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are reduced by at least 50%: MADRS overall score, MADRS Item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0512] In some embodiments, 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are below the remission criteria: MADRS overall score, MADRS item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0513] In some embodiments, 48 ​​hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are below the remission criteria: MADRS overall score, MADRS item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0514] In some embodiments, 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, one or more of the following scores are below the remission criteria: MADRS overall score, MADRS item 10 score, CGIS-SI / B score, S-STS CMCM score, S-STS CMCM risk score for suicide in the next 7 days, and C-SSRS score.

[0515] In some embodiments, the subject's overall MADRS score is at least 20 units. In some embodiments, the subject's MADRS item 10 score is 4, 5, or 6 units. In some embodiments, the subject's CGIS-SI / B score is 4 or 5 units. In some embodiments, the subject's S-STS CMCM score is at least 15 units. In some embodiments, the subject's S-STS CMCM risk score for suicide in the next 7 days is at least 5 units. In some embodiments, the subject's C-SSRS score is at least 2. In some embodiments, the subject's overall MADRS score is at least 20 units, and their CGIS-SI / B score is 4 or 5 units. In some embodiments, the subject's overall MADRS score is at least 20 units, and their S-STS CMCM score is at least 15 units. In some embodiments, the subject's overall MADRS score is at least 20 units; their CGIS-SI / B score is 4 or 5 units; and their S-STS CMCM score is at least 15 units.

[0516] In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally about once daily to about once monthly, such as once daily, every other day, twice weekly, or once weekly. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally about once daily to about once every two weeks. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally about once daily to about once weekly. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally about once weekly to about twice weekly. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice weekly. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally once daily, every other day, three times weekly, twice weekly, or once weekly. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally every four days (e.g., on day 1, day 4, day 8, day 12, day 16, etc.).

[0517] Some of the embodiments described herein provide a comparison between intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, intravenous administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and / or administration (e.g., intravenous or intranasal administration of) (S)-ketamine or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, intranasal (S)-ketamine is In some embodiments, intranasal (S)-ketamine is a solution substantially composed of 32.3 mg of (S)-ketamine hydrochloride (equivalent to 28 mg of (S)-ketamine), citric acid monohydrate, disodium edetate, sodium hydroxide, and water. In some embodiments, intranasal (S)-ketamine is a clear, colorless aqueous solution with a pH of 4.5. See also the document dated February 11, 2020. ((S)-ketamine) Packaging insert; www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 211243s003lbl.pdf, the reference of which is hereby incorporated in its entirety by reference.

[0519] Some embodiments mention the time “before” administration of intranasal or extranasal racemic ketamine or a pharmaceutically acceptable salt thereof. The time before administration can be a specific time or time range indicated (e.g., about 30 minutes, about 1 hour, about 1 day to about 1 week, 6 months, etc.), or if no specific time or range is specified, the time can be any time before administration.

[0520] Combination therapy

[0521] The methods of this disclosure also contemplate treatment comprising administering ketamine or a pharmaceutically acceptable salt thereof as described in any of the embodiments of this disclosure in combination with one or more additional therapies (e.g., antidepressants). Therefore, ketamine or a pharmaceutically acceptable salt thereof as described anywhere herein may be administered alone or in combination with one or more additional therapies. When administered in combination with one or more additional therapies, a single dosage form may be administered to the subject. If administered as a single dosage form, one or more additional therapies may be administered concurrently with an intranasal ketamine dosage form of this disclosure or sequentially with an intranasal ketamine dosage form of this disclosure in any order. In some embodiments, an intranasal ketamine dosage form and one or more additional therapies may be administered sequentially on the same day or on different days. For example, racemic ketamine or a pharmaceutically acceptable salt thereof may be administered intranasally twice weekly, and one or more additional therapies may be administered once daily.

[0522] In some embodiments, the methods described herein further include administering one or more additional therapies, which consist of: typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole.

[0523] In some embodiments, the methods described herein further include providing cognitive behavioral therapy to the subject.

[0524] In some embodiments, one or more additional therapies are standard care treatments for major depressive disorder. In some embodiments, one or more additional therapies are standard care treatments for suicidal tendencies. In some embodiments, one or more additional therapies are standard care treatments for suicidal ideation. In some embodiments, one or more additional therapies are standard care treatments for treatment-resistant depression. In some embodiments, one or more additional therapies are standard care treatments for post-traumatic stress disorder.

[0525] In some embodiments, one or more additional treatments are pramipexole.

[0526] In some embodiments, one or more additional therapies are typical antipsychotics. Representative typical antipsychotics include, but are not limited to, chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol.

[0527] In some embodiments, one or more additional therapies are atypical antipsychotics. Representative atypical antipsychotics include, but are not limited to, aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone.

[0528] In some embodiments, one or more additional therapies are antidepressants. In some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, or a selective norepinephrine reuptake inhibitor.

[0529] In some embodiments, the antidepressant is an atypical antidepressant. Representative atypical antidepressants include, but are not limited to, mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine.

[0530] In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor. Representative selective serotonin reuptake inhibitors include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.

[0531] In some embodiments, the antidepressant is a selective serotonin and norepinephrine reuptake inhibitor. Representative selective serotonin and norepinephrine reuptake inhibitors include, but are not limited to, atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, tramadol, and venlafaxine.

[0532] In some embodiments, the antidepressant is a monoamine oxidase inhibitor. Representative monoamine oxidase inhibitors include, but are not limited to, moclobemide, rasagiline, selegiline, or safinamide.

[0533] In some embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor (SNR). Representative SNRs include, but are not limited to, reboxetine.

[0534] In some embodiments, one or more additional therapies are benzodiazepines. Representative benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam.

[0535] In some embodiments, one or more additional therapies are mood stabilizers. Representative mood stabilizers include, but are not limited to, lithium, valproic acid, lamotrigine, or carbamazepine. In some embodiments, one or more additional therapies are electroconvulsive therapy or transcranial magnetic stimulation.

[0536] In some embodiments, one or more additional treatments are sertraline. In some embodiments, one or more additional treatments are venlafaxine.

[0537] In some embodiments, one or more additional therapies constitute one additional therapy. In some embodiments, one or more additional therapies constitute two, three, or four additional therapies.

[0538] In some embodiments, the subject has previously been given one or more additional therapies, which consist of: typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole; wherein the subject has not responded to the previous one or more therapies.

[0539] In some embodiments, the subject has previously received standard care for major depressive disorder and is unresponsive to the previous treatment. In some embodiments, the subject has previously received standard care for suicidal tendencies and is unresponsive to the previous treatment. In some embodiments, the subject has previously received standard care for suicidal ideation and is unresponsive to the previous treatment. In some embodiments, the subject has previously received standard care for treatment-resistant depression and is unresponsive to the previous treatment. In some embodiments, the subject has previously received standard care for post-traumatic stress disorder and is unresponsive to the previous treatment.

[0540] In some embodiments, the subject has previously been given one or more additional therapies consisting of: typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole, and the subject has not responded to the previous therapy.

[0541] In some embodiments, the subject has previously been given pramipexole and has not responded to the previous treatment.

[0542] In some embodiments, the subject has previously been treated with one or more typical antipsychotic drugs, such as chlorpromazine, chlorprothiazide, levomethazine, mesoridazine, piperazine, promazine, loxapine, motinone, perphenazine, tevothiazide, fluperidone, fluperidone, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclothiazol, and has not responded to previous treatment.

[0543] In some embodiments, the subject has previously been treated with one or more atypical antipsychotics, such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone, and has not responded to previous treatment.

[0544] In some embodiments, the subject has previously been treated with one or more antidepressants and is unresponsive to previous therapy. In some embodiments, the antidepressant is an atypical antidepressant, a selective serotonin reuptake inhibitor, a selective serotonin and norepinephrine reuptake inhibitor, a monoamine oxidase inhibitor, or a selective norepinephrine reuptake inhibitor, and is unresponsive to previous therapy.

[0545] In some embodiments, the subject has previously been treated with one or more atypical antidepressants, such as mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opramor, agomelatine, vilazorone, and vortioxetine, and has not responded to previous treatment.

[0546] In some embodiments, the subject has previously been given one or more selective serotonin reuptake inhibitors, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, and has not responded to previous treatment.

[0547] In some embodiments, the subject has previously bee...

Claims

1. Use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating suicidal tendencies in a subject in need, wherein the medicament is formulated for intranasal administration. Prior to intranasal administration of the racemic ketamine or a pharmaceutically acceptable salt thereof, the subject was determined to have an overall Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35-60 units. Intranasal administration of racemic ketamine or its pharmaceutically acceptable salts exhibits one or more of the following: The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-24 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-24 At least 1.5 times; The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-无穷大 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 At least 1.5 times; C-type ketamine was administered on day 1, day 4, or day 8 after intranasal application. 最大 The C-value of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much; Thus, the suicidal tendency of the treated subjects was compared with that of the subjects before administration of racemic ketamine or its pharmaceutically acceptable salts.

2. Use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating suicidal ideation in a subject in need, wherein the medicament is formulated for intranasal administration. Prior to intranasal administration of the racemic ketamine or a pharmaceutically acceptable salt thereof, the subject was determined to have an overall Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35-60 units. Intranasal administration of racemic ketamine or its pharmaceutically acceptable salts exhibits one or more of the following: The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-24 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-24 At least 1.5 times; The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-无穷大 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 At least 1.5 times; C-type ketamine was administered on day 1, day 4, or day 8 after intranasal application. 最大 The C-value of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much; Thus, the suicidal ideation of the treated subjects was compared with that of the subjects prior to administration of racemic ketamine or its pharmaceutically acceptable salts.

3. Use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating major depressive disorder in a subject of need, wherein the medicament is formulated for intranasal administration. Prior to intranasal administration of the racemic ketamine or a pharmaceutically acceptable salt thereof, the subject was determined to have an overall Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35-60 units. Intranasal administration of racemic ketamine or its pharmaceutically acceptable salts exhibits one or more of the following: The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-24 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-24 At least 1.5 times; The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-无穷大 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 At least 1.5 times; C-type ketamine was administered on day 1, day 4, or day 8 after intranasal application. 最大 The C-value of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much; Thus, treating subjects with major depressive disorder compared to subjects with major depressive disorder prior to administration of racemic ketamine or its pharmaceutically acceptable salts resulted in the improvement of major depressive disorder.

4. The use according to any one of claims 1 to 3, wherein the drug is used in conjunction with one or more additional therapies, said one or more additional therapies comprising: Typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole (pramipexole).

5. The use according to any one of claims 1 to 4, wherein the subject has previously received one or more additional therapies, said one or more additional therapies comprising: Typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole; wherein the subject has not responded to one or more prior therapies.

6. The use according to claim 4 or 5, wherein the typical antipsychotic drug is chlorpromazine. (chlorpromazine), chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, or zuclopenthixol.

7. The use according to claim 5 or 6, wherein the atypical antipsychotic is aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone.

8. The use according to claim 4 or 5, wherein the antidepressant comprises: Atypical antidepressants, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and selective norepinephrine reuptake inhibitors.

9. The use according to claim 8, wherein the atypical antidepressant is mirtazapine, mianserin, bupropion, trazodone, or nefazodone. (nefazodone), tianeptine, opipramol, agomelatine, vilazodone, or vortioxetine.

10. Use in the preparation of a medicament for reducing one or more side effects of ketamine in a subject in need, wherein the medicament is formulated for intranasal administration. Prior to intranasal administration of the racemic ketamine or a pharmaceutically acceptable salt thereof, the subject was determined to have an overall Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35-60 units. Intranasal administration of racemic ketamine or its pharmaceutically acceptable salts exhibits one or more of the following: The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-24 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-24 At least 1.5 times; The AUC of methylketamine on day 1, day 4, or day 8 after intranasal application 0-无穷大 The AUC of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 0-无穷大 At least 1.5 times; C-type ketamine was administered on day 1, day 4, or day 8 after intranasal application. 最大 The C-value of norketamine as observed on day 1, day 4, or day 8 after intravenous administration of an equivalent dose of racemic ketamine. 最大 At least twice as much; Thus, treatment reduces one or more side effects of ketamine in the subject compared to one or more side effects of ketamine prior to administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

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