EA046262B1 - REDUCING THE SIDE EFFECTS OF N-METHYL-D-ASPARATE (NMDA) ANTAGONISTS - Google Patents

Description

Technical field

The present invention relates to compositions and methods for treating psychiatric disorders such as suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression and post-traumatic stress disorder.

State of the art

Depression is one of the most disabling of all medical disorders ()and represents a significant public health problem. It often appears early in life, can occur chronically throughout life, and can negatively impact the prognosis of other medical conditions such as cardiovascular and neurological conditions.

Although anti-depression medications and cognitive behavioral therapy may be effective in some individuals with depression, up to 20% do not respond to these interventions, and many of those who respond will eventually relapse. Similarly, it is estimated that 50% of individuals with depression are only partially (unsatisfactorily) treatable with available clinical interventions. See Al Harbi, Patient Prefer. Adherence, Vol. 6, pp. 369388 (2012). In the NIMH Sequential Treatment Alternatives for the Relief of Depression (STAR*D) trial, approximately half of the patients who received first-line antidepressant therapy demonstrated symptom reduction of at least half of baseline intensity, and only approximately one-third of the patients achieved remission (Chan 2013). Although these patients may eventually recover, many require a trial-and-error approach to therapy, and many will eventually develop treatment-resistant depression over time. See, for example, Sackheim, J. Clin. Psychiatry, Vol. 62, Suppl. 16, pp. 10-17 (2001). This can lead to even more serious conditions such as suicidal thoughts and suicidal tendencies. Suicide remains a clear, pressing, and growing public health problem despite the fact that it is a potentially preventable tragedy. Suicide rates are particularly high in individuals with undiagnosed or inadequately treated mental disorders.

The discovery of tricyclic antidepressants and monoamine oxidase inhibitors revolutionized the treatment of depression. However, even newly developed drugs for treating depression take weeks or months to achieve their full effect and may not be effective in all subjects at any safe dose. For example, most antidepressants take an average of 6 weeks to begin to have an effect on depressive symptoms. Some patients do not respond to anti-depression medications at all, and in others only certain types seem to reduce symptoms. At the same time, 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, Clin. Psychol. Rev. Vol. 27, No. 8, pp. 959-985 (2007). Providing rapid and sustained antidepressant effects will have a significant public health impact.

The essence of the invention

A detailed description of one or more embodiments is set forth in the description below. Other features, objects and advantages of the present invention will become clear from the description and claims.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of reducing one or more side effects of ketamine in a subject in need thereof, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject has previously been diagnosed with and/or currently suffers from post-traumatic stress disorder. In some embodiments, the subject has previously been diagnosed with and/or currently suffers from major depressive disorder.

- 1 046262

Description of graphic materials Abbreviations

N: number of observations;

SD: standard deviation;

Min: minimum;

Max: Maximum;

I/N: intranasal.

In fig. 1A-1C are tables describing the pharmacokinetic parameters of ketamine on Day 1 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 1A), 75 mg racemic ketamine (Fig. 1B), or 90 mg racemic ketamine (Fig. .1C).

In fig. 2A-2C are tables describing the pharmacokinetic parameters of ketamine on Day 4 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 2A), 75 mg racemic ketamine (Fig. 2B), or 90 mg racemic ketamine (Fig. .2C).

In fig. 3A-3C are tables describing the pharmacokinetic parameters of ketamine on day 8 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 3A), 75 mg racemic ketamine (Fig. 3B), or 90 mg racemic ketamine (Fig. .3C).

In fig. 4A-4C are tables describing the pharmacokinetic parameters of norketamine on Day 1 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 4A), 75 mg racemic ketamine (Fig. 4B), or 90 mg racemic ketamine (Fig. .4C).

In fig. 5A-5C are tables describing the pharmacokinetic parameters of norketamine on Day 4 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 5A), 75 mg racemic ketamine (Fig. 5B), or 90 mg racemic ketamine (Fig. .5C).

In fig. 6A-6C are tables describing the pharmacokinetic parameters of norketamine on day 8 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 6A), 75 mg racemic ketamine (Fig. 6B), or 90 mg racemic ketamine (Fig. .6C).

In fig. 7A-7C are tables describing the pharmacokinetic parameters of hydroxynorketamine on Day 1 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 7A), 75 mg racemic ketamine (Fig. 7B), or 90 mg racemic ketamine (Fig. .7C).

In fig. 8A-8C are tables describing the pharmacokinetic parameters of hydroxynorketamine on day 4 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 8A), 75 mg racemic ketamine (Fig. 8B), or 90 mg racemic ketamine (Fig. .8C).

In fig. 9A-9C are tables describing the pharmacokinetic parameters of hydroxynorketamine on day 8 in Part A of the study described in Example 1, for 30 mg racemic ketamine (Fig. 9A), 75 mg racemic ketamine (Fig. 9B), or 90 mg racemic ketamine (Fig. .9C).

In fig. 10A-10C are tables describing ketamine pharmacokinetic parameters on day 1 (FIG. 10A), day 4 (FIG. 10B), or day 8 (FIG. 10C) in Part B of the study described in Example 1 for racemic ketamine 60 mg intranasally (i/n) + placebo IV and ketamine IV 0.3 mg/kg racemic ketamine (dose equivalent to 60 mg i/n) + placebo i/n.

In fig. 11A-11C are tables describing the pharmacokinetic parameters of norketamine on Day 1 (Fig. 11A), Day 4 (Fig. 11B), or Day 8 (Fig. 11C) in Part B of the study described in Example 1, for racemic ketamine 60 mg and /n + placebo IV and ketamine IV 0.3 mg/kg racemic ketamine (dose equivalent to 60 mg i/n) + placebo i/n.

In fig. 12A-12C are tables describing the pharmacokinetic parameters of hydroxynorketamine on Day 1 (Fig. 12A), Day 4 (Fig. 12B), or Day 8 (Fig. 12C) in Part B of the study described in Example 1, for racemic ketamine 60 mg and /n + placebo IV and ketamine IV 0.3 mg/kg racemic ketamine (dose equivalent to 60 mg i/n) + placebo i/n.

In fig. 13A-13B are a table (FIG. 13A) and graph (FIG. 13B) describing the Montgomery-Osberg Depression Rating Scale (MADRS) depression scores for Subject 1 and Subject 2 from Day 1 to Day 9 described in Example 3 research.

In fig. 14A-14B are a table (FIG. 14A) and graph (FIG. 14B) describing suicidal ideation scores on the Clinical Global Impression of Severity Scale for Suicidal Ideation and Behavior (CGIS-SI/B) for Subject 1 and Subject 2 from day 1 to day 9, described in example 3 study.

In fig. 15A-15B are a table (FIG. 15A) and graph (FIG. 15B) describing the Sheehan Suicidality Tracking Scale (S-STS) scores for suicidality for Subject 1 and Subject 2 from Day 1 to Day 9 described in Example 3 research.

In fig. 16A-16B are a table (FIG. 16A) and graph (FIG. 16B) describing suicidal ideation scores on the Patient Global Impression of Severity Scale for Suicidal Ideation and Behavior (PGIS-SI/B) for Subject 1 and Subject 2 from day 1 to day 9, described in example 3 study.

In fig. 17 is a table describing the Clinical Global Impression of Change Scale for Suicidal Ideation and Behavior (CGIC-SI/B) scores for suicidal ideation.

- 2 046262 for subject 1 and subject 2 from day 1 to day 8, described in example 3 of the study.

In fig. 18 is a table describing the Patient Global Impression of Change Scale for Suicidal Ideation and Behavior (PGIC-SI/B) scores for Subject 1 and Subject 2 from Day 1 to Day 9 described in Study Example 3.

In fig. 19A-19B are a table (FIG. 19A) and graph (FIG. 19B) describing the MADRS Item 10 scores for Subject 1 and Subject 2 from Day 1 to Day 9 described in Study Example 3.

In fig. 20A-20B are a table (FIG. 20A) and graph (FIG. 20B) describing Sheehan Suicidality Monitoring Scale (STS CMCM) Clinically Significant Change Score (Current Suicide Risk) scores for Subject 1 and Subject 2 from Day 1 to day 9, described in example 3 of the study.

In fig. 21A-21B are a table (FIG. 21A) and graph (FIG. 21B) describing the STS CMCM (suicide risk over the next 7 days) scores for Subject 1 and Subject 2 from Day 1 to Day 9 described in Study Example 3 .

In fig. 22 is a table describing the modified observer assessment of alertness/sedation (MOAA/S) scores for Subject 1 and Subject 2 during the predose period and up to 24 hours on Day 1 and Day 4 described in Study Example 3 .

In fig. 23 is a table describing the Clinical Diagnostic Dissociative State Scale (CADSS) dissociation scores for Subject 1 and Subject 2 during the predose period and up to 24 hours on Day 1 and Day 4 described in Study Example 3.

In fig. 24 is a table describing the Columbia Suicidal Severity Rating Scale (C-SSRS) scores for S from Day 1 to Day 9 for Subject 1 and Day 1 to Day 4 for Subject 2 described in Study Example 3.

Detailed Description Definitions

To facilitate understanding of the present invention, definitions of certain terms are first provided. As used herein, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

Unless otherwise indicated, all technical and scientific terms are used herein in the meaning consistent with the ordinary understanding of one skilled in the art to which this disclosure pertains. For the purposes of the present invention, the following terms are defined.

Units, prefixes and symbols are designated in the form adopted by the Systeme International de Unites (SI). Numeric ranges include numbers that define a range. The headings set forth herein are not intended to limit the various aspects of the present invention, which may be learned by reference to the description as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

As used herein, the terms denoting an element in the singular or plural (respectively a, an and the in the English source text) include not only aspects with one element, but also include aspects with more than one element. For example, singular forms (respectively a, an and the in the English source text) include their plural equivalents unless the context clearly indicates otherwise. Thus, for example, reference to a cell includes a plurality of such cells, and reference to an agent includes reference to one or more agents known to those skilled in the art, and so on.

The term and/or when used herein should be understood as specifically disclosing each of the two specified features or components, together or without each other. Thus, the term and/or as used in an expression such as A and/or B herein is intended to include A and B, A or B, A (alone) and B (alone). Likewise, the term and/or, when used in an expression such as A, B and/or C, is intended to include each of the following: 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 (separately); B (separately); and C (separately).

The terms approximately and roughly as used herein are generally intended to mean an acceptable degree of error in the quantity being measured, given the nature or accuracy of the measurements. Typical approximate degrees of error are within 10% or within 5% of the specified value or range of values. Any reference to about X specifically indicates at least the values of X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1. 04X and 1.05X. Thus, approximately X is intended to provide written descriptive support for the limitation of the claims, such as 0.98X. The terms approximately and approximately, particularly in relation to a specified quantity, embrace and describe the specified quantity itself.

When roughly applied to the start of a numeric range, it applies to both ends

- 3 046262 ranges. Thus, from about 5% to about 20% is equivalent to from about 5% to about 20%. When roughly applied to the first value in a set of values, it applies to all values in that set. Thus, about 5, 10, or 15 mg is equivalent to about 5, about 10, or about 15 mg.

Racemic ketamine refers to a 1:1 mixture of two enantiomers of ketamine: (P)-2-(2-chlorophenyl)2-(methylamino)cyclohexanone and P)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone.

Equivalent dose refers to the equivalent dose of the active agent based on bioavailability. An equivalent dose based on bioavailability can be determined by comparing the extent and rate of drug absorption at two or more dosages (e.g., dosages formulated as an intranasal formulation and as an intravenous formulation, respectively) of the active agent, e.g., by determining the area under the dependence curve blood or plasma concentrations over time (AUC) and/or maximum concentration (Cmax), respectively. Accordingly, as used herein, an equivalent dose based on bioavailability is present when two dosages each exhibit an AUC and/or C _max ranging from about 80% to about 125% of each other.

The term suicidal ideation refers to a mental disorder in which the subject experiences, for example, one or more of a wish to die, vague active suicidal thoughts, active thoughts without intent, active thoughts with some intention to act, and active 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 University Suicidal 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.

The term suicidality refers to a subject experiencing suicidal thoughts who takes active step(s) to commit suicide, including, for example, a suicide attempt. 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.

Treatment or therapy of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, reducing, inhibiting or delaying the onset, progression, development, severity or recurrence of a symptom, complication, condition or biochemical signs associated with the disease. In some embodiments, treatment includes resolving a specific disorder, including reducing one or more symptoms of the disorder and/or reducing the severity of one or more symptoms associated with the disorder.

To administer or administer (administer) refers to the physical administration of a therapeutic agent to a subject using any of the various delivery methods and systems known to those skilled in the art. Routes of administration may include oral, intravenous, intranasal, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, such as by injection or infusion (eg, intravenous infusion). Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods.

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

An effective amount or therapeutically effective amount of a therapeutic agent is any amount of a drug that, when used alone or in combination with one or more additional therapies, delays the onset of a mental disorder or promotes regression of the disorder, as evidenced by a decrease in the severity of symptoms of the disorder, an increase in the frequency and the duration of asymptomatic periods of the disorder or reduction in impairment or disability due to the disorder. The ability of one or more additional therapies to promote regression of the disorder can be assessed using various methods known to the skilled practitioner, for example, in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by activity assays agent in in vitro assays.

As used herein, the therapeutic effect measure is clinically significant based on the practical significance of the therapeutic effect. For example, does the therapeutic effect actually have a genuine, tangible and/or observable effect on the subject (e.g., lack of a clinically significant effect occurs when the difference in the subject is small enough that it can be considered similar, e.g., before and after applying the treatment as intended in this document). One skilled in the art will be able to determine whether a particular effect is

- 4 046262 clinically significant. For example, a subject who has a baseline score indicating severe depression and/or suicidality (using any of the scales described herein) and a post-treatment score indicating remission of severe depression and/or suicidality would have a clinically significant Effect.

As used herein, the term AUC _0-t refers to the area under the plasma concentration-time curve from time=0 to the time at which the last measurable concentration occurs. In some embodiments, the last measurable concentration occurs at t=32 hours (eg, AUC _0-t =AUC _0-32 ).

A subject who is refractory refers to a subject who has been treated or is currently being treated with one or more therapies that do not provide a clinically significant change in the direction of the desired outcome (eg, refractory subjects include patients who are refractory to a particular treatment). For example, a subject may not experience a measurable change in response to therapy. A nonresponsive subject may also, for example, experience a positive change in depression rating scale score, but this change is not clinically significant.

As used herein, a psychiatric score or a side effect profile test score that is substantially similar or substantially similar to a reference score is equivalent to the same score, with the understanding of the qualified individual that scores on a particular test may vary to a reasonable extent (eg, ±10%) , while still describing a certain value, for example, due to experimental error, routine subject-to-subject assessment, and routine statistical analysis.

The expression pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients included in the composition and/or with the mammal being treated with the specified composition.

As used herein, the term pharmaceutically acceptable carrier refers to a substance that facilitates the introduction of an active agent into a cell, organism, or subject. A pharmaceutically acceptable carrier refers to a carrier or excipient that can be included in the compositions of the present invention and that does not cause a significant adverse toxicological effect on a subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binding agents, excipients, disintegrants, lubricants, coatings, sweeteners, flavors and colors, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic agents and absorption retarding agents, etc. The carrier may also be substances to render the formulation stable, sterile and isotonic (e.g., antimicrobial preservatives, antioxidants, chelating agents and buffers), to prevent the action of microorganisms (e.g., antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid etc.) or to give the composition an edible aroma, etc. In some cases, the carrier is an agent that facilitates delivery of a small molecule drug or antibody to a target cell or tissue. One skilled in the art will appreciate that other pharmaceutical carriers may be used in the present invention.

In the methods described herein, the term reduction refers to a decrease in a specified parameter compared to a baseline measurement (or measurements) of the same parameter in a subject obtained before the start of administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or a decrease in a specified parameter compared to the original measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (eg, a subject who does not have a mental disorder as described herein). In some embodiments, the same parameter is measured relative to another treatment modality (eg, a standard of care for a mental disorder described herein).

Similarly, the term increase as used herein refers to an increase in a specified parameter compared to a baseline measurement (or measurements) of the same parameter in a subject obtained prior to the initiation of administration of racemic ketamine or a pharmaceutically acceptable salt thereof, or an increase in a specified parameter compared to a baseline measurement (or measurements) of the same parameter. In some embodiments, the same parameter is measured in a healthy subject (eg, a subject who does not have a mental disorder as described herein). In some embodiments, the same parameter is measured relative to another treatment modality (eg, a standard of care for a mental disorder described herein).

The term synergy or synergistic is used herein to mean that the effect of the combination of two therapeutic agents in a combination therapy is greater than the sum of the effects of each agent when administered separately. Synergistic amount or synergistically

- 5 046262 an effective amount is an amount of a combination of two components of a combination that results in a synergistic effect, as defined herein. In determining the synergistic interaction between two components of a combination, the optimal range for effect and the absolute dose ranges of each component for effect can be ultimately measured by administering the components of the combination at different ranges of mass ratios (weight to mass) and at different doses to the subjects in need of treatment. However, observation of synergy in in vitro models or in vivo models can predict the effect in humans and other species, and in vitro models or in vivo models, as described herein, exist to measure the synergistic effect. Exemplary synergistic effects include, but are not limited to, increased therapeutic efficacy, reduced dosage for equal or increased levels of efficacy, reduced or delayed development of drug resistance, and concurrently enhanced or equal therapeutic effects (e.g., the same therapeutic effect as at least one of therapeutic agents) and reducing undesirable drug effects (eg, side effects and adverse events (AEs)) of at least one of the therapeutic agents.

For example, the synergistic relationship of two therapeutic agents can be determined by determining the synergistic effect, for example, in an in vivo model of depression (e.g., an animal model) conventional in the art (e.g., a behavioral despair-based, reward-based, or anxiety-based model on mice).

As described herein, any concentration range, percentage range, ratio range, or whole number range should be understood to include the value of any whole number within the specified range and, where appropriate, fractions thereof (e.g., one tenth and one hundredth of a whole number) , unless otherwise specified.

Unless otherwise indicated, any reference to the amount of ketamine according to the present invention is based on the free equivalent weight of ketamine. For example, 30 mg of ketamine refers to 30 mg of free form ketamine or an equivalent amount of the salt form of ketamine (eg, ketamine hydrochloride).

Various aspects of the present invention are described in more detail herein.

Introduction

Depression is characterized by depressed mood and markedly decreased interest or enjoyment in activities. Other symptoms may include significant weight loss or weight gain, decreased or increased appetite, insomnia or increased sleepiness, psychomotor agitation or retardation, fatigue or lack of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, recurring thoughts of death, suicidal thoughts or suicide attempts. See Kennedy, Dialogues Clin. Neurosci., Vol. 10, No. 3, pp. 271-277 (2008). Various physical symptoms may also be present. Despite the prevalence of depressive feelings, depressive disorder is only diagnosed when symptoms reach a threshold and last for at least two weeks. Depression can range in severity from mild to very severe. Most often it is episodic, but can be recurrent or chronic. More than 50% of those who initially suffer from a single major depressive episode eventually develop another. Unfortunately, current pharmacological interventions for depression take weeks or months to achieve full therapeutic effect, and many subjects are or will become resistant to these therapies. See, for example, Kupfer, Dialogues Clin. Neurosci., Vol. 7, No. 3, pp. 191-205 (2005).

Ketamine is used as a short-acting intravenous anesthetic in both humans and animals. In addition to analgesia, ketamine induces a state of dissociative anesthesia and is also used recreationally to induce these effects. See, for example, Li and Vlisides, Front. Hum. Neurosci., Vol. 10, Article 612, pp. 1-15 (2016); and package insert for Spravato® (^)-ketamine) dated February 11, 2020; www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s003lbl.pdf, which are incorporated herein by reference in their entirety.

At low doses, ketamine causes mild sedation and euphoria, while at higher doses, individuals experience a dissociative effect similar to that of phencyclidine hydrochloride (PCP). Other physical effects of ketamine include dizziness, balance difficulties, nausea, vomiting, sweating, tremors, dystonic movements, respiratory depression and sleep apnea. See Zanos, et al., Pharmacol. Rev., Vol. 70, No. 3, pp. 621-660 (2018). The most commonly observed adverse events following ketamine administration are mental symptoms of drug withdrawal, such as floating sensations, vivid dreams, hallucinations, hypertonicity, and delirium. These effects may last up to 24 hours after administration. See Perumal, et al., J. Res. Pharm. Pract., Vol. 4, No. 2, pp. 89-93 (2015).

Once administered, ketamine is demethylated to form norketamine, and both ketamine and norketamine can be hydroxylated to form hydroxyphenylketamine, 6-hydroxyketamine,

- 6046262 hydroxyphenylnorketamine and 6-hydroxynorketamine (also referred to herein as hydroxynorketamine). The structures of these (racemic) compounds are shown below.

Each of these metabolites has a unique receptor binding profile and pharmacological activity. See, for example, Zanos, et al., Pharmacol. Rev., Vol. 70, No. 3, pp. 621-660 (2018). For example, racemic ketamine binds to the NMDA receptor with a Ki of approximately 1.06 μM, (S)norketamine and ^)-norketamine have a Ki of approximately 2.25 μM and 26.46 μM, respectively, and (2S,6S)hydroxynorketamine and ( 2R,6R)-hydroxynorketamine have a Ki of approximately 21.19 µM and more than 100 µM, respectively. See Moaddel, et al., Eur. J. Pharmacol., Vol. 698, pp. 228-234 (2013). Both ketamine and norketamine have anesthetic activity, and subjects administered ketamine or norketamine exhibit increased mobility during the recovery phase of anesthesia. In contrast, the same dose of 6-hydroxynorketamine does not produce an anesthetic effect or locomotor activity. See Leung and Baillie, J. Med. Chem., Vol. 29, pp. 2396-2399 (1986). However, like ketamine, 6-hydroxynorketamine exhibits antidepressant properties. See Pham, et al., Biol. Psychiatry, Vol. 84, No. 1, pp. e3-e6 (2018).

The present application is based in part on the unexpected discovery that intranasal administration of racemic ketamine provides beneficial properties compared to intravenous administration of racemic ketamine or intranasal administration of (R)- or ^)-ketamine (e.g., at least about 95% ^)-ketamine or at least about 95% ^)-ketamine). Moreover, exploiting the distinct physiological and psychological effects of each ketamine enantiomer and corresponding metabolites may provide useful treatments for a variety of psychiatric disorders, including treatments with reduced negative side effects.

Compositions

In some embodiments, there is provided a pharmaceutical composition comprising from about 5% (w/v) to about 20% (w/v) racemic ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; wherein said composition is prepared for intranasal administration.

In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 7.5% (w/v) to about 15% (w/v) racemic ketamine or a pharmaceutically acceptable salt thereof, such as about 7.5%, about 8 %, approximately 8.5%, approximately 9%, approximately 9.5%, approximately 10%, approximately 10.5%, approximately 11%, approximately 11.5%, approximately 12%, approximately 12.5%, approximately 13 %, about 13.5%, about 14%, about 14.5%, about 15%, or any value in between. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 7.5% (w/v) racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an aqueous solution of about 15% (w/v) racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the formulation provides from about 30 to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. For example, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, approximately 90 mg or anything in between. In some embodiments, the formulation provides from about 45 mg to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides from about 60 to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 30 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per

- 7 046262 dose. In some embodiments, the formulation provides about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides approximately 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose.

In some embodiments, the formulation provides a total amount of from about 30 to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses (eg, two sprays of a spray 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, approximately 90 mg or anything in between. In some embodiments, the formulation provides a total amount of from about 45 to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses. In some embodiments, the formulation provides a total amount of from about 60 to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides a total amount of about 30 mg, about 60 mg, about 75 mg, or about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses. In some embodiments, the formulation provides approximately 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses. In some embodiments, the formulation provides approximately 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses. In some embodiments, the formulation provides approximately 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per two doses.

In some embodiments, the composition further comprises a preservative. Examples of preservatives include, but are not limited to, parabens (eg, alkylparabens), benzyl alcohol, chlorobutanol, benzoic acid, sorbic acid, propylene glycol, quaternary ammonium salts (eg, benzalkonium chloride and benzethonium 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 a hydrochloride salt. In some embodiments, the composition further contains from about 0.01 to about 0.04 mg/ml benzalkonium chloride. In some embodiments, the composition further contains about 0.02 mg/ml benzalkonium chloride.

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

Exemplary surfactants include, but are not limited to, ionic, nonionic, and amphoteric surfactants. For example, Tweens, PEGs, sorbitan esters and ethoxylated fatty acids. In some embodiments, the composition further comprises a surfactant in an amount of from about 1 to about 10% w/v surfactant.

Exemplary antioxidants include, but are not limited to, tocopherols, butylated hydroxytoluene, sodium metabisulfite, potassium metabisulfite, and ascorbyl palmitate. In some embodiments, the composition further comprises an antioxidant in an amount of from about 0.001 to about 5 wt./wt.%.

Exemplary absorption enhancing agents include, but are not limited to, chitosan, caproic acid salts, and cyclopentadecalactone. In some embodiments, the composition further comprises an absorption enhancing agent in an amount of from about 1 to about 10 wt./wt.%.

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

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

According to some embodiments, the composition corresponds to the description in table. 1.

Table 1

Component Function Product concentration (per ml) Single injection (per 0.1 ml) Ketamine hydrochloride* Active substance 150 mg/ml 15 mg

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Benzalkonium chloride Antimicrobial preservative 0.02 mg/ml 0.002 mg Sodium hydroxide or hydrochloric acid (HCl) solution Adjusting pH in sufficient quantities in sufficient quantities Purified water Water environment in sufficient quantities up to 1.0 ml in sufficient quantities up to 0.1 ml

*1 mg ketamine=1.15 mg ketamine hydrochloride

At 15 mg per injection, the composition described in table. 1, provides a 30 mg dose with 2 injections, a 60 mg dose with 4 injections, and a 90 mg dose with 6 injections.

According to some embodiments, the composition corresponds to the description in table. 2.

table 2

Component Function Product concentration (per ml) Single injection (0.1 ml) Ketamine hydrochloride* Active substance 75 mg/ml 7.5 mg Benzalkonium chloride Antimicrobial preservative 0.02 mg/ml 0.002 mg Sodium hydroxide or hydrochloric acid (HCl) solution Adjusting pH in sufficient quantity in sufficient quantity Purified water Water environment in sufficient quantities up to 1.0 ml in sufficient quantities up to 0.1 ml

*1 mg ketamine=1.15 mg ketamine hydrochloride

At 7.5 mg per injection, the composition described in table. 2, provides a 30 mg dose with 4 injections, a 60 mg dose with 8 injections, and a 90 mg dose with 12 injections.

Treatment methods

In some embodiments, there is provided a method of treating a mental disorder (e.g., suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder) in a subject in need thereof, comprising intranasally administering to said subject a therapeutically effective amount of racemic ketamine or pharmaceutically acceptable salt.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments described herein, the mental disorder resolves more quickly compared to the resolution observed after administration of an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject's suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder resolves more quickly. In some embodiments, the mental disorder resolves approximately 1.2 to 10 times faster than the resolution observed after administration of an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, e.g., 1.2 times, 1.4 times, 1.6 times faster , 1.8x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9 .5x, 10x times or anything in between.

According to some embodiments described herein, mental

- 9 046262 the disorder resolves more quickly compared to the resolution observed after administration of an equivalent dose of (b)-ketamine (eg, intranasal (b)-ketamine) or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the subject's suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder resolves more quickly. In some embodiments, the mental disorder resolves approximately 1.2 to 10 times faster than the resolution observed after administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof, e.g., 1.2 times, 1.4 times, 1 times faster ,6x, 1.8x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x , 9.5x, 10x times or anything in between.

In some embodiments described herein, a subject's compliance with a mental health treatment protocol is improved compared to an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments described herein, a subject's compliance with a mental health treatment protocol is improved compared to an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof. For example, subject compliance with treatment protocols for suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, or post-traumatic stress disorder is improved.

Many methods can be used to measure suicidality and/or suicidal ideation in a subject. Non-limiting examples include the Brief International Psychiatric Inventory version 7.02 for Suicidal Disorders (MINI), Clinical Global Impression (CGI), Patient Global Impression (PGI), Columbia Suicidal Severity Rating Scale (CSSRS), scoring scale Montgomery-Osberg Depression Rating Scale (MADRS) and Sheehan Suicidality Tracking Scale Clinically Significant Change Score (STS-CMCM). See, for example, Ghasemi et al., Health Promot. Perspect., Vol. 5, No. 3, pp. 156-168 (2015), which is incorporated herein by reference in its entirety.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) MINI for Suicidality Disorders is a semi-structured clinical questionnaire that can be used (eg, in screening) to confirm a primary diagnosis of MDD, to assess current suicidal ideation and behavior ( SI/B), as well as for the assessment of comorbid neuropsychiatric disorders. When used by a qualified and trained professional, MINI can provide information and complement a full consultation assessment with a psychiatrist. See, for example, Sheehan et al. J Clin Psychiatry 1998; 59(suppl 20): 22-33; Sheehan and Giddens (2015). Suicidality: A Roadmap for Assessment and Treatment. (1st ed.). Tampa, FL: Harm Research Press. Nov. 2015 (Available at: HarmResearch.org) ISBN: 978-0-9969729-0-1; and Sheehan and Giddens. (2016). Suicidality Assessment and Documentation for Healthcare Providers: A Brief, Practical Guide. (1st ed.). Tampa, FL: Harm Research Press. April 2016. (Available at: HarmResearch.org) ISBN: 978-09969729-1-8).

The S-STS CMCM (version 01/01/19) is a clinician-rated outcome measure that assesses SI/B using a standard 22-item scale as well as several patient- and clinician-rated items. The first 16 items are rated on a Likert-type scale ranging from not at all at all (0) to extremely attuned (4), where a sample score (i.e. 4 specific items are rated based on the highest score on 2 of those items) yields an overall score. ranging from 0 to 52. The last 6 items are used only when the patient misses a visit and is unable to complete the scale; if this missed visit is due to an attempted or completed suicide, the possible maximum score is 100. The CMCM also provides 5 different total single-item scores: 1) subject-rated likelihood of a suicide attempt; 2) the need for treatment as assessed by the subject; 3) overall severity of suicidal impulses, thoughts, and behavior as assessed by the clinician; 4) the current risk of suicide and the level of suicidality control needed, as judged by the clinician; and 5) the likelihood that the subject will attempt suicide or die by suicide within the next 7 days, as judged by the clinician.

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

The CGIS-SI/B is a 5-item clinician-rated measure of symptom severity associated with suicidality. Clinicians rate the most severe level of suicidality experienced by a subject during a specified assessment period (eg, at screening, at baseline, or prior to intranasal administration of racemic ketamine as described herein), with the response reported on a 5-point type scale

- 10 046262

Likert scale ranging from 1 (not at all suicidal) to 5 (among the extremely suicidal). The clinician can then rate how much the subject's suicidality has changed from baseline, also on a 5-point Likert-type scale ranging from 1 (very much improved) to 5 (very much worse). See, for example, Meltzer et al. Arch Gen Psychiatry. 2003; 60(1):82-91.

In some embodiments, the subject's CGIS-SI/B score is 4 or greater prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI/B score is 4 or greater for about 5 minutes to about 24 hours prior to 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI/B score is 4, 5, 6, or 7 for about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the CGIS-SI/B score is reduced by 1-4 (eg, 1-4 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI/B score is reduced by 1-3 (eg, 1-3 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CGIS-SI/B score is reduced by 1-2 (eg, 1-2 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI/B score decreases by 3 or 4 units 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CGIS-SI/B score is reduced by 3 units. In some embodiments, the subject's CGIS-SI/B score is reduced by 4 units.

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

In some embodiments, the first CGIS-SI/B score is determined from about 1 to about 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof; and the second CGIS-SI/B score is determined from about 1 to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's first CGIS-SI/B score is determined from about 4 to about 8 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's second CGIS-SI/B score is determined about 4 to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first CGIS-SI/B score and the second CGIS-SI/B score are determined at equivalent times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 4 hours. In some embodiments, the first CGIS-SI/B score is determined. SI/B and the second CGIS-SI/B score are determined at different times before and after administration of racemic ketamine or its pharmaceutically acceptable salt, for example, 4 hours before and 12 hours later

- 11 046262 after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

The PGIS-SI/B is a 5-point subject-rated scale assessing the subject's opinion of the overall severity of their illness, which is rated on a single-item Likert-type scale ranging from 1 (not at all suicidal) to 5 (extremely suicidal). ). The PGISSI/B and PGIC-SI/B scores can be used at various time points (eg, before intranasal administration of racemic ketamine as described herein, or after one or more doses of racemic ketamine). See, for example, Mohebbi et al. Eur Psychiatry. 2018; 53:17-22.

In some embodiments, the subject's PGIS-SI/B score is 3 or greater prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI/B score is 3 or greater for about 5 minutes to about 24 hours prior to 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's PGIS-SI/B score is 3, 4, or 5 for about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 5 hours. approximately 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the PGIS-SI/B score is reduced by 1-4 (eg, 1-4 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI/B score is reduced by 1-3 (eg, 1-3 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the PGIS-SI/B score is reduced by 1-2 (eg, 1-2 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the first PGIS-SI/B score is determined from about 1 to about 12 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof; and the second PGIS-SI/B score is determined from about 1 to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's first PGIS-SI/B score is determined from about 4 to about 8 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's second PGIS-SI/B score is determined about 4 to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first PGIS-SI/B score and the second PGIS-SI/B score are determined at equivalent times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 4 hours. In some embodiments, the first

- 12 046262 the PGIS-SI/B score and the second PGIS-SI/B score are determined at different times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example 4 hours before and 12 hours after administration of racemic ketamine or its pharmaceutically acceptable salt.

In some embodiments, the CSSRS is used to measure suicidality and/or suicidal ideation in a subject. The CSSRS can assess both suicidal behavior and suicidal ideation in a subject. For example, the CSSRS can assess the mortality of suicide attempts and other features of suicidal ideation such as frequency, duration, controllability, causes of thoughts, and deterrents, all of which may significantly predict 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 aggregate data about a subject's suicidal ideation and behavior.

The CSSRS asks several questions related to suicidal ideation, to which the subject answers yes or no. Such questions relate to the desire to die; unspecified active suicidal ideation; active suicidal thoughts using any method (without a plan) without the intention to act; active suicidal ideation with some intent to act; without a specific plan; and active suicidal ideation with specific plan and intent. In addition, the CSSRS includes characteristics that are rated by the subject to help assess the intensity of thoughts. Such characteristics include questions about frequency (eg, less than once a week, once a week, 2–5 times a week, daily or almost daily, and many times a day); duration (eg, fleeting, less than an hour, 1-4 hours, 4-8 hours, more than 8 hours); Controllability (eg, is easily able to control thoughts, can control thoughts with little difficulty, can control thoughts with some difficulty, can control thoughts with great difficulty, cannot control thoughts, and does not try to control thoughts); deterrents (e.g., deterrents that definitely deterred someone from attempting suicide, deterrents that were likely to deter, uncertain deterrents that did, deterrents that most likely did not deter, and deterrents that definitely did not deter ); and causes of thoughts (eg, entirely to get attention, mostly to get attention, equally to get attention and stop/stop pain, mostly to stop/stop pain, and completely to stop/stop pain). The CSSRS may also include questions related to suicidal behavior and actual suicide attempt, such as whether an attempt was made; the question of whether something was done to harm oneself, and the question of whether the subject did something dangerous that would cause him or her to die.

In some embodiments, the CSSRS score is 3 or greater prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject answers yes to 3, 4, 5, 6, or 7 questions prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject responds yes to 4, 5, 6, or 7 questions on the CSSRS, as described herein, within about 5 minutes to about 24 hours prior to 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers yes to 3, 4, 5, 6, or 7 questions on the CSSRS described herein within about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the CSSRS score is reduced by 1-7 (eg, 1-7 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject answers yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score is reduced by 1-5 (eg, 1-5 units) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score is reduced by 1-3 (eg, 13 points) following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the CSSRS score is 3 or greater (e.g., 3, 4, 5, 6, or 7) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and decreases by 1-7 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. . For example, the subject answers yes to 3, 4, 5, 6, or 7 questions before

- 13 046262 intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and answers yes to 1, 2, 3, 4, 5, 6 or 7 or fewer questions after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS score is 6 or greater (e.g., 6 or 7) before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and is reduced by 1-7, e.g., 1, 2, 3, 4, 5, 6, or 7, after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. 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 is reduced by 1 to 5, such as 1, 2, 3, 4, or 5 , after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject responds yes to 3, 4, 5, 6, or 7 questions on the CSSRS, as described herein, within about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and responds yes for 1, 2, 3, 4, 5, 6, or 7 or fewer questions within 5 minutes to approximately 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the subject answers yes to 3, 4, 5, 6, or 7 questions on the CSSRS within 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, about 18 to 24 hours, about 12 to 24 hours, or about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and answers yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions in 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 to 24 hours, from about 12 to 24 hours or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject answers yes to 3, 4, 5, 6, or 7 questions on the CSSRS described herein within about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and answers yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions after about 1 to about 4 hours , from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the first CSSRS score is determined from about 1 to about 12 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof; and the second CSSRS score is determined from about 1 to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's first CSSRS score is determined from about 4 to about 8 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's second CSSRS score is determined about 4 to about 8 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the first CSSRS score and the second CSSRS score are determined at equivalent times before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, such as 4 hours. In some embodiments, the first CSSRS score and the second CSSRS score are determined at different times. before and after administration of racemic ketamine or a pharmaceutically acceptable salt thereof, for example, 4 hours before and 12 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

Two versions of the CSSRS can be used: the core version, which can assess the subject's lifetime and twelve-month suicidal thoughts and behavior, and the since last visit version, which can assess the subject's suicidal thoughts or behavior since the subject's last use of CSSRS. For example, a subject should answer yes only to the question about having attempted suicide in the since last visit version if the attempt was made after using the major version of CSSRS. In some embodiments, a basic version of the CSSRS is administered to a subject prior to intranasal administration of racemic ketamine as described herein. For example, the basic version of the CSSRS can be used for about 1 hour to about 6 months prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the core version of CSSRS is used for about 1 hour to about 6 hours, about 1 hour to about 1 day, about 1 hour to about 1 week, about 1 hour to about 1 month, about 1 hour to about 1 month. about 3 months, about 3 months to about 6 months, about 1 month to about 6 months, about 1 week to about 5 months, or about 1 day to about 6 months before intranasal administration of racemic ketamine as described herein .

In some embodiments, the occurrence of suicidal ideation after the baseline assessment is defined as answering yes to at least 1 of 5 subcategories for the suicidal ideation assessment.

- 14,046,262 thoughts (i.e., wish to die; unspecified active suicidal ideation; active suicidal ideation using any method without intent to act; active suicidal ideation with some intent to act; and active suicidal ideation with specific plan and intent) when using CSSRS after original CSSRS score. In some embodiments, the occurrence of suicidal behavior after the baseline assessment is defined as a response yes to at least 1 of 4 subcategories of suicidal behavior (i.e., actual attempt, aborted attempt, failed attempt, and preparatory actions or behavior) when using the CSSRS after the initial assessment on CSSRS. In some embodiments, a trained rater completes the CSSRS based on the subject's responses.

In some embodiments, the last visit version of the CSSRS is administered to a subject following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the CSSRS is administered to a subject from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof to the subject. 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the CSSRS is administered to the subject for 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 to 24 hours or about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof to the subject.

In some embodiments, the CSSRS score is from about 0 to about 2 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, a subject answers yes to 0, 1, or 2 questions on the CSSRS following intranasal administration of racemic ketamine as described herein. 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, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject responds yes to 0, 1, or 2 CSSRS questions in about 1 hour to about 4 hours, about 2 hours to about 12 hours, about 1.5 hours to about 5 hours, about 2 hours up to about 6 hours, from about 4 to about 8 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. In some embodiments, the CSSRS is the version of the CSSRS since the last visit.

In some embodiments, the subject has a CSSRS thought intensity score of about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's thought intensity score may be 0, 1, 2, 3, 4, or 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's thought intensity 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, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's thought intensity is as described herein after about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the CSSRS since last visit is administered following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the reduction in CSSRS score is from about 1 to about 7 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject may answer yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof relative to the number of questions to which the subject answered yes on the CSSRS before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject responds yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions on the CSSRS, as described herein, from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt.

- 15 046262

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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject responds yes to 1, 2, 3, 4, 5, 6, or 7 or fewer questions on the CSSRS as described herein in about 1 hour to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (eg, compared with responses before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the last visit version of the CSSRS is administered following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the basic version of the CSSRS is used prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject has lower thought intensity as measured by the CSSRS following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, the intensity of a subject's thoughts may be reduced by about 1 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the intensity of the subject's thoughts before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the subject's thoughts may be reduced by from about 1 to about 5, from about 1 to about 10, from about 1 to about 15, from about 1 to about 20, from about 20 to about 25, from about 15 to about 25, about 10 to about 25, or about 5 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the intensity of the subject's thoughts before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of a subject's thoughts, as described herein, decreases 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the intensity of the subject's thoughts decreases, as described herein, from about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (eg, compared to an assessment prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the last visit version of the CSSRS is administered following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the basic version of the CSSRS is used prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the CSSRS score of a subject administered intranasal racemic ketamine or a pharmaceutically acceptable salt thereof is lower by about 1 to 7 units than that of a subject administered an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, or γ)-ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the CSSRS score of a subject administered intranasal racemic ketamine or a pharmaceutically acceptable salt thereof improves at a greater rate than a subject administered an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, or γ)-ketamine or its pharmaceutically acceptable salt. For example, 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 intermediate value, faster than that of a subject administered an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof, or ^)-ketamine or a pharmaceutically acceptable salt thereof.

The Montgomery-Osberg Depression Rating Scale (MADRS) is a diagnostic questionnaire that can be used to measure the severity of a subject's depressive episode. In some embodiments, the MADRS can be used to measure suicidal ideation. For example, the MADRS includes 10 items targeting the following: 1) apparent depression (eg, representing dejection, sadness, and despair, which is more than the usual temporary depressed mood as reflected in speech, facial expression, and posture); 2) a message about depression (for example, representing

- 16 046262 are reports of depressed mood, whether reflected in appearance or not, and may include depressed mood, dejection, or feelings of hopelessness and hopelessness); 3) internal tension (for example, representing a feeling of vague discomfort, nervousness, internal confusion, mental tension, turning into either panic, or fear, or suffering); 4) sleep reduction (eg, representing the experience of reduced duration or depth of sleep compared to the subject's own normal profile when healthy); 5) decreased appetite (eg, which is a feeling of loss of appetite compared to normal health); 6) difficulties with concentration (for example, representing difficulties in collecting thoughts, developing into a disabling lack of concentration); 7) fatigue (eg, difficulty starting work or slowness in starting and performing daily activities); 8) inability to feel (for example, which is the subjective experience of decreased interest in the environment or activities that are usually enjoyable, as well as a decreased ability to respond appropriately emotionally to circumstances or people); 9) pessimistic thoughts (for example, thoughts of guilt, inferiority, self-blame, sinfulness, repentance and death); 10) suicidal thoughts (for example, representing the feeling that life is not worth living, that a natural death is desirable, suicidal thoughts and preparation for suicide). Each item is scored from 0 to 6, where 0 means that the subject does not at all correspond to the description in the item, and 6 means that the subject is extremely consistent with what the item describes. For example, for obvious depression, a score of 0 might indicate that the subject does not show any depression, while a score of 6 might indicate that the subject appears unhappy all the time, for example, the subject is extremely depressed. As another example, for suicidal ideation, a score of 0 may indicate that the subject enjoys life or accepts life as it comes; a score of 2 may indicate that the subject is tired of life and may have fleeting suicidal thoughts; a score of 4 may indicate that the subject feels that he or she would probably be better off dead (eg, frequent suicidal ideation and suicide is considered as a possible solution, but without specific plans or intent); and a score of 6 may indicate that the subject has clear plans to commit suicide when given the opportunity (eg, the subject was actively preparing for suicide). Thus, the total score after summing each score for each item is from 0 to 60. In some embodiments, a total MADRS score of about 0 to about 6 for a subject reflects the subject's absence of symptoms associated with depression; a score of about 7 to about 9 reflects mild depression in the subject; a score of about 20 to about 34 reflects mild depression in the subject; and a score of about 34 to about 60 reflects severe depression in the subject.

In some embodiments, the subject's total MADRS score is from about 10 to about 60 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, from about 10 to about 20, from about 10 to about 30, from about 10 to about 40, from about 10 to about 50, from about 50 to about 60, from about 40 to about 60, from about 30 to about 60 or from about 20 to about 60 before 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 prior to intranasal administration of racemic ketamine as described. in this document. In some embodiments, the subject's global MADRS score is measured from about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is as described herein for about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours or about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's overall MADRS score is from about 0 to about 6 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, from about 0 to about 2, from about 0 to about 3, from about 0 to about 4, from about 0 to about 5, from about 5 to about 6, from about 4 to about 6, from about 3 to about 6 , from about 2 to about 6 or from about 1 to about 6 after intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's overall MADRS score is 0, 1, 2, 3, 4, 5, or 6 after intranasal administration.

- 17 046262 racemic ketamine as described herein. In some embodiments, the subject's global MADRS 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is as described herein at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 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.

In some embodiments, the subject's overall MADRS score is from about 10 to about 60 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's overall MADRS score is from about 0 to about 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. . For example, from about 10 to about 20, from about 10 to about 30, from about 10 to about 40, from about 10 to about 50, from about 50 to about 60, from about 40 to about 60, from about 30 to about 60 or from about 20 to about 60 before intranasal administration of racemic ketamine as described herein, and from about 0 to about 2, from about 0 to about 3, from about 0 to about 4, from about 0 to about 5, from 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 following 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 prior to intranasal administration of racemic ketamine as described. herein, and the subject's overall MADRS score is 0, 1, 2, 3, 4, 5, or 6 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's global MADRS score is measured from about 5 minutes to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 up to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is as described herein for about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 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 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, from about 5 to about 10 hours or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's overall MADRS score is reduced by from about 1 to about 60 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's overall MADRS score may be reduced by from about 1 to about 60 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is reduced by from about 1 to about 50, from about 1 to about 40, from about 1 to about 30, from about 1 to about 20, from about 1 to about 10, from 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 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is reduced, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's overall MADRS score is reduced, as described herein, after about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 10 hours. h

- 18 046262 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (eg, compared to this evaluation before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, the subject's total MADRS score decreases by about 20 units to about 30 units 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, e.g., by about 20-25 units, about 22-27 units, or about 25 -30 units.

In some embodiments, MADRS item 10, eg, suicidal ideation, can be used to measure suicidal ideation. In some embodiments, a subject's MADRS Item 10 score is 0 or 1 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's MADRS Item 10 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, from about 5 minutes to 6 hours, from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS Item 10 score corresponds to that described herein, from about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, from about 5 to about 10 hours or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's MADRS Item 10 score is reduced by 1-6 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's MADRS Item 10 score may be reduced by 1 to 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS Item 10 score is reduced by 1-5, 1-4, 1-3, 1-2, 5-6, 4-6, 3-6, or 2-6 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS Item 10 score is reduced, as described herein, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS Item 10 score is reduced, as described herein, after about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 5 hours. approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (eg, compared to this assessment before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof).

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

In some embodiments, MADRS is administered to a subject prior to intranasal administration of racemic ketamine, as described herein. For example, MADRS can be used in a subject for from about 1 hour to about 6 months prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the MADRS is administered to the subject for about 1 hour to about 6 hours, about 1 hour to about 1 day, about 1 hour to about 1 week, about 1 hour to about 1 month, about 1 hour up to about 3 months, about 3 months to about 6 months, about 1 month to about 6 months, about 1 week to about 5 months, or about 1 day to about 6 months before intranasal administration of racemic ketamine as described herein document.

The STS-CMCM is a diagnostic questionnaire that can be used to measure change in a subject's suicidal ideation and behavior. The STS-CMCM can also provide a comprehensive description of suicidal ideation and behavior. See, for example, Sheehan et al., Innov. Clin. Neurosci. Vol. 11, No. 9-10, pp. 93-140 (2014). STS-CMCM includes 4 parts. The first part may include a 16-item scale that assesses the severity of suicidal behavior on a scale of 0 to 4, ranging from not at all (0) to extremely consistent (4). In the second

- 19 046262 part, the subject is asked to evaluate a number of additional items, including 1) a number of risk or protective items that may be important aggravating or alleviating factors in the subject's suicidal ideation and behavior; 2) a series of 11-point (0-10) discrete visual analogue (DISCAN) scales; and 3) items related to an overall assessment of the severity of suicidal impulses, thoughts and behavior, as well as the opportunity for the subject to provide his or her assessment of the need for treatment. DISCAN scales may include the subject's self-assessment of his ability and willingness to cope with his suicidal tendencies, his ability and willingness to remain safe, the degree to which his suicidal tendencies were intentional, the degree of their impulsivity, the extent to which they affected their quality of life and the extent to which it impaired work, social or the subject's family life. The third part includes the clinician's assessment, which concerns his or her opinion of the subject's risk for suicide and opinion of the required level of control of the subject's suicidal ideation and behavior. The third part may also include an overall assessment of suicidality based on all the information collected in the previous sections of the scale, with additional input from others and any additional test questions the clinician deems necessary to complete the assessment. Part of the fourth section can be completed by the clinician if the subject misses a follow-up appointment and is unavailable, allowing the scale to be completed.

In some embodiments, a subject's STS-CMCM score is reduced by at least 2 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's STS-CMCM score may be reduced by at least 2, at least 3, at least 4, or at least 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's STS-CMCM score is reduced, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's STS-CMCM score is reduced, as described herein, after about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, or about 5 hours to about 6 hours. 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (eg, compared to this assessment before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof). In some embodiments, STS-CMCM is administered to a subject prior to intranasal administration of racemic ketamine as described herein. For example, STS-CMCM can be used in a subject for about 1 hour to about 6 months prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the STS-CMCM is used in a subject for about 1 hour to about 6 hours, about 1 hour to about 1 day, about 1 hour to about 1 week, about 1 hour to about 1 month, about 1 h to about 3 months, about 3 months to about 6 months, about 1 month to about 6 months, about 1 week to about 5 months, or about 1 day to about 6 months before intranasal administration of racemic ketamine as described in this document.

In some embodiments described herein, when one or more additional therapies are administered to a subject, the subject does not experience a clinically significant increase in body weight compared to administration of one or more additional therapies in the absence of intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. Clinically significant weight gain refers to an increase in body weight of at least about 5% over the course of treatment, e.g., about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 21%, approximately 22%, approximately 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 anything in between.

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.

In some embodiments, the effectiveness of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies is greater than the sum of the effectiveness of each individual agent when administered separately. For example,

- 20 046262 in some embodiments, the change in CSSRS score after administration of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before administration of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof is greater than the change in CSSRS score after administration of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt and one or more additional therapies compared to this assessment before administration of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies. In some embodiments, the effectiveness of ketamine or a pharmaceutically acceptable salt thereof is increased. In some embodiments, the effectiveness of one or more additional therapies is increased. In some embodiments, the effectiveness of both intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies is increased. In some embodiments, the effectiveness of one or more additional therapies administered with intranasal racemic ketamine or a pharmaceutically acceptable salt thereof is increased relative to the effectiveness observed after administration of an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the effectiveness of one or more additional therapies administered with intranasal racemic ketamine or a pharmaceutically acceptable salt thereof is increased relative to the effectiveness observed after administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the dose of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and/or one or more additional therapies required to provide a therapeutic effect is reduced compared to the dose of each individual agent when administered separately. In some embodiments, the dose of one or more additional therapies required to provide a therapeutic effect is reduced compared to the dose administered with an equivalent dose of intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of one or more additional therapies required to provide a therapeutic effect is reduced compared to the dose administered with an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of ketamine or a pharmaceutically acceptable salt thereof is reduced. In some embodiments, the dosage of one or more additional therapies is reduced. In some embodiments, the dose of both intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies is reduced. For example, the dose of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof may be reduced by about 5-95%, or any amount therein between, 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 approximately 95%. Similarly, the dosage of one or more additional therapies may be reduced by about 5% to 95%, or by any amount therein, 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 approximately 95%.

In some embodiments, the onset of resistance to treatment with intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies is delayed compared to the onset of treatment resistance to each individual agent when administered separately. In some embodiments, the onset of treatment resistance to one or more additional therapies is delayed compared to the onset of treatment resistance when administered intravenous racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the onset of treatment resistance to one or more additional therapies is delayed compared to the onset of treatment resistance upon administration of (b)-ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more side effects of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof and/or one or more additional therapies required to provide a therapeutic effect are reduced compared to the side effects of each individual agent when administered separately. In some embodiments, one or more side effects of ketamine or a pharmaceutically acceptable salt thereof are reduced. In some embodiments, one or more side effects of one or more additional therapies are reduced. In some embodiments, one or more side effects of one or more additional therapies are reduced compared to one or more side effects observed after administration of an equivalent dose of intravenous racemic ketamine or pharmaceutical formulation thereof.

- 21 046262 acceptable salt. In some embodiments, one or more side effects of one or more additional therapies are reduced compared to one or more side effects observed after administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, one or more side effects of both ketamine or a pharmaceutically acceptable salt thereof and one or more additional therapies are reduced. In some embodiments, the overall incidence of side effects is reduced. In some embodiments, the severity of one or more side effects is reduced. In some embodiments, both the total number of side effects and the severity of one or more remaining side effects are reduced.

In some embodiments, one or more side effects of ketamine include cognitive impairment, movement disorder, dizziness, nausea, vomiting, sweating, high blood pressure, ulcerative cystitis, or interstitial cystitis. In some embodiments, one or more side effects of ketamine consist of cognitive impairment, movement impairment, dizziness, nausea, vomiting, sweating, elevated blood pressure, ulcerative cystitis, or interstitial cystitis.

In some embodiments, the cognitive impairment includes one or more of psychotomimetic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, hearing changes, visual changes, and hallucinations. In some embodiments, the cognitive impairment consists of one or more of psychotomimetic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, hearing changes, visual changes, and hallucinations. In some embodiments, the cognitive impairment includes sedation. In some embodiments, the cognitive impairment is sedation. In some embodiments, the movement disorder includes various types of tremors, balance problems, or dystonic movements. In some embodiments, the movement disorder consists of one or more of different types of tremors, balance problems, and dystonic movements.

A variety of methods can be used to assess ketamine-related side effects. Non-limiting examples of such methods include the Modified Observer Awareness/Sedation Scale (MOAA/S), Bowdle Visual Analog Scale (VAS), Clinical Diagnostic Dissociative States Scale (CADSS), Profile of Affective States (POMS), Decision Time Test, Test on Sternberg short-term memory and subject rating of intranasal irritation (SRAII©) (for intranasal ketamine).

In some embodiments, MOAA/S can be used to measure sedation in a subject. See, for example, Kim et al., Br J Anaesth, Vol. 115, No. 4, pp. 569-577 (2015), which is incorporated herein by reference in its entirety. MOAA/S is a scale from 0 to 5, with 0 indicating that the patient does not respond after painful compression of the trapezius muscle; 1 indicates that the subject responds only after painful compression of the trapezius muscle; 2 indicates that the patient responds only after gentle stroking or shaking; 3 indicates that the subject responds only after his name is spoken loudly and/or repeated; 4 indicates that the subject has a sluggish response to a name spoken in a normal tone; and 5 indicates that the subject responds readily to the name spoken in a normal tone.

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

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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic

- 22 046262 ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA/S score is as described herein at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's MOAA/S score is 5 or 6 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's MOAA/S score is 5 or 6 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA/S score is measured from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 up to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA/S score is 5 or 6 for about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or from 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 after about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's MOAA/S score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's MOAA/S score does not change (ie, does not increase or decrease) after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MOAA/S score is substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. acceptable salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, from about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's MOAA/S score is reduced by from about 1 to about 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's MOAA/S score may be reduced by 1, 2, 3, 4, or 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof and/or intravenous administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MOAA/S score is reduced, 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 to 24 hours, from about 12 to 24 hours, or from about 6 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 at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 5 hours. approximately 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (e.g., relative to administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof and/or intravenous administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof).

In some embodiments, the Bowdle Visual Analog Scale (VAS) can be

- 23 046262 used to measure psychedelic effects in a subject. See, for example, Bowdle, et al. Anesthesiology, Vol. 88, No. 1, pp. 82-88 (1998), which is incorporated herein by reference in its entirety. Bowdle's VAS is a questionnaire that asks the subject to rate his or her feelings at the present moment. For example, the questionnaire might include the following items: 1) my body or parts of my body seem to have changed their shape or position; 2) my surroundings seemed to change in size, depth or shape; 3) the passage of time has changed; 4) I had a feeling of unreality; 5) it was difficult to control my thoughts; 6) the intensity of colors has changed; 7) the intensity of the sound changed; 8) I heard voices or sounds that were not real; 9) I thought that events, objects or other people had special meaning concerning me; 10) I had suspicious ideas or the belief that others were against me; 11) I felt anxious; 12) I felt delighted; and 13) I felt drowsy, which must be assessed by the subject. Each item is rated by the subject from 0 to 100, with a total score reaching 1300, which indicates that the subject is experiencing significant side effects. A score of 0 reflects that the subject felt not at all as described in the item (i.e., very few side effects), while a score of 100 reflects that the subject felt extremely similar to as described in the item. Thus, lower individual and overall scores indicate fewer psychedelic effects.

In some embodiments, items 1, 2, 3, 5, 6, and 7 combine subjective external perception to estimate a derived variable. In some embodiments, items 4, 8, 9, 10, and 11 combine subjective internal perception to estimate a derived variable. In some embodiments, items 12 and 13 are scored as separate VAS items.

In some embodiments, the subject's VAS Bowdle score is from about 0 to about 50 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 25 to about 75 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 50 to about 100 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 0 to about 10, from about 0 to about 20, from about 0 to about 30, from about 0 to about 40, from about 0 to about 50, from about 0 to about 60, from about 0 to about 70, from about 0 to about 80, from about 0 to about 90, from about 90 to about 100, from about 80 to about 100, from about 70 to about 100, from 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 to intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's VAS Bowdle score is from about 5 to about 20, from about 15 to about 40, from about 10 to about 50, or from about 20 to about 60 prior to intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's VAS Bowdle score is measured for about 5 minutes to about 24 hours prior to 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is measured over about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes. up to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's VAS Bowdle score is from about 0 to about 50 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 25 to about 75 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 50 to about 100 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 0 to about 10, from about 0 to about 20, from about 0 to about 30, from about 0 to about 40, from about 0 to about 50, from about 0 to about 60, from about 0 to about 70, from about 0 to about 80, from about 0 to about 90, from about 90 to about 100, from

- 24 046262 about 80 to about 100, from about 70 to about 100, from about 60 to about 100, from about 50 to about 100, from about 40 to about 100, from about 30 to about 100, from about 20 to about 100 or from about 10 to about 100 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's Bowdle VAS score is from about 5 to about 20, from about 15 to about 40, from about 10 to about 50, or from about 20 to about 60 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's VAS Bowdle 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is measured over about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes. up to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's VAS Bowdle score is from about 0 to about 50 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's VAS Bowdle score is from about 0 to about 50 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is from about 25 to about 75 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's VAS Bowdle score is from about 25 to about 75 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 50 to about 100 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein, and the subject's VAS Bowdle score is from about 50 to about 100 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's VAS Bowdle score is from about 0 to about 10, from about 0 to about 20, from about 0 to about 30, from about 0 to about 40, from about 0 to about 50, from about 0 to about 60, from about 0 to about 70, from about 0 to about 80, from about 0 to about 90, from about 90 to about 100, from about 80 to about 100, from about 70 to about 100, from about 60 to about 100 , from about 50 to about 100, from about 40 to about 100, from about 30 to about 100, from about 20 to about 100, or from about 10 to about 100 to intranasal administration of racemic ketamine as described herein, and from 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, from about 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 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's VAS Bowdle score is from about 5 to about 20, from about 15 to about 40, from about 10 to about 50, or from about 20 to about 60 prior to intranasal administration of racemic ketamine as described herein, and the subject's VAS Bowdle score is from about 5 to about 20, from about 15 to about 40, from about 10 to about 50, or from about 20 to about 60 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's Bowdle VAS score is measured from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's VAS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine. 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is measured over about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours

- 25046262 hours, from about 5 to about 10 hours or from about 45 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's VAS Bowdle score is measured after about 1 to about 4 hours, from about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's Bowdle VAS score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's VAS Bowdle score changes (i.e., increases or decreases) by about 0-10 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the subject's VAS Bowdle score before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. . In some embodiments, the subject's VAS Bowdle 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 and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. acceptable salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, from about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's VAS Bowdle score is reduced by from about 10 to about 1300 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's VAS Bowdle score may be reduced by about 10 to about 1300 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the score observed after administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof and/or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is reduced by from about 10 to about 100, from about 10 to about 200, from about 10 to about 300, from about 10 to about 400, from about 10 to about 500, from about 10 to about 600, about 10 to about 700, about 10 to about 800, about 10 to about 900, about 10 to about 1000, about 10 to about 1100, about 10 to about 1200, about 1200 to about 1300, from about 1100 to about 1300, from about 1000 to about 1300, from about 900 to about 1300, from about 800 to about 1300, from about 700 to about 1300, from about 600 to about 1300, from about 500 to about 1300 , from about 400 to about 1300, from about 300 to about 1300, from about 200 to about 1300, or from about 100 to about 1300 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's VAS Bowdle score is reduced, 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's VAS Bowdle score is measured at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof (either after administration of an equivalent dose of (b)-ketamine or a pharmaceutically acceptable salt thereof, or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof).

In some embodiments, the Clinical Diagnosis of Dissociative States Scale (CADSS) can be used to measure dissociative states in a subject. See, for example, Luckenbaugh, et al. J. Affect. Disord., Vol. 159, pp. 56-61 (2014), which is incorporated herein by reference in its entirety. The CADSS score includes, but is not limited to, statements such as: objects in slow motion, objects seem unreal, feeling disconnected from what is happening, out-of-body experiences, feeling like a spectator or observer, feeling disconnected from the body, feeling the body changes, people appearing still/ dead/mechanical, objects look different, colors become less saturated, objects appear as if through a tunnel/wide-angle lens, everything takes longer, everything happens faster, events occur that cannot be explained, loss of understanding

- 26 046262 happening, sounds changing intensity, a special feeling of clarity, a feeling of looking through fog and a feeling that colors seem brighter. Typically, the CADSS will include 23 statements that the subject rates from 0 to 4, with scores ranging from 0 (no dissociation) to 92 (extreme dissociation). A score of 0 reflects that the subject did not feel at all as described in the item, while a score of 4 reflects that the subject agreed with the question as much as possible, for example, 0 reflects complete disagreement, 1 reflects weak agreement, 2 reflects moderate agreement. agreement, 3 reflects complete agreement, and 4 reflects the highest level of agreement with the item specified. Thus, lower individual and overall scores indicate less dissociation. In some embodiments, a portion of the scale is filled in by the subject. In some embodiments, a portion of the scale is completed by a trained observer of the subject.

In some embodiments, the subject's CADSS score is from about 0 to about 10 prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, from about 0 to about 2, from about 0 to about 3, from about 0 to about 4, from about 0 to about 5, from about 0 to about 6, from about 0 to about 7, from about 0 to about 8 , from about 0 to about 9, from about 9 to about 10, from about 8 to about 10, from about 7 to about 10, from about 6 to about 10, from about 5 to about 10, from about 4 to about 10, from about 3 to about 10, from about 2 to about 10, or from about 1 to about 10 before intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's CADSS score is from about 2 to about 6, from about 3 to about 7, or from 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 for about 5 minutes to about 24 hours prior to 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 to 24 hours, from about 12 to 24 hours, or from about 6 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 over about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes. up to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the subject's CADSS score is from about 0 to about 10 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's CADSS score is from about 0 to about 10 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, from about 0 to about 2, from about 0 to about 3, from about 0 to about 4, from about 0 to about 5, from about 0 to about 6, from about 0 to about 7, from about 0 to about 8 , from about 0 to about 9, from about 9 to about 10, from about 8 to about 10, from about 7 to about 10, from about 6 to about 10, from about 5 to about 10, from about 4 to about 10, from about 3 to about 10, from about 2 to about 10, or from about 1 to about 10 before intranasal administration of racemic ketamine as described herein, and from about 0 to about 2, from about 0 to about 3, from about 0 before

- 27 046262 about 4, from about 0 to about 5, from about 0 to about 6, from about 0 to about 7, from about 0 to about 8, from about 0 to about 9, from about 9 to about 10, from 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 approximately 10 after intranasal administration of racemic ketamine. In some embodiments, the subject's CADSS score is from about 2 to about 6, from about 3 to about 7, or from about 4 to about 8 prior to intranasal administration of racemic ketamine as described herein, and the subject's CADSS score is from about 2 to about 6, from about 3 to about 7, or from about 4 to about 8 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's CADSS score is measured from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's CADSS score is measured from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine. 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 to 24 hours, from about 12 to 24 hours, or from about 6 to 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 up to 24 hours, from about 12 to 24 hours, or from about 6 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 over about 1 hour to about 4 hours, about 1.5 hours to about 5 hours, about 2 hours to about 6 hours, about 5 hours to about 10 hours, or about 45 minutes. to about 24 hours prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and the subject's CADSS score is measured at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, from about 5 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.

In some embodiments, a subject's CADSS score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's CADSS score changes (i.e., increases or decreases) from about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score before intranasal administration of racemic ketamine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS 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 and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 h, from 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's CADSS score is reduced by from about 1 to about 92 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's CADDS score may be reduced by from 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 an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is reduced by from about 1 to about 90, from about 1 to about 80, from about 1 to about 70, from about 1 to about 60, from about 1 to about 50, from about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 80 to about 92, about 70 to about 92, about 60 to about 92, about 50 to about 92 , from about 40 to about 92, from about 30 to about 92, from about 20 to about 92, or from about 10 to about 92 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score decreases 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

- 28 046262 from about 5 minutes to 12 hours, from about 5 minutes to 18 hours, from about 18 to 24 hours, from about 12 to 24 hours, or from about 6 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 at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemic ketamine or its pharmaceutically acceptable salt (or after administration of an equivalent dose of (S)ketamine or a pharmaceutically acceptable salt thereof, or intravenous administration of an equivalent dose of racemic ketamine or a pharmaceutically acceptable salt thereof).

In some embodiments, a Profile of Affective States (POMS) (eg, POMS, 2nd edition) can be used to measure a subject's temporary feelings and mood. See, for example, Lin, et al. JPA Vol. 32, No. 3, pp. 273-277 (2014), which is incorporated herein by reference in its entirety. The emotional state profile may include items to track changes in the subject's mood.

In some embodiments, the assessment of the subject's emotional state profile is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the assessment of the subject's emotional state profile is substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours , from about 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a decision time test (CRT) may be used to measure psychomotor performance in 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 decision time test is administered using a computer where the subject is shown the on-screen equivalent of a numeric keypad. When a key is highlighted on the screen, the subject presses the corresponding key on a separate keyboard. For a given trial, four to eight numbered squares will be highlighted on the computer screen, which spatially correspond to the keys on the keyboard. The key backlighting sequence can be arbitrary. In some embodiments, the key backlight sequence follows a profile that alternates between a center button and any button that is part of a stimulus button set. In some embodiments, the size of the stimulus set increases from 4 to 6 and then to 8 during a test. The number of alternative options can increase across response blocks in each cycle. The CRT test can include three outcome variables: recognition reaction time (RRT) is the time it takes the subject to notice the light (eg, the time between the onset of the stimulus and the moment the subject lifts his/her finger away from the start button); Motor reaction time (MRT) is the time between the time a subject lifts his/her finger from the start button and touches the response button; and total reaction time (TRT) is the sum of RRT and MRT. The accuracy of the answers can also be recorded.

In some embodiments, a subject's CRT score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's CRT 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 and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. acceptable salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours , from 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's short-term memory may be measured by

- 29 046262 use the Sternberg Short-Term Memory Test (SSTM). See, for example, Sternberg, Science, Vol. 153, Issue. 3736, pp. 652-654 (1966), which is incorporated herein by reference in its entirety. SSTM may involve asking the subject to remember a series of numbers that are shown quickly on a computer screen. For example, SSTM might involve rapid presentation of target lists of 2, 4, and 6 digit stimuli (e.g., 1.2 seconds per digit), and two seconds after presentation of each digit list, a series of 24 test digits is presented. The subject must determine as quickly as possible whether each test number appeared in the target list by pressing buttons in the response box corresponding to yes or no. Test numbers that appear in the target list can be called positive, while test numbers that do not appear in the target list can be called negative. SSTM can include three trials with digit sequence lengths of 2, 4, and 6. Performance can be assessed in terms of latency and response accuracy.

In some embodiments, a subject's SSTM score is 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 is substantially the same from about 5 minutes to about 24 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof and from about 5 minutes to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. salt. 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours , from 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the Subject Rated Intranasal Irritation Index (SRAII) can be used to determine intranasal irritation in a subject who has been administered intranasal ketamine (eg, racemic ketamine or ^)-ketamine) or a pharmaceutically acceptable salt thereof. For example, the SRAII can be used to evaluate the subjective effects of intranasal administration of a drug, such as ketamine or a pharmaceutically acceptable salt thereof, as described herein. The SRAII includes five categories on which the subject is asked to rate. For example, categories might include: 1) burning sensation; 2) desire to blow your nose/sneeze; 3) runny nose and/or nasal discharge; 4) pressure or pain in the face; and 5) nasal congestion. In some embodiments, each item is scored on a 6-point scale. For example, 0 means no difficulty at all; 1 refers to a very mild difficulty; 2 refers to mild/minor difficulty; 3 refers to moderate difficulty; 4 refers to severe difficulty; and 5 refers to a very severe difficulty, such as the worst possible difficulty.

In some embodiments, a subject's SRAII score is from about 0 to about 5 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, as described herein. For example, from about 0 to about 1, from about 0 to about 2, from about 0 to about 3, from about 0 to about 4, from about 4 to about 5, from about 3 to about 5, or from about 2 to about 5 following intranasal administration of racemic ketamine as described herein. In some embodiments, the subject's SRAII score is about 1, about 2, about 3, about 4, or about 5 following administration of ketamine or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the subject's SRAII 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 to 24 hours, from about 12 to 24 hours, or from about 6 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 over about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, about 5 to about 10 hours, or about 45 minutes. up to about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's SRAII score is substantially the same before and after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's SRAII score changes (ie, increases or decreases) from about 0 to about 5 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to that score 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

- 30 046262 administration of racemic ketamine or a pharmaceutically acceptable salt thereof and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours, 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof, and 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 to 24 hours, from about 12 to 24 hours, from about 6 to 24 hours , from 1 to about 4 hours, from about 1.5 to about 5 hours, from about 2 to about 6 hours, or from about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, a subject's SRAII score is reduced by about 5 to about 25 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to intranasal administration of an equivalent dose of γ)-ketamine or a pharmaceutically acceptable salt thereof. For example, a subject's SRAII score may be reduced by about 5 to about 25 following intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof compared to the score observed after administration of an equivalent dose of γ)-ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's SRAII score is reduced by from about 5 to about 20, from about 5 to about 15, from about 5 to about 10, from about 20 to about 25, from about 15 to about 25, or from about 10 to about 25 after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's SRAII score is reduced, 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 to 24 hours, from about 12 to 24 hours, or from about 6 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 at about 1 to about 4 hours, about 1.5 to about 5 hours, about 2 to about 6 hours, or about 5 to about 10 hours after intranasal administration of racemic ketamine or a pharmaceutical thereof. acceptable salt (or after administration of an equivalent dose of (S)ketamine or a pharmaceutically acceptable salt thereof).

In some embodiments, the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, in which the subject exhibits suicidal ideation, the subject has previously been diagnosed with one or more of: suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some embodiments, in which the subject is exhibiting suicidal ideation, the subject currently suffers from one or more of: suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

In some embodiments, in which the subject exhibits suicidal tendencies, the subject has previously been diagnosed with one or more of: suicidality, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder. In some embodiments, in which the subject exhibits suicidal tendencies, the subject currently suffers from one or more of: suicidal tendencies, suicidal ideation, major depressive disorder, treatment-resistant depression, and post-traumatic stress disorder.

In some embodiments, treatment-resistant depression is stage I-IV. In some embodiments, treatment-resistant depression is stage I-IV.

- 31 046262

V. In some embodiments, the subject exhibits one or more of the following characteristics: unwanted unpleasant memories, nightmares, flashbacks, emotional distress after exposure to traumatic reminders, or physical reactivity after exposure to traumatic reminders; and one or more of trauma-related thoughts or feelings and trauma-related external reminders.

In some embodiments, the subject exhibits two or more of the following characteristics: an inability to remember key features of the traumatic event, excessively negative thoughts and assumptions about oneself or the world, exaggerated blame on oneself or others for causing the traumatic event, negative affect, decreased interest in activities, feelings of isolation and difficulty experiencing positive affect. In some embodiments, the subject exhibits one or more of the following characteristics: irritability or aggression, risk-taking or disruptive behavior, hypervigilance, increased startle response, difficulty concentrating, and difficulty sleeping. In some embodiments, the characteristics are present for more than about 1 month, cause distress and/or functional impairment in social or occupational situations, and are not associated with drug or substance abuse. In some embodiments, the characteristics are present for at least about 1 month and up to about 12 months.

In some embodiments, the subject is administered intranasally from 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, approximately 90 mg or anything in between. In some embodiments, the subject is administered intranasally from about 30 to about 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered intranasally from about 45 to about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered intranasally from about 60 mg to about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof. 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, the formulation provides about 30 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides approximately 60 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 75 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose. In some embodiments, the formulation provides about 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof per dose.

In some embodiments, there is provided a method of treating suicidality in a subject in need, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein intranasal administration of racemic ketamine results in one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

A _0-mf norketamine AUC that is at least 1.5 times higher than the _0-mf norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the _C'm of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or

- 32 046262 its pharmaceutically acceptable salt; wherein, with intranasal administration of racemic ketamine, one or more of the following is observed:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-mf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A norketamine _Cmax that is at least 2 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a _0-t norketamine AUC that is approximately 1.7 to 2.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a _0-t norketamine AUC that is approximately 1.9 to 2.3 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a _0-t norketamine AUC that is approximately 2.0 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in an AUC _0-inf of norketamine that is approximately 1.5 to 2.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in an AUC _0-inf of norketamine that is approximately 1.8 to 2.2 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine AUC0-inf that is approximately 2.0 times higher than the norketamine AUC0-inf observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Cmax that is approximately 2.2 to 3.5 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Cmax that is approximately 2.4 to 3.2 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine Cm _ax that is approximately 2.9 times higher than the norketamine Cmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Tmax that is from about 80% to about 125% of the norketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Tmax that is from about 90% to about 110% of the norketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of a single dose of racemic ketamine. In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of two doses of racemic ketamine. In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of three doses of racemic ketamine.

In some embodiments, there is provided a method of treating suicidality in a subject in need, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein intranasal administration of racemic ketamine results in one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The C _max of hydroxynorketamine is at least 2 times higher than the C _max of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, the method comprising intranasally administering

- 33 046262 to the specified subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-m f of hydroxynorketamine that is at least 1.2 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

_Cmax of hydroxynorketamine, which is at least 2 times higher than C.' _m ,,,· norketamine, observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, the method comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein intranasal administration of racemic ketamine results in one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The _Cmax of hydroxynorketamine is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a _0-t hydroxynorketamine AUC that is approximately 1.7 to 2.5 times higher than the _0-t hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a _0-t hydroxynorketamine AUC that is approximately 1.9 to 2.3 times higher than the _0-t hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a _0-t hydroxynorketamine AUC that is approximately 2.1 times higher than the _0-t hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _0-inf AUC that is approximately 1.5 to 2.5 times higher than the hydroxynorketamine _0-inf AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in an _0-t hydroxynorketamine AUC that is approximately 1.7 to 2.1 times higher than the _0-inf hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in an _0-t hydroxynorketamine AUC that is approximately 1.9 times higher than the _0-inf hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine Cmax that is approximately 2.2 to 3.2 times higher than the hydroxynorketamine Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _Cmax that is approximately 2.4 to 2.8 times higher than the hydroxynorketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _Cmax that is approximately 2.6 times higher than the hydroxynorketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a T _max of hydroxynorketamine that is from about 80% to about 125% of the T _max of hydroxynorketamine observed when intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a T _max of hydroxynorketamine that is from about 90% to about 110% of the T _max of hydroxynorketamine observed when intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, the relative ratios and percentages described in

- 34 046262 herein, 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 , approximately 60 minutes, approximately 75 minutes, approximately 90 minutes, approximately 105 minutes, approximately 2 hours, approximately 2.5 hours, approximately 3 hours, approximately 3.5 hours, approximately 4 hours, approximately 4.5 hours, approximately 5 hours , about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or any value in between. In some embodiments, the relative ratios and percentages described herein are measured over a period of from about 24 hours to about 1 month. In some embodiments, the relative ratios and percentages described herein are measured over a period of from about 24 hours to about 2 weeks. For example, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, approximately 13 days, approximately 2 weeks, or anything in between. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days or once a week, or a combination thereof during the measurement period (eg, from about 24 hours to about 1 month).

In some embodiments, the _Tmax of ketamine is from about 20 to about 120 minutes after intranasal administration of racemic ketamine, for example, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, about 120 minutes, or any value in between. In some embodiments, the _Tmax of ketamine is from about 20 minutes to about 90 minutes after intranasal administration of racemic ketamine, for example, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 min, approximately 90 min or any value in between. In some embodiments, the _Tmax of ketamine is from about 30 to about 90 minutes after intranasal administration of racemic ketamine.

In some embodiments, the _Tmax of norketamine is from about 45 to about 360 minutes after intranasal administration of racemic ketamine, for example, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 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 min, about 330 min, about 345 min, about 360 min, or any value in between. In some embodiments, the _Tmax of norketamine is from about 100 to about 250 minutes after intranasal administration of racemic ketamine.

In some embodiments, the _Tmax of 6-hydroxynorketamine is from about 45 minutes to about 8 hours after intranasal administration of racemic ketamine, for example, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or any value in between. In some embodiments, the _Tmax of 6-hydroxynorketamine is from about 2 to about 4 hours after intranasal administration of racemic ketamine, such as about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, or any another intermediate value. In some embodiments, the _Tmax of 6-hydroxynorketamine is from about 3 to about 4 hours after intranasal administration of racemic ketamine.

In some embodiments, the C _m , _x of ketamine is from about 15 ng/mL to about 225 ng/mL or any value in between after intranasal administration of racemic ketamine. In some embodiments, the _Cmax of ketamine following intranasal administration of racemic ketamine is from about 25 to about 225 ng/mL, such as about 25 ng/mL, about 35 ng/mL, about 45 ng/mL, about 55 ng/mL, about 65 ng/ml, approximately 75 ng/ml, approximately 85 ng/ml, approximately 95 ng/ml, approximately 105 ng/ml, approximately 115 ng/ml, approximately 125 ng/ml, approximately 135 ng/ml, approximately 145 ng /ml, approximately 155 ng/ml, approximately 165 ng/ml, approximately 175 ng/ml, approximately 185 ng/ml, approximately 195 ng/ml, approximately 205 ng/ml, approximately 215 ng/ml, approximately 225 ng/ml or any value in between. In some embodiments, the ketamine C _max is from about 70 ng/mL to about 205 ng/mL following intranasal administration of racemic ketamine, e.g., about 85 ng/mL, about 95 ng/mL, about 105 ng/mL, about 115 ng/mL ml, approximately 125 ng/ml, approximately 135 ng/ml, approximately 145 ng/ml, approximately 155 ng/ml, approximately 165 ng/ml, approximately 175 ng/ml, approximately 185 ng/ml, approximately 195 ng/ml, approximately 205 ng/ml or any value in between. In some embodiments, the ketamine C _max is from about 75 to about 175 ng/mL following intranasal administration of racemic ketamine,

- 35 046262 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. In some embodiments, the Cmax of ketamine is from about 95 to about 145 ng/mL following intranasal administration of racemic ketamine, e.g., about 95 ng/mL, about 105 ng/mL, about 115 ng/mL, about 125 ng/mL, about 135 ng /ml, approximately 145 ng/ml or any value in between.

In some embodiments, the _Cmax of norketamine is from about 40 to about 375 ng/mL, or any value therebetween, following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of norketamine is from about 50 to about 275 ng/mL following intranasal administration of racemic ketamine, e.g., 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 in between. In some embodiments, the C _max of norketamine is from about 90 to about 180 ng/mL following intranasal administration of racemic ketamine, e.g., about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/ml, about 140 ng/ml, about 150 ng/ml, about 160 ng/ml, about 170 ng/ml, about 180 ng/ml, or any value in between. In some embodiments, the C _max of norketamine is from about 70 to about 85 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the C _max of norketamine is from about 90 to about 130 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of norketamine is from about 120 to about 150 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of norketamine is from about 160 to about 195 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of norketamine is from about 140 to about 180 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the Cmax of norketamine is from about 215 to about 225 ng/mL following intranasal administration of racemic ketamine.

In some embodiments, the _Cmax of 6-hydroxynorketamine is from about 15 to about 275 ng/ml, or any value therebetween, following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6-hydroxynorketamine is from about 40 to about 275 ng/mL, or any value therebetween, following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6hydroxynorketamine is from about 55 to about 245 ng/mL following intranasal administration of racemic ketamine, e.g., 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 in between. In some embodiments, the C _max of 6-hydroxynorketamine is from about 55 ng/mL to about 100 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the C _max of 6-hydroxynorketamine is from about 95 ng/mL to about 135 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6hydroxynorketamine is from about 130 ng/mL to about 155 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6hydroxynorketamine is from about 150 ng/mL to about 185 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6hydroxynorketamine is from about 175 ng/mL to about 215 ng/mL following intranasal administration of racemic ketamine. In some embodiments, the _Cmax of 6hydroxynorketamine is from about 210 ng/mL to about 245 ng/mL following intranasal administration of racemic ketamine.

In some embodiments, 1½ for ketamine is from about 2 to about 9 hours after intranasal administration of racemic ketamine, for example, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4, 5 hours, approximately 5 hours, approximately 5.5 hours, approximately 6 hours, approximately 6.5 hours, approximately 7 hours, approximately 7.5 hours, approximately 8 hours, approximately 8.5 hours, approximately 9 hours or any value in between . In some embodiments, 1½ for ketamine is from about 4 to about 7 hours after intranasal administration of racemic ketamine, such as about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 h, approximately 7 h, or any value in between.

In some embodiments, the 1½ for norketamine is from about 4.5 to about 12.5 hours after intranasal administration of racemic ketamine, e.g., about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 h, 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 h, approximately 12 h, approximately 12.5 h, or any value in between. According to

- 36 046262 In some embodiments, 1½ for norketamine is from about 5 to about 10 hours after intranasal administration of racemic ketamine, for example, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7 .5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 0.5 hours, about 10 hours, or any value in between. In some embodiments, the 1½ for norketamine is from about 7 to about 8 hours after intranasal administration of racemic ketamine.

In some embodiments, the 1½ for 6-hydroxynorketamine is from about 5.5 to about 22.5 hours after intranasal administration of racemic ketamine, e.g., about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 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, about 19 hours, about 19.5 hours, about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours, about 22 hours, about 22.5 hours, or any value in between. In some embodiments, 1½ for 6-hydroxynorketamine is about 8 hours and about 15 hours after intranasal administration of racemic ketamine, e.g., about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 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 intermediate value. In some embodiments, 1 _½ for 6-hydroxynorketamine is about 10 hours and about 12 hours after intranasal administration of racemic ketamine.

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

In some embodiments, the apparent Vd/F for ketamine is from about 2.5 to about 6 L/kg, or any value in between, after intranasal administration of racemic ketamine. In some embodiments, the apparent Vd/F for ketamine is from about 1000 to about 2500 L following intranasal administration of racemic ketamine, such as about 1000 L, about 1250 L, about 1500 L, about 1750 L, about 2000 L, about 2250 L, about 2500 l or any value in between. In some embodiments, the apparent Vd/F for ketamine is from about 1250 to about 1750 L following intranasal administration of racemic ketamine, such as about 1250 L, about 1300 L, about 1350 L, about 1400 L, about 1450 L, about 1500 L, about 1550 l, approximately 1600 l, approximately 1650 l, approximately 1700 l, approximately 1750 l or any value in between.

In some embodiments, the elimination rate constant (Kel (1/h or h ^-1 )) for ketamine is from about 0.1 to about 0.25 h ^-1 after intranasal administration of racemic ketamine, such as about 0.1 h ^-1 . about 0.15 h ^-1 , about 0.2 h ^-1 , about 0.25 h ^-1 or any value in between.

In some embodiments, the elimination rate constant (Kel (1/h or h ^-1 )) for norketamine is from about 0.05 to about 0.15 h ^-1 after intranasal administration of racemic ketamine, for example, about 0.05 h ^-1 . about 0.1 h ^-1 , about 0.15 h ^-1 or any value in between. In some embodiments, the elimination rate constant (Kel (1/h or h ^-1 )) for norketamine is from about 0.09 to about 0.1 h ^-1 after intranasal administration of racemic ketamine.

In some embodiments, the elimination rate constant (Kel (1/h or h ^-1 )) for 6hydroxynorketamine is from about 0.05 to about 0.15 h ^-1 after intranasal administration of racemic ketamine, for example, about 0.05 h ^-1 . about 0.1 h ^-1 , about 0.15 h ^-1 or any value in between. In some embodiments, the elimination rate constant (Kel (1/h or h ^-1 )) for 6-hydroxynorketamine is from about 0.09 to about 0.1 h ^-1 after intranasal administration of racemic ketamine.

In some embodiments, the AUC _0-t for ketamine is from about 70 to about 675 ng-h/mL following intranasal administration of racemic ketamine, e.g., about 70 ng-h/mL, about 100 ng-h/mL, about 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

- 37 046262 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, about 625 ng-h/ml, about 650 ng-h/ml, about 675 ng-h/ml, or any value in between. In some embodiments, the AUC _0-t for ketamine is from about 70 to about 250 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-t for ketamine is from about 200 to about 450 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for ketamine is from about 400 to about 675 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-t for ketamine is from about 600 ng-h/mL to about 675 ng-h/mL following intranasal administration of racemic ketamine.

In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 70 ng-h/mL to about 350 ng-h/mL after intranasal administration of racemic ketamine, for example, about 70 ng-h/mL. 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, about 275 ng-h/ml, about 300 ng-h/ml, about 325 ng-h/ml, about 350 ng-h/ml, or any value in between. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 70 to about 150 ng-h/mL. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 100 to about 250 ng-h/mL. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC0-t for ketamine is from about 200 to about 350 ng-h/mL.

In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 225 to about 525 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 225 ng-h/mL, about 250 ng-h/mL. 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, about 425 ng-h/ml, about 450 ng-h/ml, about 475 ng-h/ml, about 500 ng-h/ml, about 525 ng-h/ml, or any value in between. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 225 to about 325 ng-h/ml. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 300 to about 425 ng-h/ml. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC0-t for ketamine is from about 400 to about 525 ng-h/mL.

In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 220 to about 675 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 220 ng-h/mL, about 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 , about 575 ng-h/ml, about 600 ng-h/ml, about 625 ng-h/ml, about 650 ng-h/ml, about 675 ng-h/ml, or any value in between. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 220 to about 375 ng-h/mL. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 350 to about 525 ng-h/mL. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for ketamine is from about 500 to about 675 ng-h/mL.

In some embodiments, the AUC0-t for norketamine is from about 250 to about 2200 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 250 ng-hr/mL, about 350 ng-hr/mL, about 450 ng-hr/mL. 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 1050 ng-h/ml, about 1150 ng-h/ml, about 1250 ng-h/ml, about 1350 ng-h/ml, about 1450 ng-h/ml, about 1550 ng-h/ml, about 1650 ng-h/ml, about 1750 ng-h/ml, about 1850 ng-h/ml, about 1950 ng-h/ml, about 2050 ng-h/ml, about 2200 ng-h/ml, or any value in between. In some embodiments, the AUC0-t for norketamine is from about 250 to about 950 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for norketamine is from about 900 to about 1550 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-t for norketamine

- 38 046262 is from about 1500 to about 2200 ng-h/ml after intranasal administration of racemic ketamine.

In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 250 to about 725 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 250 ng-h/mL, about 300 ng -h/ml, approximately 350 ng-h/ml, approximately 400 ng-h/ml, approximately 450 ng-h/ml, approximately 500 ng-h/ml, approximately 550 ng-h/ml, approximately 600 ng-h /ml, about 650 ng-h/ml, about 700 ng-h/ml, about 725 ng-h/ml, or any value in between. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 250 to about 400 ng-h/mL. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 375 to about 550 ng-h/mL. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 500 to about 725 ng-h/mL.

In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 675 to about 1800 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 675 ng-h/mL, about 800 ng -h/ml, approximately 900 ng-h/ml, approximately 1000 ng-h/ml, approximately 1100 ng-h/ml, approximately 1200 ng-h/ml, approximately 1300 ng-h/ml, approximately 1400 ng-h /ml, about 1500 ng-h/ml, about 1600 ng-h/ml, about 1700 ng-h/ml, about 1800 ng-h/ml, or any value in between. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 675 ng-hr/mL to about 1050 ng-hr/mL. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 1000 to about 1450 ng-h/mL. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 1400 ng-h/ml to about 1800 ng-h/ml.

In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 850 to about 2200 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 850 ng-h/mL, about 950 ng -h/ml, approximately 1050 ng-h/ml, approximately 1150 ng-h/ml, approximately 1250 ng-h/ml, approximately 1350 ng-h/ml, approximately 1450 ng-h/ml, approximately 1550 ng-h /ml, approximately 1650 ng-h/ml, approximately 1750 ng-h/ml, approximately 1850 ng-h/ml, approximately 1950 ng-h/ml, approximately 2050 ng-h/ml, approximately 2200 ng-h/ml or any value in between. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC0-t for norketamine is from about 850 to about 1350 ng-h/mL. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 1300 to about 1850 ng-h/mL. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for norketamine is from about 1800 to about 2200 ng-h/mL.

In some embodiments, the AUC0-t for 6-hydroxynorketamine is from about 300 to about 3100 ng-h/mL following intranasal administration of racemic ketamine, e.g., about 300 ng-h/mL, about 450 ng-h/mL, about 600 ng -h/ml, approximately 750 ng-h/ml, approximately 900 ng-h/ml, approximately 1050 ng-h/ml, approximately 1200 ng-h/ml, approximately 1350 ng-h/ml, approximately 1500 ng-h /ml, approximately 1750 ng-h/ml, approximately 1900 ng-h/ml, approximately 2050 ng-h/ml, approximately 2200 ng-h/ml, approximately 2450 ng-h/ml, approximately 2600 ng-h/ml , about 2750 ng-h/ml, about 2900 ng-h/ml, about 3100 ng-h/ml, or any value in between. In some embodiments, the AUC _0-t for 6-hydroxynorketamine is from about 300 to about 700 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for 6-hydroxynorketamine is from about 700 to about 900 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, hydroxynorketamine is from about 850 to about 950 ng-h/mL after administration of racemic ketamine. In some embodiments, hydroxynorketamine is from about 900 to about 1100 ng-h/mL after administration of racemic ketamine. In some embodiments, hydroxynorketamine is from about 1100 to about 1300 ng-hr/mL following administration of racemic ketamine. In some embodiments, hydroxynorketamine is from about 1300 to about 1700 ng-h/mL after administration of racemic ketamine. In some embodiments, hydroxynorketamine is from about 1,700 to about 2,400 ng-hr/mL following administration of racemic ketamine. In some embodiments, the hydroxynorketamine is from about 2400 to about 3100 ng-hr/mL after

AUC _0-t for 6 intranasal

AUC _0-t for 6 intranasal

AUC0-t for 6 intranasal

AUC0-t for 6 intranasal

AUC0-t for 6 intranasal

AUC0-t for 6 intranasal

- 39 046262 administration of racemic ketamine.

In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 300 to about 825 ng-h/ml after intranasal administration of racemic ketamine, for example, about 300 ng-h/ml, about 400 ng-h/ml, about 500 ng-h/ml, about 600 ng-h/ml, about 700 ng-h/ml, about 800 ng-h/ml, about 825 ng-h/ml, or any value in between . In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6hydroxynorketamine is from about 300 ng-h/ml to about 450 ng-h/ml after intranasal administration of racemic ketamine. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 400 ng-h/ml to about 550 ng-h/ml after intranasal administration of racemic ketamine. In some embodiments, about 30 mg of racemic ketamine is administered intranasally, and the AUC0-t for 6-hydroxynorketamine is from about 500 ng-h/ml to about 825 ng-h/ml after intranasal administration of racemic ketamine.

In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 650 to about 1900 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 650 ng-h/mL, about 750 ng-h/ml, approximately 850 ng-h/ml, approximately 950 ng-h/ml, approximately 1050 ng-h/ml, approximately 1150 ng-h/ml, approximately 1250 ng-h/ml, approximately 1350 ng-h h/ml, about 1450 ng-h/ml, about 1550 ng-h/ml, about 1650 ng-h/ml, about 1750 ng-h/ml, about 1900 ng-h/ml, or any value in between. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC0-t for 6-hydroxynorketamine is from about 450 ng-h/ml to about 950 ng-h/ml after intranasal administration of racemic ketamine. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6hydroxynorketamine is from about 900 to about 1400 ng-h/mL after intranasal administration of racemic ketamine. In some embodiments, about 75 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 1350 ng-h/ml to about 1900 ng-h/ml after intranasal administration of racemic ketamine.

In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 1050 to about 3100 ng-h/mL after intranasal administration of racemic ketamine, e.g., about 1050 ng-h/mL, about 1200 ng-h/ml, approximately 1350 ng-h/ml, approximately 1500 ng-h/ml, approximately 1750 ng-h/ml, approximately 1900 ng-h/ml, approximately 2050 ng-h/ml, approximately 2200 ng- h/ml, about 2450 ng-h/ml, about 2600 ng-h/ml, about 2750 ng-h/ml, about 2900 ng-h/ml, about 3100 ng-h/ml, or any value in between. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6-hydroxynorketamine is from about 1050 to about 1850 ng-h/mL after intranasal administration of racemic ketamine. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC _0-t for 6hydroxynorketamine is from about 1800 to about 2600 ng-h/mL after intranasal administration of racemic ketamine. In some embodiments, about 90 mg of racemic ketamine is administered intranasally, and the AUC0-t for 6-hydroxynorketamine is from about 2550 to about 3100 ng-h/mL after intranasal administration of racemic ketamine.

In some embodiments, the AUC0-t for ketamine is from about 70 to about 675 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 70 ng-hr/mL, about 100 ng-hr/mL, about 125 ng-hr /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, 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, about 625 ng-h/mL, about 650 ng-h/mL, about 675 ng-h/mL, and ketamine _Cmax is from about 15 to about 225 ng/mL or any value therein after intranasal administration racemic ketamine. In some embodiments, the AUC0-t for ketamine is from about 70 to about 675 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 70 ng-hr/mL, about 100 ng-hr/mL, about 125 ng-hr/mL. 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, 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

- 40 046262 ng-h/ml, about 675 ng-h/ml, and the _Cmax of ketamine is from about 70 to about 205 ng/ml after intranasal administration of racemic ketamine, 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, approximately 205 ng/ml, or any value in between. In some embodiments, the AUC _0-t for ketamine is from about 70 to about 250 ng-hour/ml, from about 200 ng-hour/ml to about 450 ng-hour/ml, from about 400 ng-hour/ml to about 675 ng-hour/ml, from about 600 to about 675 ng-hour/ml after intranasal administration of racemic ketamine, and _Cmax of ketamine is from about 75 to about 1755 ng/ml, for example about 75 ng/ml, about 100 ng/ml ml, about 125 ng/ml, about 150 ng/ml, about 175 ng/ml, or any value in between after intranasal administration of racemic ketamine.

In some embodiments, the AUC _0-t for norketamine is from about 250 to about 2200 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 250 ng-hr/mL, about 350 ng-hr/mL, about 450 ng-hr /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 1050 ng-h/ml , approximately 1150 ng-h/ml, approximately 1250 ng-h/ml, approximately 1350 ng-h/ml, approximately 1450 ng-h/ml, approximately 1550 ng-h/ml, approximately 1650 ng-h/ml, approximately 1750 ng-hour/ml, about 1850 ng-hour/ml, about 1950 ng-hour/ml, about 2050 ng-hour/ml, about 2200 ng-hour/ml, or any value in between, and the Cmax of norketamine is from about 40 to approximately 375 ng/mL or any value in between following intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for norketamine is from about 250 to about 2200 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 250 ng-hr/mL, about 350 ng-hr/mL, about 450 ng-hr/mL. 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 1050 ng-h/ml, about 1150 ng-h/ml, about 1250 ng-h/ml, about 1350 ng-h/ml, about 1450 ng-h/ml, about 1550 ng-h/ml, about 1650 ng-h/ml, about 1750 ng-h/ml, about 1850 ng-h/ml, about 1950 ng-h/ml, about 2050 ng-h/ml, about 2200 ng-h/ml, or any value in between, and the _Cmax of norketamine is from about 50 to about 275 ng/mL following intranasal administration of racemic ketamine, e.g., 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 in between. In some embodiments, the _Cmax of norketamine is from about 50 to about 135 ng/mL, from about 130 to about 15 ng/mL, from about 210 to about 245 ng/mL, from about 240 to about 275 ng/mL after intranasal administration racemic ketamine, and the AUC0-t for norketamine is about 250 to about 950 ng-h/mL, about 900 to about 1550 ng-h/mL, or about 1500 to about 2200 ng-h/mL following intranasal administration of racemic ketamine . In some embodiments, the AUC _0-t for 6-hydroxynorketamine is from about 300 to about 3100 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 300 ng-hr/mL, about 450 ng-hr/mL, about 600 ng-h/ml, approximately 750 ng-h/ml, approximately 900 ng-h/ml, approximately 1050 ng-h/ml, approximately 1200 ng-h/ml, approximately 1350 ng-h/ml, approximately 1500 ng- h/ml, approximately 1750 ng-h/ml, approximately 1900 ng-h/ml, approximately 2050 ng-h/ml, approximately 2200 ng-h/ml, approximately 2450 ng-h/ml, approximately 2600 ng-h/ ml, about 2750 ng-h/ml, about 2900 ng-h/ml, about 3100 ng-h/ml, or any value therebetween, and the _{Cmax of} 6-hydroxynorketamine is from about 15 to about 275 ng/ml or any value therebetween after intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for 6-hydroxynorketamine is from about 300 to about 3100 ng-h/mL following intranasal administration of racemic ketamine, e.g., about 300 ng-h/mL, about 450 ng-h/mL, about 600 ng-h/mL. h/ml, approximately 750 ng-h/ml, approximately 900 ng-h/ml, approximately 1050 ng-h/ml, approximately 1200 ng-h/ml, approximately 1350 ng-h/ml, approximately 1500 ng-h/ ml, approximately 1750 ng-h/ml, approximately 1900 ng-h/ml, approximately 2050 ng-h/ml, approximately 2200 ng-h/ml, approximately 2450 ng-h/ml, approximately 2600 ng-h/ml, about 2750 ng-h/ml, about 2900 ng-h/ml, about 3100 ng-h/ml, or any value in between after intranasal administration of racemic ketamine, and the _Cmax of 6hydroxynorketamine is from about 55 to about 245 ng/ml, for example about 55 ng/ml, approximately 65 ng/ml, approximately 75 ng/ml, approximately 85 ng/ml, approximately 95 ng/ml, approximately 105 ng/ml, approximately 115 ng/ml, approximately 125 ng/ml, approximately 135 ng /ml, approximately 145 ng/ml, approximately 155 ng/ml, approximately 165 ng/ml, approximately 175 ng/ml, approximately 185 ng/ml, approximately 195 ng/ml, approximately 205 ng/ml, approximately 215 ng/ml , about 225 ng/mL, about 235 ng/mL, about 245 ng/mL, or any value in between after intranasal administration of racemic ketamine. In some embodiments, the AUC0-t for 6-hydroxynorketamine is from about 700 to about 1550 ng-hour/ml, from about 1500 to about 2050 ng-hour/ml, from about 2000 to about 2550 ng-hour/ml, from about 2500 to approximately 3100 ng-h/mL after intranasal administration of racemic ketamine, and

- 41 046262

The Cmax of 6-hydroxynorketamine is from about 55 to about 125 ng/mL, from about 120 to about 180 ng/mL, or from about 175 to about 245 ng/mL after intranasal administration of racemic ketamine.

In some embodiments, the AUC _0-inf for ketamine is from about 80 to about 675 ng-h/mL following intranasal administration of racemic ketamine, e.g., about 80 ng-h/mL, about 125 ng-h/mL, about 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 , about 625 ng-h/ml, about 675 ng-h/ml, or any value in between. In some embodiments, the AUC _0-inf for ketamine is from about 80 to about 175 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for ketamine is from about 150 to about 275 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for ketamine is from about 250 to about 375 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for ketamine is from about 350 to about 475 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for ketamine is from about 450 to about 575 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for ketamine is from about 550 to about 675 ng-h/mL following intranasal administration of racemic ketamine.

In some embodiments, the AUC _0-inf for norketamine is from about 250 to about 875 ng-hr/mL following intranasal administration of racemic ketamine, e.g., about 250 ng-hr/mL, about 275 ng-hr/mL, about 300 ng-hr /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, about 800 ng-h/ml, about 825 ng-h/ml, about 850 ng-h/ml, about 875 ng-h/ml, or any value in between. In some embodiments, the AUC _0-inf for norketamine is from about 250 to about 475 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for norketamine is from about 450 to about 675 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for norketamine is from about 650 to about 875 ng-h/mL following intranasal administration of racemic ketamine.

In some embodiments, the AUC _0-inf for 6-hydroxynorketamine is from about 375 to about 3700 ng-h/mL following intranasal administration of racemic ketamine, e.g., about 375 ng-h/mL, about 500 ng-h/mL, about 650 ng -h/ml, approximately 900 ng-h/ml, approximately 1050 ng-h/ml, approximately 1200 ng-h/ml, approximately 1350 ng-h/ml, approximately 1500 ng-h/ml, approximately 1650 ng-h /ml, approximately 1800 ng-h/ml, approximately 1950 ng-h/ml, approximately 2100 ng-h/ml, approximately 2250 ng-h/ml, approximately 2400 ng-h/ml, approximately 2550 ng-h/ml , approximately 2700 ng-h/ml, approximately 2850 ng-h/ml, approximately 3000 ng-h/ml, approximately 3150 ng-h/ml, approximately 3300 ng-h/ml, approximately 3450 ng-h/ml, approximately 3600 ng-h/ml, approximately 3700 ng-h/ml, or any value in between. In some embodiments, the AUC _0-inf for 6-hydroxynorketamine is from about 375 to about 1250 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for 6-hydroxynorketamine is from about 1200 to about 1400 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for 6-hydroxynorketamine is from about 1350 to about 2700 ng-h/mL following intranasal administration of racemic ketamine. In some embodiments, the AUC _0-inf for 6-hydroxynorketamine is from about 2600 to about 3700 ng-h/mL following intranasal administration of racemic ketamine.

In some embodiments, the residual area for ketamine is from about 2.5% to about 8%, such as 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 intermediate value after intranasal administration of racemic ketamine. In some embodiments, the residual area for ketamine is from about 2.5 to about 5% after intranasal administration of racemic ketamine. In some embodiments, the residual area for ketamine is from about 4% to about 6% after intranasal administration of racemic ketamine. In some embodiments, the residual area for ketamine is from about 5 to about 8% after intranasal administration of racemic ketamine.

In some embodiments, the residual area for norketamine is between

- 42 046262 about 6 to about 15% after intranasal administration of racemic ketamine, for example about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9% , approximately 9.5%, approximately 10%, approximately 10.5%, approximately 11%, approximately 11.5%, approximately 12%, approximately 12.5%, approximately 13%, approximately 13.5%, approximately 14% , approximately 14.5%, approximately 15%, or any value in between. In some embodiments, the residual area for norketamine is from about 2.5 to about 5% after intranasal administration of racemic ketamine. In some embodiments, the residual area for norketamine is from about 4 to about 6% after intranasal administration of racemic ketamine. In some embodiments, the residual area for norketamine is from about 5 to about 8% after intranasal administration of racemic ketamine.

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

In some embodiments, the AUC _0-t for intranasal racemic ketamine is from about 80 to about 125% of the AUC _0-t for an equivalent dose of intravenous racemic ketamine. For example, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or any value therein. In some embodiments, the AUC _0-t for intranasal racemic ketamine is from about 80 to about 95% of the AUC _0-t for an equivalent dose of intravenous racemic ketamine. In some embodiments, the AUC _0-inf for intranasal racemic ketamine is from about 80% to about 125% of the AUC _0-inf for an equivalent dose of intravenous racemic ketamine. For example, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%, about 110%, about 115%, about 120%, about 125%, or any value therein. In some embodiments, the AUC _0-inf for intranasal racemic ketamine is from about 80 to about 95% of the AUC _0-inf for an equivalent dose of intravenous racemic ketamine.

In some embodiments, the AUC of _0-t norketamine following administration of intranasal racemic ketamine is about 1.1 to 4.0 times greater than the AUC _{of 0-t} norketamine following administration of an equivalent dose of intravenous racemic ketamine. In some embodiments, the AUC _{0-inf of} norketamine following administration of intranasal racemic ketamine is about 1.1 to 4.0 times greater than the AUC _{0-inf of} norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, large in about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9 or about 4.0 times or any value in between.

In some embodiments, the AUC of _0-t 6-hydroxynorketamine following administration of intranasal racemic ketamine is approximately 1.3 to 3.6 times greater than the AUC _{of 0-t} norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, greater in about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, or about 3.6 times, or any value in between. In some embodiments, the AUC of _0-inf 6-hydroxynorketamine following administration of intranasal racemic ketamine is approximately 1.1 to 3.1 times greater than the AUC _{of 0-inf} norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, greater than about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0 or about 3.1 times or any value in between.

In some embodiments, the Cm for intranasal racemic ketamine is from about 25% to about 125% of the _Cmax for an equivalent dose of intravenous racemic ketamine. For example, about 25%, about 30%, about 35%, about 40%,

- 43 046262 approximately 45%, approximately 50%, approximately 55%, approximately 60%, approximately 65%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 100% , about 105%, about 110%, about 115%, about 120%, about 125%, or any value in between. In some embodiments, the _Cmax for intranasal racemic ketamine is from about 25% to about 100% of the _Cmax for an equivalent dose of intravenous racemic ketamine. In some embodiments, the _Cmax for intranasal racemic ketamine is from about 30% to about 75% of the _Cmax for an equivalent dose of intravenous racemic ketamine. In some embodiments, the _Cmax for intranasal racemic ketamine is from about 50% to about 70% of the _Cmax for an equivalent dose of intravenous racemic ketamine.

In some embodiments, the Cmax of norketamine following administration of intranasal racemic ketamine is about 1.5 to 6.0 times greater than the Cmax of norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, greater in about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2 ,4, approximately 2.5, approximately 2.6, approximately 2.7, approximately 2.8, approximately 2.9, approximately 3.0, approximately 3.1, approximately 3.2, approximately 3.3, approximately 3, 4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0 times, or any value in between.

In some embodiments, the Cmax of 6-hydroxynorketamine following administration of intranasal racemic ketamine is approximately 1.4 to 5.0 times greater than the Cmax of 6-hydroxynorketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, more in about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about

1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2 ,9, approximately 3.0, approximately 3.1, approximately 3.2, approximately 3.3, approximately 3.4, approximately 3.5, approximately 3.6, approximately 3.7, approximately 3.8, approximately 3, 9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9 or approximately 5.0 times or any value in between.

In some embodiments, the T _m ax for intranasal racemic ketamine is about 1.6 to 6.0 times greater than the T _max for an equivalent dose of intravenous racemic ketamine. For example, greater in about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about

2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4 ,1, approximately 4.2, approximately 4.3, approximately 4.4, approximately 4.5, approximately 4.6, approximately 4.7, approximately 4.8, approximately 4.9, approximately 5.0, approximately 5.1 , about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9 or about 6.0 times, or any value therebetween.

In some embodiments, the _Tmax of norketamine following administration of intranasal racemic ketamine is from about 30% to about 550% of the _Tmax of norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, about 30%, about 45%, about 60%, about 75%, about 90%, about 105%, about 120%, about 140%, about 155%, about 170%, about 185%, about 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 %, about 415%, about 430%, about 445%, about 460%, about 475%, about 490%, about 505%, about 520%, about 540%, about 550%, or any value therein. In some embodiments, the Tmax of norketamine after administration of intranasal racemic ketamine is from about 80 to about 240% of the _Tmax of norketamine after administration of an equivalent dose of intravenous racemic ketamine. For example, about 80%, about 100%, about 120%, about 140%, about 160%, about 180%, about 200%, about 220%, about 240%, or any value in between. In some embodiments, the _Tmax of norketamine following administration of intranasal racemic ketamine is from about 90% to about 180% of the _Tmax of norketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, or any value therein.

In some embodiments, the Tmax of 6-hydroxynorketamine following administration of intranasal racemic ketamine is from about 20 to about 200% of the Tmax of 6-hydroxynorketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%,

- 44 046262 about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200% or any value in between. In some embodiments, the _Tmax of 6-hydroxynorketamine following administration of intranasal racemic ketamine is from about 50% to about 100% of the _Tmax of 6-hydroxynorketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, or any value in between. In some embodiments, the _{Tmax of} 6-hydroxynorketamine following administration of intranasal racemic ketamine is from about 65% to about 85% of the _Tmax of 6-hydroxynorketamine following administration of an equivalent dose of intravenous racemic ketamine. For example, about 65%, about 70%, about 75%, about 80%, about 85%, or any value in between.

In some embodiments, administration of intranasal racemic ketamine provides greater exposure and/or higher plasma concentrations of one or more active ketamine metabolites compared to an equivalent dose of intravenous racemic ketamine. In some embodiments, the one or more active metabolites are selected from norketamine, 6-hydroxynorketamine, and a combination thereof.

In some embodiments, administration of intranasal racemic ketamine provides greater exposure and/or higher plasma concentrations of norketamine compared to an equivalent dose of intravenous racemic ketamine. In some embodiments, administration of intranasal racemic ketamine provides greater exposure and/or higher plasma concentrations of 6-hydroxynorketamine compared to an equivalent dose of intravenous racemic ketamine. In some embodiments, administration of intranasal racemic ketamine provides greater exposure and/or higher plasma concentrations of norketamine and 6-hydroxynorketamine compared to an equivalent dose of intravenous racemic ketamine.

In some embodiments, equivalent doses of intranasal racemic ketamine and intravenous racemic ketamine and/or intravenous γ)-ketamine or a pharmaceutically acceptable salt of any of the above are determined by equivalence of AUC _0-inf values.

In some embodiments, when racemic ketamine is administered intranasally, one or more of

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a _0-t norketamine AUC that is approximately 1.7 to 2.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a _0-t norketamine AUC that is approximately 1.9 to 2.3 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine AUC0-t that is at least 1.8 times higher (e.g., at least 1.9 times higher or at least 2 times higher) than the AUC0-t. t of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in an AUC _0-inf of norketamine that is approximately 1.5 to 2.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in an AUC _0-t of norketamine that is approximately 1.8 to 2.2 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _0-t AUC that is at least 1.7 times higher (e.g., at least 1.8 times higher, at least 1.9 times higher, or at least 2-fold higher) than the _0-inf AUC of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Cmax that is approximately 2.2 to 3.5 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Cmax that is approximately 2.4 to 3.2 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. According to some options

- 45 046262 implementations with intranasal administration of racemic ketamine, a Cm _ax of norketamine is observed that is at least 2.5 times higher (for example, at least 2.8 times higher or at least 3 times higher) than the C _{max of} norketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Tmax that is from about 80% to about 125% of the norketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Tmax that is from about 90% to about 110% of the norketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a norketamine _Tmax that is from about 95% to about 105% of the norketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of a single dose of racemic ketamine. In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of two doses of racemic ketamine. In some embodiments, one or more of norketamine AUC _0-t , AUC _0-inf , C _max , and T _max are determined after administration of three doses of racemic ketamine.

In some embodiments, upon intranasal administration of racemic ketamine, one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The C _max of hydroxynorketamine is at least 2 times higher than the C _max of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a _0-t hydroxynorketamine AUC that is approximately 1.7 to 2.5 times higher than the _0-t hydroxynorketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, when racemic ketamine is administered intranasally, a hydroxynorketamine AUC0-t is observed that is about 1.9 to 2.3 times higher than the hydroxynorketamine AUC0-t observed when an equivalent dose of racemic ketamine is administered intravenously. In some embodiments, intranasal administration of racemic ketamine results in an AUC0-t of hydroxynorketamine that is at least 1.9 times higher (e.g., at least 2 times higher or at least 2.1 times higher) than the AUC _{0 -t of} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in an AUC _0-inf of hydroxynorketamine that is approximately 1.5 to 2.5 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, when racemic ketamine is administered intranasally, a hydroxynorketamine AUC0-t is observed that is about 1.7 to 2.1 times higher than the hydroxynorketamine AUC0-inf observed when an equivalent dose of racemic ketamine is administered intravenously. In some embodiments, intranasal administration of racemic ketamine results in an AUC0-t of hydroxynorketamine that is at least 1.7 times higher (e.g., at least 1.8 times higher or at least 1.9 times higher) than AUC _{0-inf of} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _Cmax that is approximately 2.2 to 3.2 times higher than the hydroxynorketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _Cmax that is approximately 2.4 to 2.8 times higher than the hydroxynorketamine Cmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine C _max that is at least 2.4 times higher (e.g., at least 2.5 times higher or at least 2.6 times higher) than the C _max hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, when racemic ketamine is administered intranasally

- 46 046262 observed T _max of hydroxynorketamine is from about 80 to about 125% of the T _max of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, intranasal administration of racemic ketamine results in a hydroxynorketamine _Tmax that is from about 90% to about 110% of the hydroxynorketamine _Tmax observed with intravenous administration of an equivalent dose of racemic ketamine. In some embodiments, when racemic ketamine is administered intranasally, the hydroxynorketamine T _max is observed to be from about 95 to about 105% of the hydroxynorketamine T _max observed when an equivalent dose of racemic ketamine is administered intravenously.

In some embodiments, one or more of the AUC _0-t , AUC _0-mf , C _max , and T _max of hydroxynorketamine is determined after administration of a single dose of racemic ketamine. In some embodiments, one or more of the AUC _0-t , AUC _0-mf , C _max , and T _max of hydroxynorketamine is determined after administration of two doses of racemic ketamine. In some embodiments, one or more of the AUC _0-t , AUC _0-mf , C _max , and T _max of hydroxynorketamine is determined after administration of three doses of racemic ketamine.

In some embodiments, the subject's total Montgomery-Osberg Depression Rating Scale (MADRS) score is 20-60 units prior to intranasal administration of said racemic ketamine or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the subject's MADRS Item 10 score is 4, 5, or 6 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's MADRS Item 10 score is 5 or 6 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's MADRS Item 10 score decreases by at least 1 point 4 hours after administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the subject's Sheehan Suicidality Tracking Scale (S-STS) Clinically Important Change Measure (CMCM) score is 1552 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM score is 20-52 before intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, a subject's STS CMCM score is reduced by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's STS CMCM score is 1-3 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject's Sheehan Suicidality Tracking Scale (S-STS) Clinically Important Change Measure (CMCM) score for suicide over the next 7 days is 5-10 units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM risk score for suicide over the next 7 days is reduced by at least 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM risk score for suicide over the next 7 days is 0-2 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's S-STS CMCM risk score for suicide over the next 7 days is 0-1 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

- 47 046262

In some embodiments, the subject's Modified Observer Awareness/Sedation 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.

In some embodiments, the subject's Clinical Diagnostic Dissociative States Scale (CADSS) score is zero units prior to intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's CADSS score is zero units 1 to 6 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

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

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein said subject does not experience clinically significant sedation for approximately 24 hours following intranasal administration of racemic ketamine or its

- 48 046262 pharmaceutically acceptable salt. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof; wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) a C-SSRS score of at least 2 and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A norketamine _Cmax that is at least 2 times higher than the norketamine _Cmax observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, a method of treating major depressive disorder is provided.

- 49 046262 disorders in a subject in need, including:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the _Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The C _max of hydroxynorketamine is at least 2 times higher than the C _max of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The _Cmax of hydroxynorketamine is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising:

- 50 046262 (a) determining whether a subject has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

an AUC of _0-t hydroxynorketamine that is at least 1.5 times higher than the AUC _{of 0-t} hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of hydroxynorketamine that is at least 1.2 times higher than the AUC _0-inf of hydroxynorketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

The C _max of hydroxynorketamine is at least 2 times higher than the C _max of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

- 51 046262 (iii) CGIS-SI/B score of 4 or 5 units;

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein, with intranasal administration of racemic ketamine, one or more of:

A _0-t norketamine AUC that is at least 1.5 times higher than the _0-t norketamine AUC observed with intravenous administration of an equivalent dose of racemic ketamine;

an AUC _0-inf of norketamine that is at least 1.5 times higher than the AUC _0-inf of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine; And

A _Cmax of norketamine that is at least 2 times higher than the Cmax of norketamine observed with intravenous administration of an equivalent dose of racemic ketamine.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidality in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; And

- 52 046262 (b) intranasally administering to a subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein the subject does not experience clinically significant sedation and clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating suicidal ideation in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein said subject does not experience clinically significant sedation and clinically significant dissociation for approximately 24 hours after intranasal administration of the racemic

- 53 046262 ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein the subject does not experience clinically significant sedation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein said subject does not experience clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not exhibit clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a method of treating major depressive disorder in a subject in need thereof, comprising:

(a) determining whether an entity has one or more of the following:

(i) a total MADRS score of at least 20 units;

(ii) MADRS Item 10 score of 4, 5, or 6 units;

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

(iv) S-STS CMCM score of at least 15 units;

(v) S-STS CMCM Risk of Suicide in the Next 7 Days score of at least 5 units;

(vi) C-SSRS score of at least 2; and (b) intranasally administering to the subject a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof;

wherein the subject does not experience clinically significant sedation and clinically significant dissociation for about 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinically significant sedation and clinically significant dissociation approximately 4 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience clinical

- 54 046262 significant sedation and clinically significant dissociation approximately 1 hour after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CgIS-SI/B, S-STS CMCM, risk of suicide over the next 7 days on the S-STS CMCM, and C-SSRS is reduced by at least by 50% 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CgIS-SI/B, S-STS CMCM, risk of suicide over the next 7 days on the S-STS CMCM, and C-SSRS is reduced by at least by 50% 48 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CGIS-SI/B, S-STS CMCM, risk of suicide over the next 7 days on the S-STS CMCM, and C-SSRS is reduced by at least by 50% 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CGIS-SI/B, S-STS CMCM, risk of suicide in the next 7 days on the S-STS CMCM, and C-SSRS is below the standard for remission 24 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CGIS-SI/B, S-STS CMCM, risk of suicide in the next 7 days on the S-STS CMCM, and C-SSRS is below the standard for remission 48 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more of the MADRS total score, MADRS Item 10 scores, CGIS-SI/B, S-STS CMCM, risk of suicide in the next 7 days on the S-STS CMCM, and C-SSRS is below the standard for remission 96 hours after intranasal administration of racemic ketamine or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject has a total MADRS score of at least 20 units. In some embodiments, the subject has a MADRS Item 10 score of 4, 5, or 6 units. In some embodiments, the subject has a CGIS-SI/B score of 4 or 5 units. In some embodiments, the subject has an S-STS CMCM score of at least 15 units. In some embodiments, the subject has an S-STS CMCM Suicide Risk Over the Next 7 Days score of at least 5 units. In some embodiments, the subject has a C-SSRS score of at least 2. In some embodiments, the subject has an overall MADRS score of at least 20 units and a CGIS-SI/B score of 4 or 5 units. In some embodiments, the subject has a total MADRS score of at least 20 units and an S-STS CMCM score of at least 15 units. In some embodiments, the subject has a total MADRS score of at least 20; a CGIS-SI/B score of 4 or 5 units and an S-STS CMCM score of at least 15 units.

In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once per month, such as once daily, once every other day, twice per week, or once per week. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once every two weeks. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once daily to about once per week. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally from about once per week to about twice per week. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice a week. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally once daily, once every two days, three times a week, twice a week, or once a week. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally every four days (eg, day 1, day 4, day 8, day 12, day 16, etc.).

Certain 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 ^)-ketamine or a pharmaceutically acceptable salt thereof. acceptable salt.

In some embodiments, the intranasal ^)-ketamine is Spravato®. In some embodiments, intranasal ^)-ketamine is a solution consisting essentially of 32.3 mg ^)-ketamine hydrochloride (equivalent to 28 mg ^)-ketamine), citric acid monohydrate, edetate disodium salt, sodium hydroxide, and

- 55 046262 water. In some embodiments, intranasal (S)-KemaMUH is a clear, colorless aqueous solution with a pH of 4.5. See Spravato® (/(-ketamine) package insert dated February 11, 2020; www.accessdata.fda.gov/drugsatfda_docs/label/2020/2n243s003lbl.pdf, which is incorporated herein by reference in its entirety.

In some embodiments, the time before administration of intranasal racemic ketamine or a pharmaceutically acceptable salt thereof is mentioned. The time to administration may be a specific time or time range as indicated (e.g., about 30 minutes, about 1 hour, about 1 day to about 1 week, 6 months, etc.), or it can be any time before administration unless a specific time or range is specified.

Combination therapy

The methods of the present invention also provide methods of treatment comprising administering ketamine or a pharmaceutically acceptable salt thereof, as described in any embodiment of the present invention, in combination with one or more additional therapies (such as an antidepressant). Accordingly, ketamine or a pharmaceutically acceptable salt thereof, as described elsewhere herein, can be administered alone or in combination with one or more additional therapies. When administered in combination with one or more additional therapies, separate dosage forms may be administered to the subject. When administered as a separate dosage form, one or more additional therapies can be administered concurrently with the intranasal ketamine dosage form of the present invention or sequentially with the ketamine dosage form of the present invention in any order. In some embodiments, the intranasal ketamine dosage form and one or more additional therapies are administered sequentially on the same or different days. For example, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally twice a week, and one or more additional therapies are administered once daily.

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

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

In some embodiments, one or more complementary therapies constitute the standard of care for major depressive disorder. In some embodiments, one or more complementary therapies constitute the standard of care for suicidality. In some embodiments, one or more complementary therapies constitute the standard of care for treatment of suicidal ideation. In some embodiments, one or more complementary therapies constitute the standard of care for treatment-resistant depression. In some embodiments, one or more complementary therapies constitute the standard of care for treatment of post-traumatic stress disorder.

In some embodiments, one or more additional therapies is pramipexole.

In some embodiments, the one or more additional therapies are a typical antipsychotic. Representative typical antipsychotics include, but are not limited to, chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopentic sol.

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

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

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.

In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor. Representative selective reuptake inhibitors

- 56 046262 serotonin include, but are not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.

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, sibutramine, tramadol and venlafaxine.

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.

In some embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor. Representative selective norepinephrine reuptake inhibitors include, but are not limited to, reboxetine.

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

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

In some embodiments, one or more additional therapies is sertraline. In some embodiments, one or more additional therapies is venlafaxine.

In some embodiments, the one or more additional therapies constitute one additional therapy. In some embodiments, the one or more additional therapies constitute two, three, or four additional therapies.

In some embodiments, the subject has previously been administered one or more additional therapies consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers, and pramipexole; wherein said subject has not responded to a previous one or more therapies.

In some embodiments, the subject has previously received standard treatment for major depressive disorder and the subject has not responded to prior therapy. In some embodiments, the subject has previously received standard treatment for suicidality, and the subject has not responded to previous therapy. In some embodiments, the subject has previously received standard treatment for suicidal ideation, and the subject has not responded to previous therapy. In some embodiments, the subject has previously received standard treatment for treatment-resistant depression and the subject has not responded to previous therapy. In some embodiments, the subject has previously received standard treatment for post-traumatic stress disorder, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered 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 prior therapy.

In some embodiments, the subject has previously been administered pramipexole and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more typical antipsychotics, such as chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupenthixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine and zuclopenthixol, and the subject was unresponsive to previous therapy.

In some embodiments, the subject has previously been administered one or more atypical antipsychotics, such as aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone, or lurasidone, and the subject has not responded to prior therapy.

In some embodiments, the subject has previously been administered one or more antidepressants and the subject has not responded to previous therapy. In some embodiments, the antidepressant is an atypical antidepressant,

- 57 046262 selective serotonin reuptake inhibitor, selective serotonin-norepinephrine reuptake inhibitor, monoamine oxidase inhibitor or selective norepinephrine reuptake inhibitor, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more atypical antidepressants, such as mirtazapine, mianserin, bupropion, trazodone, nefazodone, tianeptine, opipramol, agomelatine, vilazodone, and vortioxetine, and the subject has not responded to prior therapy.

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

In some embodiments, the subject has previously been administered one or more selective serotonin and norepinephrine reuptake inhibitors, such as atomoxetine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, and venlafaxine, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more monoamine oxidase inhibitors, such as moclobemide, rasagiline, selegiline, or safinamide, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more selective norepinephrine reuptake inhibitors, such as reboxetine, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more benzodiazepines, such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam, and the subject has not responded to previous therapy.

In some embodiments, the subject has previously been administered one or more mood stabilizers, such as lithium, valproic acid, lamotrigine, or carbamazepine, and the subject has not responded to previous therapy.

In some embodiments, one or more of the additional therapies is electroconvulsive therapy or transcranial magnetic stimulation, and wherein the subject has not responded to the previous therapy.

In some embodiments, the subject has previously been administered sertraline and the subject has not responded to previous therapy. In some embodiments, the subject has previously been administered venlafaxine, and the subject has not responded to previous therapy.

In some embodiments, the one or more additional therapies previously administered to the subject constitute one additional therapy. In some embodiments, the one or more additional therapies previously administered to the subject constitute two additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject constitute three additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject constitute four additional therapies. In some embodiments, the one or more additional therapies previously administered to the subject constitute five, six, seven, eight, nine, or ten additional therapies.

In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered transiently through the intranasal route. For example, a suicidal subject may be administered racemic ketamine or a pharmaceutically acceptable salt thereof for one to four weeks or until the suicidality resolves. In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered chronically through the intranasal route. For example, a subject suffering from major depressive disorder may be administered racemic ketamine or a pharmaceutically acceptable salt thereof for several months to several years or until the depression resolves.

In some embodiments described herein, (b)-ketamine is administered intravenously. In some embodiments described herein, (b)-ketamine is administered intranasally.

In some embodiments, there is provided a composition for intranasal administration comprising a therapeutically effective amount of racemic ketamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Some embodiments provide the use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for intranasal administration to treat suicidality in a subject in need thereof.

- 58 046262

Some embodiments provide the use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for intranasal administration to treat suicidal ideation in a subject in need thereof.

Some embodiments provide the use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for intranasal administration for the treatment of major depressive disorder in a subject in need thereof.

Some embodiments provide the use of racemic ketamine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for intranasal administration to reduce one or more side effects of ketamine in a subject in need thereof.

Intranasal delivery

In some embodiments, racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally. Administration can be accomplished using a suitable intranasal delivery device.

In some embodiments, the device (eg, an intranasal device) can administer one or more doses of racemic ketamine into the nasal cavity of a subject. In some embodiments, the device is provided for the nostril of a subject. In some embodiments, the device is configured to dispense a specific amount or a specific dose of racemic ketamine. In some embodiments, the device is configured to be actuated by the breath of a subject. In some embodiments, the device is configured to deliver more than one dose to the nasal cavity of a subject. In some embodiments, the device may inject racemic ketamine into the nasal cavity of a subject.

In some embodiments, the device includes a tip for delivering an aerosol through a nasal nozzle. The tip includes a head, which is located, in some embodiments, coaxially within the nosepiece, and a delivery tube, which is in fluid communication with the head. In some embodiments, the nozzle may be configured to deliver a stream of substance through the nosepiece. In some embodiments, the device further includes a delivery unit for delivering a metered dose of racemic ketamine to the tip. In some embodiments, the agent delivery unit includes a mechanical pressure pump that is in fluid communication with the tip and is configured to be actuated to deliver a metered dose of racemic ketamine to the tip, wherein the tip generates an aerosol. The pressure pump may be moved relative to the tip from a first non-activated position to a second activated position to deliver a metered dose of racemic ketamine to the tip and thereby create an aerosol.

In some embodiments, the mechanical pressure pump includes a fluid pressure pump to deliver a metered volume of fluid containing racemic ketamine, such as a suspension or solution, to the tip when actuated.

In some embodiments, the substance delivery unit further comprises a biasing element, in this embodiment, an elastic element, in particular a pressure spring, for biasing the pressure pump in the actuation direction when in a non-activated position, and a loading mechanism, and in some embodiments, comprising first and second levers for loading the bias element, for example, for biasing the injection pump when it is in a non-activated position, with an actuation force. In some embodiments, the loading mechanism may move between a first rest position in which the bias element is not loaded and a second operating position in which the bias element, when held by the injection pump, loads the injection pump with an actuation force.

In some embodiments, the device further includes a trigger mechanism that is operable to operate the substance delivery unit. In some embodiments, the trigger mechanism is operable to actuate the substance delivery unit when a predetermined pressure is created in a chamber in the housing. In some embodiments, the trigger mechanism may be operable to actuate the substance delivery unit when a predetermined flow rate is created through the mouthpiece.

In some embodiments, the trigger mechanism includes first and second locking elements, as well as first and second biasing elements, which include elastic elements, such as compression springs, that bias the corresponding element of the first and second stopping elements inward to a stop position at which the first and second the second locking elements prevent the injection pump from moving from the non-activated position to

- 59 046262 activated position.

In some embodiments, the trigger mechanism further comprises first and second arms that are rotatable about respective hinges and are coupled at one end thereof to a corresponding member of the first and second locking members such that rotation of the arms to a release position causes the corresponding member of the locking members to move toward to which the levers are attached, outwardly against displacement of the first and second biasing elements to a release position, in which the locking elements are located outside the injection pump head so that the injection pump, when biased by the biasing element, is driven to an activated position. When moved to the activated position, a metered dose of racemic ketamine is delivered from the pressure pump to the tip, causing the tip to create an aerosol.

In some embodiments, the trigger mechanism further includes a diaphragm as a resilient element that is part of a chamber wall in the housing. The diaphragm is configured such that when a predetermined actuation pressure is generated within the chamber in the housing, it is deflected so as to engage the other distal ends of the arms and cause them to rotate to the release position. This actuation pressure cannot be achieved until the nosepiece is sufficiently inserted into the subject's nostril for the device to operate effectively, in which position preventing exhaled air as the subject exhales from escaping directly into the atmosphere. While the nose piece is not sufficiently inserted into the subject's nostril to allow the device to operate effectively, the exhaled air as the subject exhales is released into the atmosphere, which prevents the generation of actuation pressure within the chamber in the housing.

In this configuration, the device, preconditioned and actuated by exhalation through the subject's mouth, does not require the subject to apply an actuation force at the time of actuation and ensures closure of the subject's oropharyngeal velum.

In some embodiments, the apparatus comprises a mechanical fluid injection pump that is actuated by manually compressing a chamber containing a volume of fluid to displace a stream of a metered volume of fluid.

In some embodiments, the device further includes one or more filters, a flow meter, a flow regulator, and a sprayer.

In some embodiments, the tip may be configured to deliver an aerosol spray with an asymmetric injection profile, wherein the aerosol spray has a significantly greater injection angle in the vertical sagittal plane than in the horizontal plane. Such an aerosol spray has been found to be particularly advantageous for delivering the substance to the posterior nasal cavities, particularly the olfactory region.

In some embodiments, the injection angle in the vertical sagittal plane is greater than about 35°, greater than about 40°, greater than about 45°, or greater than about 50°. In some embodiments, the horizontal injection angle is no more than about 35°, no more than about 30°, no more than about 25°, no more than about 20°, or no more than about 15°.

In some embodiments, the aerosol injection may be an elliptical injection zone. In some embodiments, the aerosol injection may be a substantially rectangular injection zone. In some embodiments, the device further comprises a delivery unit for delivering metered doses of a composition containing racemic ketamine, which is fluidly coupled to a nozzle for delivering the composition from a nasal nozzle in the form of an aerosol spray. In some embodiments, the substance delivery unit is a multi-dose unit for delivering multiple metered doses of the composition. In some embodiments, the substance delivery unit is a single-dose unit for delivering a single metered dose of the composition. In some embodiments, the agent delivery unit may be preconditioned by loading a resilient element such that, upon release, the elastic element actuates the agent delivery unit to deliver a metered dose of the composition through the nozzle. In some embodiments, the device includes a plunger for delivering a metered dose of the composition through the nozzle.

In some embodiments, the device includes one or more indicators, for example, to indicate a first dose and a second dose. In some embodiments, the indicator may be a color change or a number change. For example, after the dose is administered, the indicator is positioned behind the viewing window so that it can be visible to the subject. In some embodiments, the device includes one or two viewing windows. In some embodiments, after the first dose is administered, the first viewing window may turn red while the second viewing window may remain blank. After the second dose is given, both viewing windows may be red. Thus, the subject will not have difficulty quickly

- 60 046262 by determining whether the first and/or second dose has been given, and thus he is not at risk of overdosing and/or underdosing.

In some embodiments, the device requires no prior preparation and can be operated with one hand. In some embodiments, the device is disposable. In some embodiments, each device provides one or two doses of racemic ketamine. In some embodiments, the device includes a reservoir containing one or two doses of racemic ketamine and a dispenser element (such as a plunger) configured to slide into the reservoir. Movement of the dispensing element results in the delivery of a dose of racemic ketamine. In a two-dose device, the piston moves in two successive strokes, resulting in the first and second doses being delivered separately. In some embodiments, the device further includes an indicator that allows the user to visually determine that (i) a dose has not been delivered; (ii) only the first dose was given and (ii) both the first dose and the second dose were given. For example, a colored indication area within a viewing window in the device may change color after the first dose is administered and change color again (or another colored indication area, if present, may change color) after the second dose is administered. Likewise, actuating the dispenser element may cause the first color display zone to darken after the first dose is delivered and may cause the second color display zone to darken after the second dose is delivered.

In some embodiments, the device is an Aptar Biodose System (BDS).

Other suitable devices for intranasal delivery are described in US patent No. 7299949 (see, for example, Fig. 1-3); 9555950 (see, for example, Fig. 1-3); 10099019 (see, for example, Fig. 1-41); 10179216 (see, for example, Fig. 1-5); 10525218 (see, for example, Fig. 1-26); 10549052 (see, for example, Fig. 1-19); 7784460 (see, for example, Fig. 1-8); 8146589 (see, for example, Fig. 1-5); 8875711 (see, for example, Fig. 1); and 8985116 (see, for example, Fig. 1); and US Publications No. 20040039352; 20090054923; 20120000459; 20120017902; 20130245560; 20140018295; 20150190268; 20170020383; 20170151397; 20170216540; 20180256836;

20180256867; 20180272085; 20180361085; 20190054016; 20190070372; 20190083722; 20190117916;

20190117918; 20190143054; 20190269867; 20190290863; 20190290864; 20190314588; 20190358078;

20190358417; 20200023146; 20200054843; 20200060972; 20200206012; 20200206441 and 20200206547, each of which is incorporated by reference in its entirety, including any drawings.

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included within the spirit and scope of this application and the scope of the accompanying claims. All publications, patents, patent applications and sequence accession numbers cited herein are incorporated herein by reference in their entirety for all purposes.

The present invention will be better understood with reference to the following examples. However, they should not be construed as limiting the scope of the present invention. It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and should be included within the spirit and scope of this application and the scope of the accompanying claims.

Examples

Example 1: A two-part, randomized, double-blind, placebo-controlled, parallel-group, and partially crossover study of the pharmacodynamics, pharmacokinetics, and safety of multiple doses of intranasal and intravenous ketamine in normal healthy volunteers.

This case study describes a two-part, randomized, double-blind, placebo-controlled, parallel group, and partially crossover study to determine the pharmacodynamics (PD), pharmacokinetics (PK), and safety of multiple doses of intranasal and intravenous ketamine in normal healthy volunteers.

Study Overview

This protocol has two parts. Part A is a randomized, double-blind, placebo-controlled, multiple-dose parallel cohort study to evaluate the psychotomimetic effects, pharmacokinetics, and safety of different doses of intranasal racemic ketamine administered 3 times over 8 days. This part consists of a screening visit, a treatment phase, and a follow-up visit. Within 30 days of screening, subjects meeting inclusion criteria are enrolled and randomized into the treatment phase. Subjects are referred to the clinic 1 day before dosing (day -1), where they remain as an inpatient at the study clinic for 10 days (9 nights).

Part A consists of repeated single doses of racemic ketamine or placebo administered

- 61 046262 intranasally on Days 1, 4 and 8. There are 4 dose levels:

Treatment W: intranasal placebo

Treatment X: racemic ketamine 30 mg intranasally

Treatment Y: racemic ketamine 75 mg intranasally

Treatment Z: racemic ketamine 90 mg intranasally

The studies included six consecutive cohorts of 8 subjects each. Subjects in each cohort were randomized such that there was an even distribution of subjects to dose level (ie, 2 subjects received placebo, 2 subjects received 30 mg, 2 subjects received 75 mg, and 2 subjects received 90 mg). After treatment in each cohort, the Safety Review Panel assessed whether any dose level could be continued based on available safety information.

Pharmacodynamics, pharmacokinetics, and safety assessments were performed up to 24 hours after dosing. At the discretion of the investigator, subjects were discharged approximately 24 hours after the last dose. Subjects return for a safety follow-up visit 12 days (±1 day) after the first drug administration. In the case of early study withdrawal, study withdrawal procedures were completed at the time of withdrawal (or shortly thereafter), and subjects could be asked to return for a follow-up safety assessment visit 12 days (±1 day) after the first drug administration at the discretion of the investigator.

Part B was a randomized, double-blind, double-masked, placebo-controlled, two-stage, partial crossover study to evaluate the psychotomimetic effects, pharmacokinetics, and safety of a single dose of ketamine administered intranasally versus intravenously administered 3 times over 8 days. Within 30 days of screening, subjects who met inclusion criteria were enrolled and randomized into the treatment phase. Subjects participate in two 10-day (9 night) inpatient stays at the study clinic, separated by a washout period of at least 4 days.

Part B consists of a single dose level of 60 mg administered randomly as racemic ketamine intranasally on Days 1, 4, and 8 in one treatment period and as 0.3 mg/kg IV on Days 1, 4, and 8 in another period. An intravenous dose of 0.3 mg/kg ketamine was considered equivalent to a 60 mg dose of racemic ketamine based on expected plasma exposure. Subjects were randomized to receive the treatments listed below such that 2 subjects received placebo and 12 subjects received active treatment. To maintain the study mask, each study treatment was administered both intranasally and intravenously.

Treatment A: placebo (intranasal + i.v.)

Treatment B: racemic ketamine 60 mg intranasal + placebo IV

Treatment C: ketamine IV 0.3 mg/kg (dose equivalent to 60 mg intranasally) + placebo intranasally

PD, PK, and safety assessments were performed up to approximately 24 hours after dosing. At the discretion of the investigator, subjects were discharged approximately 24 hours after the last dose in each treatment period. Subjects returned for a safety follow-up visit 12 days (±1 day) after the first drug administration in Treatment Period 2. In the event of early study withdrawal, study withdrawal procedures were completed at the time of withdrawal (or shortly thereafter), and subjects asked to return for a safety assessment follow-up visit 12 days (±1 day) after the last drug administration, as determined by the investigator.

Goals

The primary objective of this study was to:

(1) determine the pharmacodynamic (PD) effects of racemic ketamine (intranasal ketamine HCl) and IV ketamine after multiple doses (repeated single doses) as assessed by scoring scales and psychomotor tests for psychotomimetic and dissociative effects.

Secondary objectives were as follows:

(2) evaluate the pharmacokinetic (PK) parameters of ketamine and its metabolites (norketamine and 6hydroxynorketamine) after single and multiple intranasal and intravenous doses of ketamine;

(3) compare the bioavailability of racemic ketamine 60 mg and ketamine 0.3 mg/kg IV after single and multiple doses;

(4) evaluate the correlation between plasma ketamine concentrations and electrocardiogram parameters; and (5) evaluate the safety of single and multiple intranasal and IV doses of ketamine.

The research objectives were as follows:

(6) investigate the dose dependence of ketamine and norketamine after intranasal administration

- 62 046262 racemic ketamine and (7) examine the correlation between PK parameters and various PD effects for ketamine and its metabolites.

Number of subjects

A sufficient number of healthy subjects were screened and randomized into the treatment phase to provide evaluable data from at least 9 subjects per dose level in part A (36 subjects total) and at least 11 subjects in part B.

Subjects who participated in Part A may be eligible for Part B.

Inclusion criteria

Inclusion criteria are given below. Subjects must meet each of the following inclusion criteria to be eligible for inclusion in the study:

(1) healthy male or female subjects aged 20 to 55 years inclusive;

(2) body mass index (BMI) within the range of 18.0 to 35.0 kg/m ² inclusive and a minimum weight of at least 50.0 kg;

(3) nonsmokers for at least 3 months and a negative urine cotinine test;

(4) female subjects of childbearing potential with male sexual partners must be using and are willing to continue using medically acceptable contraception for at least 1 month prior to screening (at least 3 months for oral and transdermal contraceptives), and at least 1 month after the last dose of study drug;

(5) female subjects who are not fertile must be surgically sterile (hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy, as determined by the subject's medical history) or congenitally sterile, or postmenopausal, with postmenopause defined as amenorrhea for at least 1 year without any other reason and FSH level >26 IU/L.6;

(6) resting heart rate from 50 to 100 beats per minute inclusive;

(7) are able to speak, read, and understand English or French sufficiently to understand the nature of the study, provide written informed consent, and allow completion of all study evaluations; and (8) must provide written informed consent prior to the initiation of any protocol-related procedures.

Exclusion criteria

The exclusion criteria are given below. Subjects were not considered eligible for participation in this study if any of the following exclusion criteria were met at screening:

(1) have reported a lifetime history of substance or alcohol dependence or abuse (excluding nicotine and caffeine) and/or have ever participated or are planning to participate in a substance or alcohol rehabilitation program to treat their substance dependence, or alcohol;

(2) reported lifetime abuse of ketamine or phencyclidine (PCP);

(3) clinically significant abnormalities as assessed by physical examination, history, 12-lead electrocardiogram, vital signs, or clinical laboratory tests, as determined by the investigator or designee;

(4) history or presence of any clinically significant disease (eg, cardiac, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, oncologic, or musculoskeletal) or any condition that, in the opinion of the investigator or authorized representative, may compromise the safety of the subject or the integrity of the research results;

(5) a history or family history of psychosis in first-degree relatives, a history of any of: mood disorder, anxiety disorder, obsessive-compulsive disorder, somatoform disorder, and conduct disorder;

(6) history of a neurological disorder of the central nervous system (CNS): congenital brain malformation, brain tumor, multiple sclerosis, degenerative disease of the central nervous system, or inflammatory disease of the central nervous system within the last year or had consequences;

(7) history or current diagnosis of glaucoma;

(8) known hypertension or blood pressure above 140/90 mmHg. (Blood pressure may be re-measured according to the centre's SOP);

(9) presence or history of a cardiac disorder, including congenital heart disease, coronary artery disease, heart failure, supraventricular and ventricular heart rhythm disorder, long QT syndrome (ie, QTcF > 450 ms), and

- 63 046262 associated risk factors (for example, hypokalemia, family history of long QT syndrome);

(10) any history of suicidal ideation or suicidal behavior (lifetime), as assessed by the Columbia Suicidal Severity Rating Scale (C-SSRS; main version);

(11) current (ie, within the last 3 months) treatment with any psychotropic medications;

(12) color blindness (for the perception of color intensity according to Bowdle's VAS) based on the subject's report;

(13) the presence of a piercing or any medical condition that may interfere with the absorption or pharmacokinetics of intranasal racemic ketamine (eg, nasal polyps, clinically significant deviated septum [corrected or permanent] or other physical abnormalities of the nose);

(14) any indication of a history of epilepsy or seizures, excluding febrile seizures in childhood;

(15) a history of severe allergic reaction (including anaphylaxis) to ketamine or related drugs (other NMDA receptor antagonists) or to any food, drug or bee sting, or previous status asthmaticus;

(16) use of a prohibited drug;

(17) use of recreational drugs (such as marijuana) within 3 months before the screening visit or hard drugs (such as cocaine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year before screening;

(18) positive urine drug screen (UDS);

(19) regular alcohol consumption in the 6 months before the screening visit (more than 14 units of alcohol per week, where 1 unit = 150 ml of wine, 360 ml of beer or 45 ml of 40% alcohol);

(20) a positive breath alcohol test, but the subject may be scheduled for another visit date at the discretion of the investigator or designee;

(21) difficulty with venous access or unsuitability or unwillingness to undergo catheter insertion;

(22) female subjects with a positive pregnancy test who are currently pregnant or lactating, or who planned to become pregnant within 30 days of the last administration of the study drug;

(23) donation of plasma within 7 days prior to dosing or donation or loss of blood (excluding volume collected at screening) of 50 to 499 mL of blood within 30 days or more than 499 mL within 56 days prior to administration of the first dose;

(24) test positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV);

(25) treatment with the investigational drug for 5 times the half-life if known (eg, marketed product), or for 30 days (if the half-life is unknown), or for 90 days for a biological drug before the first drug administration funds or concurrent enrollment in any study determined to be scientifically or medically inappropriate to the study;

(26) an employee of the sponsor, clinical research organization, or research site personnel directly associated with the study, or their immediate family member, defined as a spouse, parent, child, or sibling, whether biological or legally adopted;

(27) a subject who, in the opinion of the investigator or authorized representative, was considered unsuitable or unlikely to comply with the requirements of the study protocol for any reason; or (28) a subject who was facing legal charges or was on probation.

Dietary and other restrictions

In addition to the inclusion and exclusion criteria, the subject must agree to comply with each of the following restrictions for a specified time:

(1) subjects were required to abstain from alcohol consumption for 24 hours before each study visit, and abstinence was confirmed by a breath alcohol test;

(2) subjects were required to abstain from recreational drug use throughout the study, from screening to the end of the follow-up visit;

(3) subjects were required to fast (fast) for at least 8 hours before dosing and for at least 4 hours after dosing, and water was allowed ad libitum except for at least 1 hour before dosing dose and at least 1 hour after dosing;

- 64 046262 (4) subjects were asked to abstain from the following foods starting 1 week before the treatment phase and ending after the follow-up visit: grapefruit or products containing grapefruit, pomegranate, pomelo, carambola juice/products, products containing poppy seeds, Seville oranges and orange juice (5) Subjects were asked not to consume more than 450 mg of caffeine per day (eg, approximately 5 cups of tea or 3 cups of regular coffee, or 8 cans of cola, or 2 energy drinks), starting 1 week before the treatment phase and ending after the follow-up visit, and subjects were not allowed to consume caffeinated beverages while at the study site;

(6) subjects were asked to refrain from driving, operating machinery, or participating in hazardous activities until they and the investigator were confident that the study drug would not impair their judgment and/or ability to perform skilled tasks, and subjects were informed of that driving under the influence of alcohol, drugs or other substances was a criminal offense and that if they were caught driving while under the influence of alcohol, drugs or other substances, they could be prosecuted to the fullest extent of the law;

(7) Subjects were asked to refrain from vigorous physical activity for 48 hours prior to each study visit, subjects were not permitted to engage in vigorous physical exercise during the subjects' inpatient stay at the study center, and for safety reasons subjects were required to remain in a sitting or reclining position. bedside during the first 4 hours after administration of the drug;

(8) subjects were required to abstain from donating blood during the study and for 30 days after the follow-up visit; and (9) subjects were required to follow the informed consent form (ICF) and the clinic code of conduct.

Test product(s), dose and route of administration:

In Part A, subjects were randomized to receive either placebo or racemic ketamine (30 mg, 75 mg, or 90 mg), with subjects equally allocated to dose level. Study drug (placebo and active substance) was administered intranasally after an overnight fast of at least 8 hours on Days 1, 4, and 8.

In Part B, the following study treatments were administered double-masked so that each subject would receive the study drug (placebo and/or active drug) intranasally and intravenously:

Treatment A: intranasal placebo + IV placebo

Treatment B: racemic ketamine 60 mg intranasal + placebo IV

Treatment C: ketamine 0.3 mg/kg IV + placebo intranasally

Study treatment was administered on Days 1, 4, and 8 of both treatment periods after an overnight fast of at least 8 hours.

The timing of study drug administration was set as the first spray administration in part A and was set at the start of the infusion in part B.

Intranasal administration

On dosing days there was a total of 6 sprays per subject per day. Subjects were instructed to gently blow their nose before drug administration. The start of dosing was considered time zero. The drug was administered by trained study personnel as 2 sprays (0.1 mL per spray), one in each nostril, from each two-dose device. The procedure specifically developed for this study details the required standard position of the subject's head during drug administration and the instructions given to subjects regarding nasal retraction after administration of the sprays. A nasal cavity check was performed after each dose to confirm correct inhalation.

Drug administration from each two-dose device was separated by approximately 5 min to ensure optimal drug absorption into the nasal cavity by doubling the spray volume compared to previous studies. Subjects are unable to blow their nose for 1 hour after dosing. Smell/taste assessments were performed on day 9, approximately 24 hours after the last dose of intranasal medication. The time of study drug administration was set as the first spray administration.

Efforts were made to administer 6 squirts into part B during the IV infusion period, so the first squirt was administered after the start of the infusion and the last squirt was administered before the end of the infusion.

Intravenous administration

In Part B, the IV ketamine dose was based on the subject's weight at the time of admission. Researched

- 65 046262 IV drugs were administered as an IV infusion over approximately 10 minutes. The actual start and end times of the subject's infusion were recorded in the primary documentation. The time of study drug administration was set as the start of the study drug infusion.

Evaluation criteria: pharmacodynamics

Primary pharmacodynamic endpoints were maximum (peak) effect ( _Emax ), maximum change from baseline ( _CFBmax ) and time-averaged area under the effect curve (TA_AUE), if applicable, for:

(1) Bowdle Visual Analog Scale (VAS) and E _max for internal and external perception and TA AUE (2) Clinical Diagnostic Dissociative States Scales (CADSS) E _max and CFB _max for global assessment.

Secondary endpoints include _Emax , minimal effect ( _Emin ), _CFBmax , minimal change from baseline ( _CFBmin ) and TA_AUE, if applicable, for:

(3) Decision time (CRT);

CFB _max and baseline-adjusted TA_AUE motor reaction time (MRT), recognition reaction time (RRT), and total reaction time (TRT);

CFB _min and baseline-adjusted TA_AUE in percent;

(4) Sternberg Short-Term Memory Test (SSTM) and

E _min and CFB _min for combined d';

Emax and CFBmax for mean reaction time pooled across all valid responses; (5) POMS 2 (only for Treatment B and Treatment C in Part B);

CFB _max General mood disorder;

(6) Subject Ratings of Intranasal Irritation (SRAII);

Emax and CFBmax.

Evaluation criteria: pharmacokinetics

Pharmacokinetic parameters assessed in this study for ketamine, norketamine, and 6-hydroxynorketamine (if applicable) include:

(1) time to reach maximum observed plasma concentration ( _Tmax );

(2) maximum observed plasma concentration ( _Cmax );

(3) the area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC _0-t );

(4) area under the plasma concentration-time curve extrapolated to infinity (AUC _0-inf );

(5) a first-order rate constant associated with the final (log-linear) portion of the curve (λ);

(6) terminal half-life (t%);

(7) apparent clearance (ketamine only) (CL/F) and (8) apparent volume of distribution (ketamine only) (V _d /F);

Evaluation criteria: safety

Security endpoints include:

(1) Holter monitoring to determine whether there is a correlation between electrocardiogram parameters and plasma PK concentrations of intranasal racemic ketamine;

(2) adverse events, including type, frequency, and severity;

(3) vital signs (blood pressure, respiratory rate, heart rate, oxygen saturation, and oral temperature);

(4) 12-lead electrocardiogram (ventricular rate and PR, QRS, QT and QTc intervals);

(5) clinical laboratory tests;

(6) physical examination;

(7) nasal examination; and (8) the Columbia Suicidal Severity Rating Scale (C-SSRS).

Withdrawal of subjects from the study

Any subject who voluntarily withdrew consent or was withdrawn (eg, due to an adverse event) from the study before completion was considered withdrawn from the study. Subjects may be excluded from the study under any of the following circumstances:

(1) the occurrence of an intolerable AE as assessed by the investigator or authorized representative;

(2) clinically significant abnormality in vital signs, electrocardiogram, clinical laboratory tests, or physical examination as assessed by the investigator or authorized representative;

- 66 046262 (3) withdrawal of consent;

(4) loss to follow-up;

(5) administrative reasons;

(6) sponsor's decision;

(7) significant protocol disorder;

(8) if, in the judgment of a qualified investigator, it is in the best interests of the subject;

(9) pregnancy;

(10) failure to comply with study requirements and limitations (eg, positive urine cotinine test at any study visit, use of a concomitant medication) and (11) study discontinuation.

If an event, such as a family emergency, a temporary intercurrent illness (such as a cold) not related to the study drug, or a remediable non-compliance prevents the subject from participating in the scheduled visit, but the subject wishes to continue to participate in the study, with the consent of the investigator Study site staff may attempt to reschedule the visit if possible in the study and keep the subject in the study.

If a subject is withdrawn early from the study for any reason after drug administration, the investigator or authorized representative must make every effort to complete the assessments scheduled for the follow-up visit. Substitute subjects may be added at the discretion of the sponsor in consultation with the principal investigator.

Statistical methods

Treatment Population Definitions:

For Part A, the following analysis populations were used:

Part A randomized population: all subjects who were randomized into the study.

Part A Safety Population: All randomized subjects who receive any study treatment.

Part A pharmacodynamics (PD) population: All subjects in the Part A safety population who receive any investigational treatment and who do not have protocol deviations or other circumstances that would cause their data to be excluded from the PD analysis.

Part A pharmacokinetics (PK) population: all subjects in the Part A safety population who receive at least 1 dose of study drug, have evaluable PK data, and do not have protocol deviations or other circumstances that could lead to to the exclusion of their data from the PK analysis.

For Part B, the following analysis populations were used:

Part B randomized population: all subjects who were randomized into the study.

Part B Safety Population: All randomized subjects who receive any study treatment.

Part B Completer Population: All subjects in the Part B safety population who receive both study treatments (eg, ketamine 60 mg intranasally and intravenously) and complete both treatment periods, regardless of whether they fail protocol.

Part B pharmacokinetics (PK) population: all subjects in the Part B safety population who receive at least 1 dose of study drug, have evaluable PK data, and who do not have protocol deviations or other circumstances that could lead to to the exclusion of their data from the PK analysis.

Part B bioavailability population: All subjects in the Part B PK population who receive both study treatments (eg, ketamine 60 mg intranasally and intravenously) and complete both treatment periods.

Pharmacodynamics and pharmacokinetics

Statistical analyzes of PK and PD were performed using SAS® (version 9.4 or higher). PK parameter derivation was performed using Phoenix WinNonlin (version 8.0 or higher on Windows 7 or higher platform).

For Part A, descriptive statistics were provided for the population for the Part A PD assessment. PD data at each time point were summarized using summary statistics including n, mean, standard error (SE), minimum, first quartile ( _Q1 ), median , third quartile (Q ₃ ) and maximum. PD-derived endpoints were summarized across treatments using descriptive statistics. PD data were presented graphically (where applicable) and listed for

- 67 046262 randomized Part A population.

Descriptive statistics were obtained for Part B and inferential analyzes were performed on the Part B completion population. Lists for each PD parameter and endpoint were provided for the Part B randomized population.

PD data at each time point were summarized using descriptive statistics including n, mean, standard error (SE), minimum, first quartile (Q1), median, third quartile (Q3), and maximum. The resulting endpoints were summarized by treatment and pairwise differences using descriptive statistics. PD data were presented graphically (where applicable) and listed for the randomized Part B population.

For Part A and Part B, descriptive PK statistics were obtained using the Part A and Part B PK assessment populations. Descriptive statistics parameters, including n, arithmetic mean, standard deviation (SD), CV%, median, minimum and maximum, were calculated and were presented at each treatment time point for plasma concentrations of the following analytes: ketamine, norketamine, and 6-hydroxynorketamine. Graphs of mean values (SD) and individual concentration dynamics (initial and logarithmically transformed) were plotted as a function of time.

PK parameters for all analytes were calculated using non-compartmental analysis (Phoenix WinNonlin®, version 8.0) and summarized by treatment using descriptive statistics including n, arithmetic mean, SD, CV%, median, minimum, maximum, geometric mean and geometric CV% , with the exception of T _max , 1½ and λ. _Tmax data were summarized with minimum, Q1, median, Q3 and maximum. Data ^½ and λ were summarized with n, mean, SD, EF, minimum, median and maximum. PK blood samples collected at the follow-up visit for both Part A and Part B will not be used to calculate PK parameters.

results

The results of Part A of the clinical study described in Example 1 are shown in FIG. 1-9. In fig. 1-3 describe the pharmacokinetic parameters of ketamine on Days 1, 4 and 8 (Fig. 1, Fig. 2 and Fig. 3, respectively). In fig. 4-6 describe the pharmacokinetic parameters of norketamine on Days 1, 4 and 8 (Fig. 4, Fig. 5 and Fig. 6, respectively). In fig. 7-9 describe the pharmacokinetic parameters of hydroxynorketamine on Days 1, 4 and 8 (Fig. 7, Fig. 8 and Fig. 9, respectively).

The results of Part B of the clinical study described in Example 1 are shown in FIG. 10А10С, fig. 11A-11C and figs. 12A-12C.

Example 2: Open-label drug interaction study of multiple doses of oral sertraline or venlafaxine coadministered with intranasal ketamine in healthy adult volunteers

This example describes an open-label study to determine the drug interactions of multiple doses of oral sertraline or venlafaxine when coadministered with intranasal ketamine in healthy adult volunteers.

Study Overview

This study is a single-center, open-label study in healthy volunteers. Each subject participates in a medical screening visit, a treatment period, and a follow-up visit. The total duration of this study is approximately 7 weeks. Within 30 days of screening, subjects who meet inclusion criteria are randomized to 1 of 2 groups:

Group 1: racemic ketamine (60 mg) + venlafaxine extended release (Effexor® XR)

Group 2: racemic ketamine (60 mg) + sertraline (Zoloft®)

Subjects are referred to the clinic on day -1 and placed in the clinical research unit for 13 days (12 nights). On day 1, subjects were administered a single dose of racemic ketamine 60 mg, followed by sampling for PK and PD and safety assessments. Approximately 44 hours elapse between doses of racemic ketamine and venlafaxine/sertraline. On Day 3, subjects are administered single oral doses of either venlafaxine or sertraline for 9 consecutive days (Day 3 to Day 11), starting with the lower dose (75 mg venlafaxine, 50 mg sertraline) followed by an increase to a higher dose (150 mg venlafaxine, 100 mg sertraline) to achieve steady-state concentrations of venlafaxine and sertraline.

A second dose of racemic ketamine 60 mg is administered intranasally 4 hours after venlafaxine or sertraline on day 11 to coincide with the time of peak venlafaxine/sertraline concentration to ensure detection of any drug interaction. Racemic ketamine or a pharmaceutically acceptable salt thereof is administered intranasally at least 3 hours after a meal due to the effect of food on sertraline and to mimic fasting conditions implemented in previous studies.

Samples for ketamine PK assessment are collected on day 1 and day 2 after the first dose, and on day 11 and day 12 after the second dose of ketamine. Serial sampling for PK assessment of venlafaxine or sertraline is performed in the expected steady state, starting on day 10 without

- 68 046262 ketamine and day 11 in the presence of ketamine, with simultaneous PD and safety assessments. Pre-dose PK samples of venlafaxine or sertraline from day 3 to day 10 are used to verify the achievement of steady state for these drugs.

Subjects are discharged on day 12 with a follow-up visit on day 15.

Goals:

The primary objective of this study is to determine the effect of concomitant administration of sertraline or venlafaxine on the PK and metabolism of a single dose of racemic ketamine (i/n ketamine HCl).

Secondary objectives are as follows:

(1) evaluate the effect of a single dose of racemic ketamine and its metabolites on the PK of sertraline or venlafaxine;

(2) evaluate the PD interaction (ID) between racemic ketamine and sertraline or venlafaxine and (3) evaluate the safety and tolerability of racemic ketamine when coadministered with sertraline or venlafaxine.

Number of subjects

Approximately 48 healthy subjects (24 subjects per group) are randomized to one of 2 study treatment groups, with the goal of providing complete data from at least 14 subjects per treatment group (28 subjects total).

Inclusion criteria

Subjects are considered eligible for participation in this study if any of the following inclusion criteria are met at screening:

(1) healthy male or female subjects aged 20 to 55 years inclusive;

(2) body mass index (BMI) within the range of 18.0 to 35.0 kg/m ² inclusive and a minimum weight of at least 50.0 kg;

(3) nonsmokers for at least 3 months and a negative urine cotinine test;

(4) female subjects of childbearing potential with male sexual partners must be using and are willing to continue using medically acceptable contraception for at least 1 month prior to screening (at least 3 months for oral and transdermal contraceptives), and at least 1 month after the last administration of the study drug;

(5) female subjects who are not fertile must be surgically sterile (hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy, as determined by the subject's medical history) or congenitally sterile, or postmenopausal, with postmenopause defined as amenorrhea for at least 1 year without any other reason and FSH level >26 IU/L.6;

(6) male subjects with fertile female partners must be using and willing to continue using medically acceptable contraception from screening and for at least 90 days after the last study drug administration;

(7) resting heart rate between 50 bpm and 100 bpm inclusive, and heart rate measurements may be repeated in accordance with the center's standard operating procedure (SOP);

(8) are able to speak, read, and understand English or French sufficiently to understand the nature of the study, provide written informed consent, and allow completion of all study evaluations;

(9) must provide written informed consent prior to commencing any protocol-related procedures; and (10) must be willing and able to comply with all requirements and limitations of the study.

Exclusion criteria

Subjects are not considered eligible for participation in this study if any of the following exclusion criteria are met at screening:

(1) have reported a lifetime history of substance or alcohol dependence or abuse (excluding nicotine and caffeine) and/or have ever participated or are planning to participate in a substance or alcohol rehabilitation program to treat their substance dependence, or alcohol;

(2) reported lifetime abuse of ketamine or phencyclidine (PCP);

(3) clinically significant abnormalities, as assessed by physical examination, history, electrocardiogram, vital signs, or clinical laboratory tests, as determined by the investigator or designee;

(4) history or presence of any clinically significant disease (eg,

- 69 046262 cardiac, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunological, dermatological, oncological or musculoskeletal) or any condition which, in the opinion of the investigator or authorized representative, may compromise subject safety or integrity research results;

(5) history or family history of first-degree relatives of psychosis, history of mood disorder, anxiety disorder, obsessive-compulsive disorder, somatoform disorder, conduct disorder;

(6) history of a neurological disorder of the central nervous system: congenital brain malformation, brain tumor, multiple sclerosis, degenerative disease of the central nervous system, or inflammatory disease of the central nervous system within the last year or having had consequences;

(7) history or current diagnosis of glaucoma;

(8) known hypertension or blood pressure above 140/90 mmHg. (Blood pressure may be re-measured according to the centre's SOP);

(9) presence or history of a cardiac disorder, including congenital heart disease, coronary artery disease, heart failure, supraventricular and ventricular heart rhythm disorder, long QT syndrome (ie, QTc >450 ms), and associated risk factors (eg , hypokalemia, family history of long QT syndrome);

(10) any history of suicidal ideation or behavior (lifetime), as assessed by the Columbia Suicidal Severity Rating Scale (C-SSRS; main version);

(11) current (ie, within the last 3 months) treatment with any psychotropic medications;

(12) presence of a piercing or any medical condition that may interfere with the absorption or PK of i/n ketamine (eg, nasal polyps, clinically significant deviated septum [corrected or permanent] or other physical abnormalities of the nose);

(13) any history of epilepsy or seizures (excluding febrile seizures in childhood);

(14) a history of severe allergic reaction (including anaphylaxis) to ketamine or related drugs (other NMDA receptor antagonists), venlafaxine or related drugs (other SNRIs), sertraline or related drugs (other SSRIs), or to any food, drug or bee sting, or previous asthmatic status;

(15) use of a prohibited drug;

(16) use of recreational drugs (such as marijuana) within 3 months before the screening visit or hard drugs (such as cocaine, crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year before screening;

(17) positive urine drug screen (UDS);

(18) regular alcohol consumption in the 6 months before the screening visit (more than 14 units of alcohol per week [1 unit=150 ml wine, 360 ml beer or 45 ml 40% alcohol]);

(19) a positive breath alcohol test, but the subject may be scheduled for another visit date at the discretion of the investigator or designee;

(20) difficulty with venous access or unsuitability or unwillingness to undergo catheter insertion;

(21) female subjects who are currently pregnant (have a positive pregnancy test), lactating, breastfeeding, or planning to become pregnant within 30 days of the last study drug administration;

(22) testing positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV);

(23) donation of plasma within 7 days prior to dosing or donation or loss of blood (excluding volume collected at screening) of 50 to 499 mL of blood within 30 days or more than 499 mL within 56 days prior to administration of the first dose;

(24) treatment with the investigational drug for 5 times the half-life if known (eg, marketed product), or for 30 days (if the half-life is unknown), or for 90 days for a biological product before the first drug administration or concurrent enrollment in any study determined to be scientifically or medically incompatible with the study;

(25) an employee of the sponsor, clinical research organization, or research site personnel directly associated with the study, or their immediate family member, defined as a spouse, parent, child, or sibling, whether biological or legally adopted;

(26) a subject who, in the opinion of the investigator or authorized representative, is considered unsuitable or unlikely to comply with the study protocol for any reason; and (27) a subject who is facing legal charges or is on trial

- 70 046262 probationary period.

Dietary and other restrictions

In addition to the inclusion and exclusion criteria, the subject must agree to comply with each of the following restrictions for a specified time:

(1) subjects must abstain from drinking alcohol for 24 hours before each study visit, and abstinence is confirmed by a breath alcohol test;

(2) subjects must abstain from recreational drug use throughout the study, from screening through the follow-up visit;

(3) subjects should not eat (fast from food) for at least 3 hours before ketamine administration and for at least 1 hour after ketamine administration;

(4) with the exception of water given with venlafaxine or sertraline and liquids given with food, no liquids are allowed from 1 hour before administration to 1 hour after administration of venlafaxine or sertraline, but for all other purposes water is provided without restrictions;

(5) Subjects are asked to abstain from the following foods, starting 1 week before the treatment phase and ending after the follow-up visit: grapefruit or products containing grapefruit, pomegranate, pomelo, carambola juice/products, products containing poppy seeds, Seville oranges and orange juice (6) subjects are asked not to consume more than 450 mg of caffeine per day (eg, approximately 5 cups of tea or 3 cups of regular coffee, or 8 cans of cola, or 2 energy drinks), starting 1 week before the treatment phase and ending after the follow-up visit observation, and subjects are not allowed to consume caffeinated beverages while at the study site;

(7) subjects are asked to refrain from driving, operating machinery, or participating in hazardous activities until they and the investigator are confident that the study medicinal product does not impair their judgment and/or ability to perform skilled tasks, and subjects are informed about that driving under the influence of alcohol, drugs or other substances is a criminal offense and that if they are caught driving while under the influence of alcohol, drugs or other substances, they may be prosecuted to the fullest extent of the law;

(8) Subjects are asked to refrain from vigorous physical activity for 48 hours prior to each study visit, subjects are not permitted to engage in vigorous physical exercise while subjects are inpatients at the study site, and for safety reasons subjects must remain seated or reclining in bed during the first 4 hours after intranasal administration of racemic ketamine on day 1 and day 11, as well as after the first administration of venlafaxine or sertraline on day 3 and after increasing the dose of venlafaxine or sertraline on day 7 and day 5, respectively;

(9) subjects must refrain from donating blood during the study and for 30 days after the follow-up visit and (10) subjects must follow the informed consent form (ICF) and the clinic code of conduct.

Test product(s), dose and route of administration:

Subjects are randomized to 1 of 2 groups:

Group 1: racemic ketamine 60 mg with venlafaxine

Group 2: racemic ketamine 60 mg with sertraline

On Day 1, 60 mg of racemic ketamine is administered intranasally in 4 sprays (total) using 2 single-dose, two-dose devices. Two injections are administered from the first device (1 injection into each nostril). After approximately 5 minutes, two additional sprays are administered from the second disposable device (1 spray into each nostril). Subjects should not blow their nose for 1 hour after a dose of racemic ketamine.

Subjects are instructed to gently blow their nose prior to intranasal administration of racemic ketamine. The procedure specifically developed for this study details the required standard position of the subject's head during drug administration and the instructions given to subjects regarding nasal retraction after administration of the sprays.

Group 1.

From day 3 to day 6, subjects were administered single oral doses of 75 mg venlafaxine (1 capsule containing 75 mg venlafaxine) and from day 7 to day 10 the dose of venlafaxine was increased to 150 mg (2 capsules containing 75 mg venlafaxine).

Group 2.

On day 3 and day 4, subjects were administered a single oral dose of 50 mg sertraline (1 capsule with 50 mg sertraline), and from day 5 to day 10, the sertraline dose was increased to 100 mg (2 capsules with 50 mg sertraline).

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Each day from day 3 to day 11, venlafaxine or sertraline is administered approximately 45 minutes after the start of the meal, and subjects will have approximately 30 minutes to complete the meal. Any residual food is recorded. The food served in the morning of Day 10 and Day 11 is standardized and similar in composition. The test drug is administered with approximately 240 ml of water and must be swallowed whole within 5 minutes. Dosing time is set to the first capsule, if applicable.

On day 11, venlafaxine 150 mg or sertraline 100 mg is first administered and a second dose of racemic ketamine 60 mg is administered at approximately the same time as day 1 (approximately 4 hours after venlafaxine or sertraline administration), following the same procedure as for administration of nasal sprays. The time of administration of racemic ketamine is set as the first administration of the spray. A nasal cavity check is performed after each dose of racemic ketamine to confirm proper inhalation.

Evaluation criteria: pharmacokinetics

PK parameters to be assessed in this study for ketamine, norketamine and hydroxyketamine with and without sertraline or venlafaxine, as appropriate, include the following:

(1) _Cmax : maximum observed plasma concentration;

(2) AUC _0-inf : area under the plasma concentration-time curve extrapolated to infinity;

(3) AUC _0-t : area under the plasma concentration-time curve from 0 to the last measurable concentration (for doses 1 and 3);

(4) _Tmax : time to maximum observed plasma concentration;

(5) kel: first-order rate constant associated with the terminal (log-linear) part of the curve (for dose 3 with and without sertraline or venlafaxine);

(6) t%: apparent first-order terminal half-life (calculated as 0.693/kel);

(7) CL/F: apparent clearance (total ketamine only) and (8) Vd/F: apparent volume of distribution (total ketamine only).

Other pharmacokinetic parameters of venlafaxine and sertraline and their respective metabolites will include the following:

(9) Cmax;

(10) AUC _t : area under the plasma concentration-time curve for the dosing interval;

(11) CL _ss : steady state clearance and (12) Tmax.

Evaluation criteria: pharmacodynamics

PD parameters to be assessed in this study include:

(13) blood pressure maximum change in blood pressure from baseline (CFB _max ) time to reach CFB _max blood pressure

If necessary, other PD endpoints may be assessed.

Evaluation criteria: safety

Security endpoints include:

(14) AEs (type, frequency and severity);

(15) vital signs (blood pressure, respiratory rate, heart rate, oxygen saturation, and oral temperature);

(16) 12-lead electrocardiogram (electrocardiogram; heart rate and PR, QRS, QT, and QTc intervals);

(17) clinical laboratory tests;

(18) the Columbia Suicidal Severity Rating Scale (C-SSRS);

(19) Clinical Diagnosis of Dissociative States Scale (CADSS);

(20) physical examination and (21) examination of the nasal cavity.

Stopping Criteria

Any subject who voluntarily withdraws consent or withdraws (eg due to an adverse event) from the study before completion is considered withdrawn from the study. Subjects may be excluded from the study under any of the following circumstances:

(1) the occurrence of an intolerable AE as assessed by the investigator or authorized representative;

(2) clinically significant abnormalities in vital signs, electrocardiogram, clinical laboratory tests, or physical examination by

- 72 046262 assessment of the researcher or authorized representative;

(3) withdrawal of consent;

(4) loss to follow-up;

(5) administrative reasons;

(6) sponsor's decision;

(7) significant protocol disorder;

(8) if, in the judgment of a qualified investigator, it is in the best interests of the subject;

(9) pregnancy;

(10) failure to comply with study requirements and limitations (eg, positive urine cotinine test at any study visit, use of a concomitant medication) and (11) study discontinuation.

Subjects experiencing vomiting following administration of venlafaxine or sertraline may be excluded from the study. The assessment is carried out on a case-by-case basis.

If an event, such as a family emergency, a temporary intercurrent illness (such as a cold) not related to the study drug, or a remediable non-compliance prevents the subject from participating in the scheduled visit, but the subject wishes to continue to participate in the study, with the consent of the investigator Study site staff may attempt to reschedule the visit if possible in the study and keep the subject in the study.

If a subject is withdrawn from the study early for any reason after drug administration, the investigator or authorized representative must make every effort to complete the assessments scheduled for the follow-up visit. Substitute subjects may be added at the discretion of the sponsor in consultation with the principal investigator.

Statistical methods

Treatment Population Definitions:

Randomized population: all subjects who are randomized to one of the treatment groups

Safety population: all randomized subjects who receive any investigational drug

Pharmacokinetics (PK) population: all subjects in the safety population who receive at least 1 dose of study drug, have evaluable PK data, and do not have protocol deviations or other circumstances that would lead to exclusion of the subject from the population for FC assessment.

Bioavailability population: all subjects in the safety population who complete all treatments for at least one PK parameter. Subjects with more than 3 consecutive samples missing or a total of more than 5 samples missing will not be included in the bioavailability assessment population

Pharmacodynamics (PD) population: all subjects in the safety population who have any post-baseline BP measurements.

Analysis of safety ratings

Safety analysis is performed using a safety assessment population. Rates of adverse events, adverse events leading to dropout, and serious adverse events are summarized by treatment group and show the number and percentage of subjects who experienced at least 1 adverse event. These summary data are presented by organ system class and preferred terms using the Medical Regulatory Dictionary (MedDRA, version 22.0 or later), as well as by maximum severity and relationship to study treatment.

Laboratory data are summarized by laboratory panel, laboratory test, treatment group, and visit. Deviations in laboratory test results are summarized by treatment group and subject in the form of a list. For each laboratory panel, laboratory data are listed by treatment group and subject. Vital signs (BP, respiratory rate, heart rate, oxygen saturation) are summarized at each treatment time point for absolute values and change from baseline. Particular attention is paid to blood pressure, as this is a known safety factor for ketamine.

12-lead electrocardiogram data (absolute values and change from baseline in ventricular rate and PR, QRS, QT, and QTc intervals) are summarized by treatment and time point using descriptive statistics. Frequencies (numbers and percentages) are calculated for the overall estimate by treatment and time point.

Clinical Diagnostic Dissociative Conditions Scale (CADSS) scores are aggregated across treatment and time point for the following summary scores:

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Subscale rated by the subject (sum of items 1 to 19)

Observer-rated subscale (sum of items 20 to 23)

Overall score (sum of points 1 to 23)

In addition, responses to individual CADSS items and total scores are listed.

Columbia Suicidal Severity Rating Scale (C-SSRS).

Any findings or lack of findings regarding the physical and nasal examination of each subject at baseline are documented. Any abnormal result noted after dosing is documented as an adverse event if judged to be a clinically significant change from baseline.

Pharmacokinetic analysis

Pharmacokinetic descriptive statistics are performed using the population to estimate PK. The bioavailability population is used for logical analysis. Treatment is defined as Day 1 ketamine 60 mg, Day 10 venlafaxine 150 mg or sertraline 100 mg, Day 11 ketamine 60 mg, and Day 11 venlafaxine 150 mg or sertraline 100 mg.

Plasma concentration data for ketamine, norketamine, and hydroxyketamine are summarized using descriptive statistics for each treatment and time point. Pharmacokinetic parameters were obtained using non-compartmental methods for all analytes. A similar analysis is performed for venlafaxine and sertraline and their metabolites (N-desmethylvenlafaxine and O-desmethylvenlafaxine, N-desmethylsertraline).

Descriptive statistics, including n, mean, standard deviation (SD), coefficient of variation (CV), minimum, median, and maximum, are summarized by treatment and time point. PK parameters are summarized by treatment. Draw graphs of concentration (initial and logarithmically transformed) versus time. Concentrations below the limit of quantitation (LOQ) are set to zero to obtain summary statistics and plots of mean concentration versus time.

To calculate PK parameters, concentration-time data are processed as follows: LLOQ concentrations before the first quantifiable concentration are set to zero; LLOQ concentrations after the first quantifiable concentration are considered missing; and the pre-dose sampling time relative to the dosage is set to zero. PK blood samples collected at the follow-up visit will not be used to calculate PK parameters. Descriptive statistics, including n, mean, SD, geometric mean, geometric EF, minimum, median, and maximum, are calculated by dose level for all PK parameters except _Tmax , t/ ₂ , and λ. The T _max data are summarized with n, minimum, median, maximum and quartiles 1 and 3. The t _/ and λ data are summarized with n, mean, SD, EF, minimum, median and maximum.

Pharmacokinetic profiles are analyzed for all subjects, even if some sampling time points for PK assessment are missing. FC parameters are checked to ensure they meet quality control criteria. If quality control criteria are met, PK parameters are used in analyzes and models. PK quality control criteria are sufficient to exclude unreliable data.

Comparisons of _Cmax , AUC _0-inf and CL/F are performed for ketamine alone and in combination with venlafaxine or sertraline. Comparisons of Cmax, AUC _T and CL _ss are performed for venlafaxine and sertraline with and without ketamine. Comparisons are performed using a mixed effects model for analysis of variance (ANOVA) with the logarithm of the parameter as the outcome. Treatment is included as a fixed effect and subject as a random effect.

Metabolic ratios are calculated for the conversion of ketamine to norketamine and hydroxyketamine using metabolite-to-parent ratios adjusted for molecular weight. The conversion of venlafaxine and sertraline to their respective metabolites individually and in combination with ketamine will also be assessed to better understand the metabolic interactions through different pathways.

Analysis of pharmacodynamic parameters

PD endpoint analysis is performed using the PD population. PD endpoints will include CFB _max and time to CFB _max .

Changes in blood pressure are analyzed as CFB on dosing days 1, 10, and 11. Statistical models are used to compare the effect of ketamine or venlafaxine/sertraline alone with the effect of the drug combination for each time point and associated parameters.

Possible PD interactions between ketamine and sertraline and between ketamine and venlafaxine are being studied. Pharmacodynamic data at each time point are summarized using descriptive statistics and presented graphically (where applicable). The resulting endpoints are summarized using descriptive statistics.

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Example 3: Two-Part Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Racemic Ketamine Administered to Adults with Major Depressive Disorder at Imminent Risk for Suicide

This case study describes a 2-part, multicenter, phase 2 study to determine the efficacy, safety, and tolerability of intranasally (n/n) racemic ketamine plus standard of care (ST) in adult subjects diagnosed with MDD at imminent risk for suicide.

Study Overview

This two-part, multicenter, phase 2 study in adult subjects diagnosed with MDD at imminent risk of suicide will evaluate the efficacy, safety, and tolerability of intranasally (i/n) racemic ketamine plus SL. In Part 1, 16 subjects will receive unmasked racemic ketamine (90 mg). Part 2 of the study is a double-blind study and 120 subjects will be randomized 1:1 to receive either racemic ketamine (90 mg) or a matching placebo.

The study schedule is identical for parts 1 and 2. Upon admission to the emergency department or hospital, each subject will participate in a 1-2 day screening phase, a 16-day treatment phase, including SL, during which study drug will be administered twice a day. week, and a 2-week observation phase to assess safety for a total of up to 5 weeks of study participation. Subjects will be treated as an inpatient for approximately 7 days (including screening) and, provided the subject meets discharge readiness criteria, will be discharged on day 6 to continue the study as an outpatient, provided clinically appropriate. Subjects will return to the clinic to receive study drug and complete study assessments 2 times per week until Day 16. Subjects' efficacy will be assessed using multiple psychometric scales, and safety will be assessed using clinical laboratory test scores, electrocardiograms (ECGs), vital signs and physical examinations. After the final dose of study drug, subjects will continue to be monitored for safety assessment for 2 weeks, including 4 in-person follow-up visits to assess safety on Days 19, 22, 25/26, and 29/30.

Safety data will be reviewed regularly by the Safety Review Committee (SRC) throughout the study. In addition, SRC members will confirm readiness for hospital discharge.

Goals:

The primary objective of this study is to evaluate the effectiveness of racemic ketamine in combination with standard of care (ST) on depressive symptoms in adults with major depressive disorder (MDD) who are at imminent risk for suicide.

Secondary objectives are as follows:

(1) To evaluate the effectiveness of racemic ketamine plus SL on suicidality symptoms in adults with MDD who are at imminent risk for suicide; and (2) Assess the safety and tolerability of racemic ketamine plus SL in adults with MDD who are at imminent risk for suicide.

The research objective is to evaluate the psychometric properties of the Sheehan Suicidality Tracking Scale (S-STS) Clinically Meaningful Change Measure (CMCM).

Number of subjects

Part 1: 16 subjects planned. Part 2: Approximately 120 randomized subjects are planned, including 60 subjects per arm.

Inclusion criteria

Subjects must meet all of the following requirements for enrollment in the study:

(1) The subject is able to speak, read, and understand English and/or the language of research personnel to sufficiently understand the nature of the study, provide written informed consent, and allow completion of all study evaluations.

(2) The subject is between 18 and 65 years of age at the time of informed consent.

(3) Sexually active male subjects must agree to abstain from sexual activity or must be willing to use medically acceptable contraception if they become sexually active, from the time consent is given until 3 months after the last dose of the study drug. medicine.

(4) Female subjects of childbearing potential must have a negative serum pregnancy test at screening and must not be breastfeeding or lactating. Female subjects must be willing to abstain from sexual activity or use medically acceptable contraception if sexually active, from the time of consent until 1 month after the last dose of the study drug.

- 75 046262 medicines.

(5) Subject meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a diagnosis of current MDD (unipolar without psychotic features), with symptoms present for at least 4 weeks, based on consultation with a psychiatrist and validated using the Brief International Psychiatric Questionnaire for Suicidal Disorders (MINI), version 7.02.

(6) The subject has a total Montgomery-Osberg Depression Rating Scale (MADRS) score of >28 before dosing on Day 1.

(7) The subject has a score of 5 or 6 on MADRS Item 10.

(8) In the opinion of the investigator, the subject requires psychiatric hospitalization due to a significant risk of suicide, has a total S-STS CMCM score of >15 and a score of 6-9 (inclusive) on the S-STS CMCM based on the clinician's judgment of the subject's risk current suicide or death by suicide (page 12, top).

(9) In the opinion of the investigator, the subject currently has suicidal ideation with intent, as evidenced by the MINI Suicidality Assessment Module at screening and baseline, specifically a positive symptom-related response to question B3, as well as a positive response related to symptoms during the last 24 hours to question B10 or B11.

(10) In the opinion of the investigator, if imminent suicidality is based on a precipitating event (i.e., a clearly identifiable situational stressor that contributes to the initiation or exacerbation of the subject's current suicidality), active suicidality should be present for >72 hours.

(11) The subject has a history of previous suicide attempt(s), confirmed in the C-SSRS with at least one history of actual attempt, or, if the attempt was aborted or failed, is considered to be a serious intent in the opinion of the investigator .

(12) As part of a treatment such as SL, the subject agrees to voluntarily be hospitalized for a recommended period of approximately 7 days (from screening to day 6) and fully understands that the length of hospitalization may be longer if clinically indicated (i.e., it is not safe to discharge him/her on day 6).

(13) The subject is willing and able to take prescribed non-study antidepressant therapy(s) at the discretion of the investigator for at least the duration of the study.

(14) Subject is willing and able to maintain other existing treatments and avoid alcohol and recreational drug use, as well as specific protocol-prohibited therapies, from screening to the final study visit (Day 29/30). Subjects with acute alcohol intoxication should not be screened (but may be screened while sober); subjects with suspected intoxication may be confirmed by BAC or breathalyzer.

(15) The subject is able to complete i/n administration of the study drug.

Exclusion criteria

The presence of any of the following criteria excludes the subject from participation in the study:

(1) Subjects who currently have sequelae of prior COVID illness, or subjects who have either documented COVID infection or symptoms suggestive of recent COVID infection within 1 month of screening.

(2) The subject has a lifetime diagnosis of bipolar disorder, any mood disorder with psychotic features, schizophrenia or other psychotic disorder, obsessive-compulsive disorder, or antisocial personality disorder, as verified by the MINI. (Note that subjects with PTSD and generalized anxiety disorder (GAD)/panic disorder are not necessarily excluded as MDD is the most relevant diagnosis.) (3) In the opinion of the investigator, the subject has chronic, refractory, treatment-resistant depression after > 4 appropriate therapeutic attempts with antidepressants (with or without adjuvants and/or electroconvulsive therapy [ECT]), as confirmed by the ATRQ.

(4) In the opinion of the investigator, the subject has a current diagnosis of borderline personality disorder or, if the subject has not met full diagnostic criteria for borderline personality disorder within the past 5 years, the subject has a history of recurrent non-suicidal self-harm or self-injurious behavior.

(5) The subject has an S-STS CMCM score of 10 based on the clinician's judgment of the subject's current risk of attempting suicide or dying by suicide (top of S-STS CMCM p12).

(6) The subject has a diagnosis of mental retardation, a neurocognitive disorder including dementia, or a history of moderate to severe traumatic brain injury. Mild traumatic brain injuries do not necessarily lead to exclusion if

- 76 046262 the investigator believes that the presenting symptoms will not interfere with the conduct or interpretation of safety and/or effectiveness assessments.

(7) The subject has a history or current history of any clinically significant hematologic, hepatic, respiratory, renal, neurologic disorder, known positive human immunodeficiency virus (HIV) infection, gastrointestinal disorder, or other condition that may confound the results safety assessments performed in the study.

(8) Subject has a history of seizures (other than childhood febrile seizures).

(9) The subject has a body mass index (BMI) >40 or <18 at screening.

(10) The subject has known uncontrolled hypertension or blood pressure (BP) that, in the judgment of the investigator, should exclude the subject at screening or baseline (BP measurements may be repeated in accordance with center standard operating procedures [SOPs]).

(11) The subject has a history or current history of cardiovascular disease, progressive atherosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm disorder, coronary heart disease, congenital heart disease, coronary artery disease, heart failure, supraventricular and ventricular heart disease rhythm, long QT syndrome (ie, QTcF > 450 ms) and associated risk factors (ie, hypokalemia, family history of long QT syndrome), syncope, cardiac conduction disorders (eg, clinically significant heart block) , exercise-related cardiac events, including syncope and near-syncope, clinically significant bradycardia, or other serious heart problems.

(12) The subject has a known family history of sudden cardiac death or ventricular arrhythmia.

(13) The subject has any clinically significant abnormality on the 12-lead ECG performed at screening or baseline, such as a significant arrhythmia, cardiac conduction disorder, or other abnormality that is considered a potential safety concern.

(14) The subject has a concurrent chronic or acute illness, disability, or other condition (eg, narcolepsy) that may confound the safety assessments conducted in the study.

(15) The subject has any medical condition that may interfere with the absorption of i/n ketamine (eg, nasal polyps, clinically significant deviated septum [corrected or permanent], or other physical abnormalities of the nose).

(16) Subject meets DSM-5 criteria for moderate to severe substance use disorder in the 6 months prior to screening, OR is considered by the investigator to be at risk for substance withdrawal (eg, dependent on opiates or alcohol), OR has a lifetime history of disorders associated with the use of ketamine, phencyclidine, lysergic acid diethylamide, or the hallucinogen 4-methylenedioxymethamphetamine. Nicotine use disorder resolved.

(17) Subject has a positive urine test for phencyclidine (PCP), cocaine, or amphetamines (including amphetamine, methamphetamine [mAMP], and 3,4-methylenedioxymethamphetamine [MDMA]) at screening.

(18) The subject tests positive for hepatitis B, hepatitis C, or HIV at screening.

(19) Subject had any history of using ketamine or esketamine for the treatment of any mental illness.

(20) The subject has a known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any ingredients.

(21) In the opinion of the investigator, the subject has any clinically significant laboratory abnormality, including an abnormality indicating clinically significant hematologic, hepatobiliary, or renal disease.

(22) The subject received the investigational product, including vaccines, within 30 days prior to the first dose of the investigational drug.

(23) The subject was previously enrolled in the current study. Subjects previously screened but not randomized in the current study may be rescreened with the approval of the study's medical monitor.

(24) The subject does not comply or is not prepared to comply with the requirements regarding prohibited and restricted drugs and mandatory washout periods prior to participation. Illicit drugs include, but are not limited to, monoamine oxidase inhibitors (MAOIs), opioids or drugs acting on opioids.

- 77 046262 receptors, psychostimulants, lamotrigine, N-methyl-E-aspartate (NMDA) receptor modulators, magnesium or any drug that may bias the safety assessments conducted in the study. Subjects who received any of these prohibited drugs within 2 weeks of screening were excluded from the study. Strong CYP3A4 inhibitors are not allowed for 1 week after the first dose until at least 1 day after the last dose. Strong CYP3A4 inducers are not allowed for 30 days after the first dose and until at least 1 day after the last dose. Subjects who had recently stopped taking lithium or calcium channel blockers within 3 months before screening were also excluded.

(25) The subject is an employee of the sponsor, clinical research organization, or research site personnel directly associated with the study, or their immediate family member, defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

(26) The subject is facing legal charges or is on probation.

(27) A subject who, in the opinion of the investigator, is considered unsuitable or unlikely to comply with the research protocol for any reason.

(28) The subject is legally incompetent, has been involuntarily hospitalized in the past year, or has another serious mental health problem, physical problem, or life circumstance that may interfere with the conduct or interpretation of study assessments.

Concomitant treatment

SL is required for all subjects during the study, which must include evidence-based/empirically based antidepressant options at the discretion of the investigator. In addition, subjects are permitted to participate in SL psychotherapy, including behavioral therapy. Benzodiazepine drugs (dose equivalent to <6 mg/day lorazepam) may be taken in limited quantities as needed, as defined in the restricted drugs section of the protocol, but should never be taken within 24 hours prior to administration of the study drug. means and assessments. Short-acting non-benzodiazepine hypnotics (eg, zolpidem, zaleplon) are permitted.

Criteria for evaluation:

Primary efficacy endpoint:

The primary efficacy endpoint will be the change from baseline in MADRS total score at 24 hours after the initial dose.

Secondary efficacy endpoints:

Secondary endpoints will be change from baseline at 24 hours and at day 16 in the following:

(1) S-STS Global Score (2) MADRS Global Score at Day 16 (only) (3) Clinical Global Impression (CGI) of SI/B Severity (CGIS-SI/B) and Change in SI/B (CGICSI /B) (4) Patient Global Impression (PGI) of Severity of SI/B (PGIS-SI/B) and Change in SI/B (PGIC-SI/B) (5) Clinician's S-STS ratings of overall severity of suicidal impulses, thoughts and behavior (6) The S-STS clinician's assessment of the subject's current risk of attempting or dying by suicide (7) The S-STS clinician's assessment of the subject's likelihood (risk) of attempting or dying by suicide within the next 7 days (8) Subject's S-STS ratings of overall severity of suicidal impulses, thoughts, and behavior (9) Subject's S-STS ratings of need for treatment (10) MADRS Item 10 response frequencies (response <3) (11) MADRS response ( >50% decrease in total score from baseline) (12) MADRS remission (total score <12)

Exploratory endpoint:

The exploratory endpoint is an analysis of the validity, reliability, and ability to detect change using the CMCM S-STS.

Security endpoints:

The safety and tolerability of i/n racemic ketamine will be assessed by:

(1) Frequency and severity of treatment-emergent adverse events (TEAEs) (2) Frequency of new or worsening clinically significant abnormalities in laboratory tests, vital signs, ECG, or physical examination (3) Clinical Diagnosis of Dissociative Conditions Scale (CADSS) ) (4) Modified Observer Awareness/Sedation Scale (MOAA/S) (5) Columbia Suicidal Severity Rating Scale (CSSRS)

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Statistical methods

Separate summaries will be prepared based on the results of Part 1 and Part 2. Descriptive statistics will be used to summarize the results from Part 1. To analyze the data from Part 2, the primary efficacy endpoint, change from baseline in MADRS total score at 24 hours after the initial dose, will be analyzed using an ANCOVA model including baseline MADRS total score. as a covariate, treatment as a fixed effect, and subject as a random effect. A sensitivity analysis will be performed using MADRS item 10 as a covariate. Details of statistical analyses, including secondary analyzes of efficacy, safety, and sensitivity, will be described in the protocol and/or statistical analysis plan (SAP).

Determining Sample Size

In Part 1, the planned sample size is 16 subjects and is considered sufficient to provide meaningful estimates of variability in efficacy endpoints that can be used in the design of future studies.

In Part 2, the planned sample size is calculated based on an effect size of 0.50, a two-sided significance level of 0.10, and an estimated attrition rate of approximately 15%. Based on these assumptions, 60 subjects would be randomized to each treatment group to achieve 80% power. The difference between treatment groups and the standard deviation used in this calculation were based on the results of previous studies of ketamine and on clinical judgment.

Duration of study and treatment

The sequence and maximum duration of study periods will be as follows:

1-2 day screening phase

16-day treatment phase

2-week follow-up phase to assess safety

Therefore, the maximum study duration for each subject is approximately 5 weeks.

After completion of the study, all subjects will be referred for follow-up; this includes subjects who do not qualify for study participation, subjects who discontinue participation, and subjects who complete the study.

results

This research is currently ongoing. Data for the first eight days (16 days total) for two subjects are described below and in FIG. 13A-24.

Both subjects were enrolled in the study with severe major depressive disorder (MDD) based on pre-dose MADRS scores of 35 and 38 for subjects 1 and 2, respectively. Scores of 35 and above are considered severe, and scores of 18-34 indicate moderate MDD.

Subject 1's total MADRS score decreased from a baseline score of 35 to 8 24 hours after administration of intranasal racemic ketamine. Similarly, Subject 2's total MADRS score decreased from a baseline score of 38 to 15 24 hours after administration of intranasal racemic ketamine. In summary, both subjects demonstrated an extremely rapid, clinically significant (>50% reduction) response, going from severe MDD to remission in just 24 hours based on the MADRS total score. Intranasal racemic ketamine also provided a sustained response until the next dose, and after receiving the second dose on day 4, symptoms were further reduced, with subject 2 having a total MADRS score of 16 on day 8, just above the remission score. See fig. 13A-13B.

Subject 1's MADRS item 10 (suicidality) score (range 0–6) decreased from a baseline score of 5 to 0 24 hours after administration of intranasal racemic ketamine. The MADRS item 10 score also decreased from a predose baseline score of 5 to 0 24 hours after intranasal racemic ketamine administration. In summary, both subjects also demonstrated a rapid, clinically significant response (meeting the MADRS Item 10 definition of response; score <3) that was maintained until the next dosing. See fig. 19A-19B.

Subject 1's CGIS-SI/B score (range 1-5) decreased from a baseline score of 4 to 1 (not at all suicidal) 24 hours after administration of intranasal racemic ketamine and remained at 1 thereafter. CGIS-SI/B score subject 2 decreased from a baseline score of 4 to 2 (moderately suicidal) 24 hours after administration of intranasal racemic ketamine and further decreased to 1 on day 3. Thus, both subjects demonstrated marked clinical improvement. See fig. 14A-14B.

Subject 1's S-STS CMCM score (range 0-52) decreased from 18 to zero 24 hours after administration of intranasal racemic ketamine. Subject 2's S-STS CMCM score similarly decreased from 22 to 3 24 hours after administration of intranasal racemic ketamine. IN

- 79 046262 Consistent with previous results, both subjects showed rapid and clinically significant improvement. See fig. 15A-15B.

Subject 1's PGIS-SI/B score (range 1-5) decreased from a baseline score of 3 to 1 (absent), and Subject 2's PGIS-SI/B score decreased from 4 to 1 24 hours after intranasal racemic ketamine administration. and both subjects remained at PGIS-SI/B score 1 thereafter. This indicates rapid clinical improvement. See fig. 16A-16B.

Subject 1's CGIC-SI/B score (range 1-7) was 1 4 hours after intranasal racemic ketamine, and Subject 2's CGIC-SI/B score was 1 24 hours after intranasal racemic ketamine, and both subjects thereafter remained at CGIC-SI/B score 1. See fig. 17.

Subject 1's PGIC-SI/B score (range 1-5) decreased from 2 to 1 24 hours after administration of intranasal racemic ketamine and remained at PGIC-SI/B score 1 thereafter. Subject 2's PGIC-SI/B score decreased from 3 to 2 24 hours after administration of intranasal racemic ketamine and further decreased to 1 on day 3. See FIG. 18.

Subject 1's S-STS CMCM score (range 0-9) decreased from a baseline score of 7 to 3 24 hours after administration of intranasal racemic ketamine. Subject 2's S-STS CMCM score decreased from 7 to 3 24 hours after administration of intranasal racemic ketamine. This score dropped to 2 on day 8; subject 1 remained at level 2 on day 9, while subject 2's score was zero on day 9. Consistent with previous results, both subjects showed rapid and clinically significant improvement. See fig. 20A-20B.

Subject 1's S-STS CMCM Risk of Suicide Over the Next 7 Days (range 1-10) decreased from 5 to 2 24 hours after administration of intranasal racemic ketamine. Subject 2's S-STS CMCM Risk of Suicide Over the Next 7 Days score decreased from a baseline score of 7 to 1 24 hours after administration of intranasal racemic ketamine. Scores remained at 1 on day 4 and further decreased to 0 on day 8. Consistent with previous results, both subjects showed rapid and clinically significant improvement. See fig. 21A-21B.

Subject 1's C-SSRS score (yes or no) of suicidal ideation improved from baseline yes to no 24 hours after administration of intranasal racemic ketamine, and Subject 2's CSSRS score of suicidal ideation improved from baseline yes to no 24 hours after administration of intranasal racemic ketamine. C-SSRS scores for suicidal ideation and suicidal behavior for both subjects remained unavailable for the remainder of the study. See fig. 24.

The CADSS measures dissociation, a well-known adverse event with ketamine. Indeed, the label for Spravato® (intranasal (b)-ketamine) contains a black box warning about the risk of dissociation, for which patients should be monitored for at least 2 hours after dosing. The label also states that in approximately 61-69% of patients administered (b)-ketamine. developed dissociative changes as assessed by CADSS (at doses of 56 or 84 mg).

In contrast, intranasal racemic ketamine surprisingly provides less dissociation, as shown in FIG. 23. Subject 1 never had a CADSS score greater than zero (no dissociation), and subject 2 had a score of 2 40 minutes after administration of intranasal racemic ketamine, which does not meet the clinical threshold for dissociation (score >4). Subject 2 received a CADSS score of zero 1 hour after administration. Thus, no clinically significant dissociation was observed in any of the subjects.

The MOAA/S score is a measure of a patient's sedation. Intranasal (I)-ketamine also carries a black box warning about the risk of sedation (patients should be monitored for at least 2 hours after dosing) as 48-61% of subjects developed sedation at the 56 or 84 mg dose. Before dosing, subject 1 had a MOAA/S score of 5, which decreased to 4 15 minutes after administration of intranasal racemic ketamine, but was 5 after 30 minutes. Subject 2 remained at MOAA/S score level 5 throughout the study. Thus, in contrast to intranasal β)-ketamine, subjects administered intranasal racemic ketamine unexpectedly exhibited little or no sedation at doses sufficient to provide rapid and clinically significant treatment. See fig. 22.

Preliminary data indicate that intranasal racemic ketamine provides rapid, significant, and sustained improvement in depression and suicidality without significant sedation or dissociation. There is no loss of effect at Day 16 (i.e., sustained effect) and no change in the safety or tolerability of intranasal racemic ketamine.

The contents of each of the references cited herein are incorporated herein by reference in their entirety.

Several embodiments of the present invention have been described. However, it should be understood that various modifications may be made without departing from the spirit and scope of

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Claims (14)

of the present invention. Accordingly, other embodiments are included within the scope of the following claims. CLAIM 1. A method of treating suicidal tendencies in a subject in need thereof, characterized in that said method involves intranasally administering to said subject 30 to 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein racemic ketamine is administered once daily, once every two days, three times a week, twice a week or once a week. 2. A method of treating suicidal ideation in a subject in need thereof, characterized in that said method comprises intranasally administering to said subject 30 to 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein racemic ketamine is administered once daily, once every two days, three times a week, twice a week or once a week. 3. A method of treating major depressive disorder in a subject in need thereof, wherein said method comprises intranasally administering to said subject 30 to 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein the racemic ketamine is administered once daily, once per two days, three times a week, twice a week or once a week. 4. The method according to any one of claims 1 to 3, further comprising administering one or more additional therapies consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers and pramipexole. 5. The method according to any one of claims 1 to 4, characterized in that said subject has previously been administered one or more additional therapies consisting of typical antipsychotics, atypical antipsychotics, antidepressants, electroconvulsive therapy, transcranial magnetic stimulation, benzodiazepines, mood stabilizers and pramipexole ; and where said subject has not responded to said one or more therapies. 6. The method according to claim 4 or 5, characterized in that said typical antipsychotic is chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine , thioproperazine, trifluoperazine or zuclopenthixol. 7. The method according to claim 4 or 5, characterized in that said atypical antipsychotic is aripiprazole, risperidone, olanzapine, quetiapine, asenapine, paliperidone, ziprasidone or lurasidone. 8. The method according to claim 4 or 5, characterized in that said benzodiazepine is alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam. 9. The method according to claim 4 or 5, characterized in that said mood stabilizer is lithium, valproic acid, lamotrigine or carbamazepine. 10. The method according to claim 4 or 5, characterized in that said one or more additional types of therapy are electroconvulsive therapy or transcranial magnetic stimulation. 11. A method of reducing one or more side effects of ketamine in a subject in need thereof, wherein said method comprises intranasally administering to said subject 30 to 90 mg of racemic ketamine or a pharmaceutically acceptable salt thereof, wherein the racemic ketamine is administered once daily, once every two days, three times a week, twice a week or once a week. 12. The method according to claim 11, characterized in that said one or more side effects include cognitive impairment; movement disorder; dizziness, nausea, vomiting, sweating, increased blood pressure, ulcerative cystitis or interstitial cystitis, where the cognitive impairment, if present, includes one or more of the psychotomimetic effects, dizziness, dysgeusia, sedation, dissociation, euphoria, hearing changes, vision changes and hallucinations and where motor disturbances, if present, include tremors, balance problems or dystonic movements. 13. The method according to any one of claims 1-12, characterized in that said subject has previously been diagnosed with one or more of: suicidal tendencies; suicidal thoughts; major depressive disorder; treatment-resistant depression; wherein said treatment-resistant depression corresponds to stages I-V, and post-traumatic stress disorder. 14. The method according to any one of claims 1 to 13, characterized in that said subject currently suffers from one or more of: suicidal tendencies, suicidal ideation, major depression -