Treatment methods for depression

Abstract

This invention provides a method for treating depression in human patients who require treatment for depression. [Solution] A method for treating depression, comprising administering approximately 56 mg or approximately 84 mg of esketamine intranasally for each induction treatment session, wherein the induction treatment sessions are performed twice a week during the induction period, and prior to each treatment session, the patient has a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg, and after at least the first two treatment sessions, the patient is monitored for adverse events for at least 90 minutes after each treatment session, wherein if the patient does not experience any severe adverse events and does not experience any of the specified adverse events after any two consecutive treatment sessions, the patient becomes eligible for a post-treatment session monitoring period of less than 90 minutes in the next treatment session.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 031,346, filed on May 28, 2020, the disclosure of which is incorporated herein by reference.

[0002] (Field of the Invention) The present invention relates to a method for treating depression.

Background Art

[0003] The skillful use of drugs in psychiatry requires a balance between effectively treating the underlying symptoms and minimizing adverse events (AE). Achieving a risk - benefit balance is typically done in collaboration with the patient, where the clinician provides knowledge of the typical profile of the drug, and the patient provides their individual experience of the positive and unwanted effects of the drug. (adverse event, AE) All patients are not equally likely to be affected by each possible AE that may occur with treatment. However, in many cases, the average incidence rates listed on the drug's product label are the only guidance available to the clinician. Furthermore, these rates do not dynamically adapt to how well a patient tolerates a repeatedly administered drug, and such adaptability is an essential aspect of individualizing the drug for each patient. Therefore, useful additional items to the summary - level information provided in the product label are data that inform the clinician of how the drug's AE profile changes over time and the degree of a patient's tolerance early in the treatment process.

[0004] ​​​​​​​​​​This provides insights into how adverse events (AEs) may appear as treatment progresses. do.

[0005] Esketamine (ESK) is a non-competitive N-methyl-D-aspartate ( It is an N-methyl-D-aspartate (NMDA) receptor antagonist and is approved orally by the Food and Drug Administration. In combination with antidepressants (oral antidepressants, OADs), treatment-resistant major depressive disorder (TRE) Approved for the treatment of adults with palsy-resistant major depressive disorder (TRD). In this field, therapeutic programs for patients who respond well to esketamine during treatment are being developed. Rotor adjustment is necessary. [Overview of the project] [Means for solving the problem]

[0006] In some embodiments, this disclosure relates to the treatment of depression in human patients who require treatment for depression. The subject is a method for treating illness, and the method consists of an introduction phase and treatment sessions, with the introduction phase being 4 The treatment has a duration of one week. Prior to each treatment session, the patient's blood pressure was below 140 mmHg. The patient has a systolic blood pressure of full and a diastolic blood pressure of less than 110 mmHg. The method is an induction treatment set. Administer approximately 56 mg or 84 mg of esketamine intranasally to the patient. The introductory treatment sessions, including the initial treatment, are conducted twice a week during the introductory period. After the two treatment sessions, the patient will be monitored for adverse events for at least 90 minutes. The patient experienced a severe adverse event after either of two consecutive treatment sessions. Without, and with a clinically meaningful increase in blood pressure, a clinically meaningful increase in heart rate, moderate Dissociation of a level greater than or equal to moderate to severe disorientation, moderate to severe sedation, moderate Severe or greater levels of dizziness, moderate or greater levels of nausea without vomiting, and / or moderate If the patient does not experience any degree of rotational vertigo, the next treatment session will be In this context, patients who qualify for a post-treatment session monitoring period of less than 90 minutes are eligible. In this context, depression is defined as major depressive disorder, major depressive disorder with suicidal ideation, or treatment-resistant depression. It is a type of depression. For example, the method is to treat severe major depressive disorder when emergency symptom management is needed. It is suitable for treatment.

[0007] The method involves patients who do not currently have poorly controlled hypertension, and who require sedation or an increase in blood pressure. Applicable to patients who are not taking any medications or substances, and / or patients under 65 years of age. .

[0008] In other embodiments, the method involves administering approximately 56 mg or approximately 84 mg per maintenance treatment session. The subsequent maintenance phase further includes intranasal administration of esketamine to the patient, and the maintenance phase Treatment sessions are conducted once a week during the first four weeks of the maintenance phase, and then once a week thereafter. This will be adjusted to once every two weeks. [Brief explanation of the drawing]

[0009] [Figure 1] This is a schematic diagram of the patient included in Example 2. [Figure 2A] This line graph shows the percentage of esketamine treatment participants experiencing adverse events, based on the incidence of dissociation reported by clinicians at weeks 1 and 4. [Figure 2B] This line graph shows the percentage of participants in esketamine treatment who experienced adverse events, based on the incidence of sedation reported by clinicians at weeks 1 and 4. [Figure 2C] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for the reported increase in blood pressure by clinicians. [Figure 3A] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for dissociation based on CADSS. [Figure 3B] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for MOASS-based sedation. [Figure 3C] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for the increase in blood pressure based on measurement. [Figure 3D] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for dizziness reported by clinicians. [Figure 3E] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for nausea reported by clinicians. [Figure 3F] A line graph showing the percentage of esketamine treatment participants with adverse events based on the incidence frequencies at week 1 and week 4 for rotary dizziness reported by clinicians. [Figure 4A] A line graph showing the percentage of esketamine treatment patients with adverse events based on the esketamine nasal spray dosage for dissociation reported by clinicians. [Figure 4B] A line graph showing the percentage of esketamine treatment patients with adverse events based on the esketamine nasal spray dosage for sedation reported by clinicians. [Figure 4C] A line graph showing the percentage of esketamine treatment patients with adverse events based on the esketamine nasal spray dosage for the reported increase in blood pressure by clinicians. [Figure 4D] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the dose of esketamine nasal spray, for dizziness reported by clinicians. [Figure 4E] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the dose of esketamine nasal spray, based on nausea reported by clinicians. [Figure 4F] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the dose of esketamine nasal spray, for rotational vertigo reported by clinicians. [Figure 4G] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on CADSS-based dissociation and esketamine nasal spray dose. [Figure 4H] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the esketamine nasal spray dose, for MOASS-based sedation. [Figure 4I] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the measured increase in blood pressure, according to the esketamine nasal spray dose. [Modes for carrying out the invention]

[0010] In one aspect of the present invention, appropriate precautions for dealing with patients at risk of rare side effects. The location has been disclosed, and a shorter post-treatment session (after administration) for eligible patients has been disclosed. The monitoring period will be disclosed. By monitoring and releasing patients for shorter periods, time and Resources are saved. Part of developing esketamine dosage instructions is that for that class of patients There are certain patient populations that may require special precautions for certain individuals. The objective is to understand the onset of possible side effects. Therefore, the methods discussed herein The clinician is concerned about the possibility of certain adverse events recurring during future ESK treatment sessions. It facilitates communication between the doctor and the patient, thereby promoting treatment compliance and for the patient Determine the treatment that is most likely to be accepted. This method will also be used in future administration sessions. To formulate a clinician's thinking about the strategies most relevant to the management of a given patient in a given situation. It is useful. By doing so, patient treatment can be personalized.

[0011] Frequency of AEs occurring in patients during the first two treatment sessions (e.g., the first week of treatment) Studies have shown that the higher the severity, the higher the percentage of patients who experience relapse. An AE pattern was observed in week 4, and the pattern in week 4 is more predictive of subsequent AEs. For example, the percentage of dissociation reported by clinicians between weeks 2 and 4 for the entire patient population. The figure was 16.1%, compared to 86.5% in patients who reported two dissociations in the first week. (64 out of 74 patients), 48.2% (out of 85 patients) reported one dissociation in the first week. Among 41 patients, 5.6% (out of 790) reported dissociation during the first week. There were 4 people. For all AEs reported by the surveyed clinicians, at least 78% Patients were associated with the category with the lowest recurrence rate, i.e., no adverse events were reported in week 1. They had been doing so. After long-term drug administration (e.g., 4 weeks, 8 weeks, or 12 weeks), all serious complications The severity of AEs also decreases. Therefore, based on the data that has been accumulated regarding AEs, It is possible to stratify patients based on the various frequencies of AE recurrence. The key meaning is to use patient stratification linked to knowledge of AE incidence data to identify patients. Patients can be stratified into various groups, and eligible patients with a low frequency of adverse events will be evaluated for relief by a physician. This means that a shorter monitoring period for AEs (Expertise Acquisitions) should be requested before taking the test.

[0012] The methods described herein are for treating depression (i.e., major depressive disorder). Major depressive disorder (MDD), treatment-resistant depression (TRD), major depressive disorder with suicidal ideation (major Depressive disorder with suicidal ideation (MDSI), or severe major depressive disorder This focuses on the treatment of human patients with disabilities who require medical treatment. The method is preferably a special method. Certain patients, i.e., eligible patients, can have a shorter post-treatment session (post-administration) monitoring period. In some cases, patients who are not eligible or those established as a conventional monitoring period (or as indicated on the conventional product label) It enables the ability to leave the treatment facility earlier than the period during which it might have been necessary. Typically, Such patients are considered clinically stable based on clinical judgment.

[0013] When used herein, unless otherwise specified, the terms “subject” and “patient” are used in a manner that is not limited to the subject. Refers to a human being who has been the subject of treatment, observation, or experimentation. Preferably, the patient is one who should be treated, and / or experiencing and / or showing at least one symptom of a disease or disorder that should be prevented In some embodiments, the patient is an adult. When used herein, "adult" refers to an adult. The term “person” as used herein refers to a person who is under approximately 65 years of age. Morphologically, the term "adult" refers to human patients who are between 18 and approximately 64 years of age. When used, the term "elderly person" refers to someone over 65 years of age.

[0014] As used herein, the term “depression” (also known as depressive disorder) is used with the great Depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, Situational depression, anhedonia, melancholy, middle-age depression, late-life depression, and identifiable stressors This includes depression, treatment-resistant depression, or a combination thereof. In certain embodiments, Depression is major depressive disorder. In other embodiments, major depressive disorder is characterized by melancholy. Or it is accompanied by distress due to anxiety. In a further embodiment, the depression is treatment-resistant depression. In some embodiments, depression is major depressive disorder accompanied by suicidal ideation.

[0015] As is known in the art, patients have five or six changes from their previous function. One or more of the following symptoms are present during the same two-week period, along with a depressed mood and / or loss of interest / pleasure. If it is necessary to have symptoms that are clearly attributable to another physical illness, the patient may have major depressive disorder. It is believed that the person has a disability. 1. Depressed mood: almost all day, almost every day, subjective (e.g., sadness, emptiness, (feeling despair), or being observable by others (for example, appearing to be crying) ), children and adolescents may experience irritability. 2. Loss of interest / pleasure: almost all day, almost every day, all (or almost all) A significant decrease in interest / pleasure in the activity, which can be observed by the individual or others. 3. Weight loss or gain: Significant weight loss (without dietary changes) or weight gain (5% in one month) Significant weight changes, or a decrease or increase in appetite on a nearly daily basis, or in children, as expected. There is a possibility that you will not gain weight. 4. Insomnia or excessive sleep: almost every day 5. Psychomotor disturbances or stillness: Observable by others almost daily (simply primary) (Not just restless or slow in appearance) 6. Fatigue: or a decline in energy, almost daily. 7. Feelings of worthlessness or excessive / inappropriate guilt almost daily: Guilt is paranoid almost daily. It is possible, and not merely self-reproach or guilt about being ill. 8. Decreased concentration: You may experience difficulty making decisions almost every day, whether self-aware or observed by others. can 9. Thoughts of death / suicide, recurring thoughts about death (not just fear of death), special plans Repeated suicidal thoughts, suicide attempts, or specific plans for suicide

[0016] To be diagnosed with MDD, the following criteria must also be met: 1. The symptoms must be clinically significant, or impair social, occupational, or other important functions. It is causing problems in the region. 2. The episode is not caused by the physiological effects of a substance or another medical condition. 3. The episodes include schizoaffective disorder, schizophrenia, schizophrenia-like disorder, delusional disorder, or other identified and unidentified schizophrenia spectrum disorders and other psychotic disorders Not better explained by harm 4. No history of manic or hypomanic episodes.

[0017] Major depressive disorder can be classified as mild, moderate, or severe. In some embodiments, In other embodiments, MDD is mild. In other embodiments, MDD is moderate. Further embodiments Therefore, MDD is severe. When used herein, "mild MDD" is used when making a diagnosis. Even if there are symptoms that exceed what is necessary, they are usually not severe enough to cause distress. However, if it is manageable and the symptoms result in mild impairment of social or occupational functioning. This applies to patients. Mild MDD is defined as a single episode (DSM ICD-10F32). 0) or recurrent episodes (DSM ICD-10F33.0). "Moderate M "DD" refers to a condition between those designated as "mild" and those designated as "severe" in terms of symptoms. Applies to patients with a number, severity of symptoms, and / or functional impairment. Moderate MDD is, A single episode (DSM ICD-10F32.1) or recurrent episodes (DSM It may be ICD-10F33.1). "Severe MDD" is a diagnosis made based on the number of symptoms. It is applied to far more patients than necessary, and the severity of the symptoms is severe and painful. This significantly impairs social and occupational functioning and requires emergency symptom management. Several implementation methods In this context, severe MDD is defined as a single episode (DSM ICD-10F32.2) or recurrent episodes. This could be a sexual episode (DSM ICD-10F33.2).

[0018] As used herein, the term “episode of major depressive disorder” means that a patient experiences a major depressive disorder. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition Disorders, 5 th Meeting the criteria for major depression as defined in Edition: DSM-5) This refers to a continuous period (e.g., approximately two or three weeks or longer) in which symptoms of depressive disorder are present. do.

[0019] When used herein, the terms “treatment-refractory or treatment-resistant depression” and the abbreviation “TRD” are used. "In the current depressive episode, at least two different antidepressants, preferably It is defined as major depressive disorder in patients who do not respond adequately to 2 to 5 types of antidepressants. Such patients shall be considered to have severe depression or episodes of severe depression. It may require emergency treatment. In other embodiments, TRD is present in the current depressive episode. In patients who have not responded to at least two oral antidepressants at appropriate doses and durations, It is defined as major depressive disorder.

[0020] As used herein, “suicide” means “the act of taking one’s own life.” / en.wikipedia.org / wiki / Suicide - cite_no See te-7. Suicide includes attempted suicide or non-lethal suicidal behavior, and this is one's own It is self-inflicted injury accompanied by a desire to end one's life, but does not result in death. A suicide attempt is a series of actions that begin at the start of the process. A series of self-initiated actions by individuals that are expected to lead to their own death. It is Kens.

[0021] As used herein, "suicidal ideation" refers to thoughts about suicide or an abnormality related to suicide. An obsession, or thoughts of ending one's own life, or a desire to no longer live, but not necessarily to commit suicide. It refers to thoughts that do not involve any active attempts to achieve them. The scope of suicidal ideation is transient. From simple things to chronic and detailed planning, role-playing, and progress to failed attempts These are diverse and can be intentionally constructed to fail or be discovered. or may be fully intended to cause death. In some embodiments, the patient suffers When a person has an average baseline MADRS total score of approximately 38 or higher, they are considered to have "suicidal tendencies." It is classified as such. In other embodiments, the patient has an average baseline of 22 or more. When a person has a BBSS score, they are classified as having suicidal tendencies. In a further embodiment, The patient has a score of 6 or higher on the SIBAT clinical global assessment for suicide risk. At that time, they are classified as having suicidal tendencies. In further embodiments, patients are classified as having suicidal tendencies. Having one or more combinations of A. "Suicidal ideation accompanied by intent" is described in this document. The scales / tools disclosed in the book can be considered and confirmed through questions to the patient, and the results One's own wounds, accompanied by at least some degree of intention or awareness that they may result in death. Thoughts about harm, pain, or injury (even if only for a moment); or thoughts about suicide (that is, The act of killing oneself, and the intention to act in accordance with the thought of killing oneself. (including the fact that there is such a thing.)

[0022] Prior to any treatment session described herein, for safety reasons, the patient should take approximately 1 Systolic blood pressure less than 40 mmHg and less than approximately 110 mmHg, preferably about 100 mmHg. The diastolic blood pressure should be less than, more preferably about 90 mmHg or less. In this embodiment, if the systolic blood pressure is considered normal, the patient has a blood pressure of approximately 140 mmHg and approximately 13 8mmHg, approx. 135mmHg, 130mmHg, 125mmHg, 120mmHg, 1 Systolic pressure of 15 mmHg, 100 mmHg, 110 mmHg, 90 mmHg, or lower. The patient has blood pressure. In a further embodiment, the systolic blood pressure is about 90 to about 135, and about 90 to about 13 0, approximately 90-120, approximately 90-110, approximately 90-100, approximately 100-135, approximately 100-130, 100-120, 100-110, 110-135, approx. 110-approximately 130, approximately 110-approximately 120, approximately 120-approximately 135, or approximately 130-approximately 135 It is mmHg. In other embodiments, the patient's diastolic blood pressure is less than approximately 110 mmHg. In other embodiments, if diastolic blood pressure is considered normal, the patient's diastolic blood pressure is approximately 11 It is 0, 100, 105, 100, 90, 80, 70, 60, or less than 50. In this embodiment, the patient's diastolic blood pressure is approximately 50-110, approximately 50-100, and approximately 50- Approximately 90, approximately 50-80, approximately 50-70, approximately 50-60, approximately 60-110, approximately 60 ~100, 60~90, 60~80, 60~70, 70~110, approx 70-100, 70-90, 70-80, 80-110, 80-10 The blood pressure is 0, approximately 80-90, approximately 90-110, or approximately 90-100 mmHg. If you do not have a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg, The treatment session should be rescheduled.

[0023] Preferably, the patient has currently uncontrolled hypertension before or after administration of esketamine. No. When used herein, the terms "hypertension" and "high blood pressure" are interchangeable. This is stage 2 hypertension, meaning having a systolic pressure of approximately 140 mmHg or higher. It refers to a patient. Typically, "poorly managed" hypertension involves the use of medication and exercise. This involves forming a group, following a special diet, limiting alcohol, and losing weight. And, by eliminating smoking or other factors known to contribute to high blood pressure, This is understood to mean that systolic blood pressure cannot be lowered to below approximately 140 mmHg. In some embodiments, hypertension is associated with cardiovascular complications, endocrine complications, or the like. It is related to the combination.

[0024] Before being eligible for a shortened post-treatment session monitoring period, the patient or several practitioners In this context, the caregiver gives consent to the methods described herein, i.e., informed consent. To provide this, patients can be assured that even if there are any possible adverse events, The meaning of the treatment method is recognized. In some embodiments, informed consent The document is documented, i.e., one or more guidelines regarding the disclosed method. This includes creating a consent form. In other embodiments, informed consent is, This includes verbal consent to one or more guidelines relating to the methods described herein. Generally, patients are aware of the potential risks associated with monitoring for less than two hours. If the patient is aware of the potential risks and is deemed eligible, the administration of esketamine and I agree to proceed to monitoring for less than two hours. In some cases, the patient will be in a treatment session. If the patient is unwell or has any other related health problems after the follow-up monitoring period, In that case, you agree to follow the instructions provided by the clinician. In other cases, the caregiver Alternatively, if the responsible adult has completed the treatment session, the post-treatment monitoring period will end. After that, and until an agreed-upon follow-up evaluation, i.e., a phone call with the clinician, is made. Preferably, at least two hours after the end of the treatment session, or at the latest, during the day, the patient and I agree to stay together. In further circumstances, the clinician may determine the care of the patient and the adult caregiver / responsibility In case an adult requires medical intervention after leaving the clinic, the healthcare provider Provide instructions to the patient and caregiver or responsible adult based on the process and procedures. In this configuration, if a patient requires medical intervention, the patient will follow the instructions provided by the clinician. I agree to abide by this rule.

[0025] However, the attending physician considered the possibility of concomitant medications in patients taking esketamine. Use clinical judgment when deciding whether to prescribe certain concomitant medications due to certain effects. In some cases, certain concomitant / contraindicated medications, opioids, and alcohol may be contraindicated in eligible patients. It can cause adverse effects such as sedation, which may affect the patient's ability to become or maintain that ability. Therefore, the administration of such concomitant / contraindicated drugs, opioids, and alcohol should be restricted, Minimizing or eliminating makes a patient eligible for the treatment method described herein and the patient It helps to maintain eligibility. In some embodiments, the concomitant medication is used for dizziness, It may promote sedation, i.e., a sedative effect, or an increase in blood pressure. In other embodiments, as a concomitant agent For example, central nervous system depressants (e.g., benzodiazepines, opioids, alcohol), psychotropic drugs. Stimulants (e.g., amphetamine, methylphenidate, modaphanil, almodafinil) ), and monoamine oxidase inhibitors (MAOIs) Examples of harmful substances include, but are not limited to, diazepam. Zetran, Prosom (Pro), Quazepam (Dora) l(Pro)), alprazolam (Niravam(Pro)), diazepam (Diaz epam Intensol), alprazolam Intens ol(Pro)), chlorazepic acid (Tranxene), alprazolam (Xanax XR(Pro)), clonazepam (KlonopinWafer), chlordiazepoxy (Librium(Pro)), Oxazepam (Serax), Alprazolam (Xa nax(Pro)), Lorazepam (Lorazepam Intensol(Pro)) , Flurazepam (Dalmane), Clonazepam (Klonopin(Pro)), Azepam (Valium(Pro)), Triazolam (Halcion(Pro)), Ro Lazepam (Ativan(Pro)), Chlorazepate (Tranxene T-Tab( (Pro)), Temazepam (Restoril(Pro)), Chlorazepate (Tranxe ne SD), Midazolam (Versed), Midazolam (Nayzilam (Pro) Examples include ), and midazolam (Seizalam).

[0026] The terms “adverse event,” “side effect,” and “AE” are used interchangeably in this specification. Adverse events are used and refer to undesirable medical occurrences. It is any undesirable and unintended sign, symptom, or disease. Several implementations In this case, the adverse events are not related to the methods described herein. In other embodiments, adverse events The events are related to the methods described herein. Adverse events include new onset or baseline abnormalities. Any occurrence of worsening severity or frequency from the initial condition, or abnormalities in clinical tests. This includes abnormal results from diagnostic procedures. In some embodiments, adverse events include tachycardia, etc. This is cardiac dysfunction. In other embodiments, adverse events include ear and inner ear disorders such as vertigo. It is harmful. In further embodiments, the adverse events include constipation, diarrhea, dry mouth, nausea, or vomiting. Or gastrointestinal disorders such as a combination thereof. In yet another embodiment, the adverse event is different This refers to common disturbances / conditions at the administration site, such as a normal sensation, intoxication, or a combination thereof. In further embodiments, the adverse event is an increase in blood pressure. The adverse event is a clinically significant increase in heart rate. In other embodiments, the adverse event is effusion. Dizziness, dysarthria, dysgeusia, headache, hypoesthesia, lethargy, mental disorders, sedation, or tremors. These are neurological disorders such as warts or combinations thereof. In further embodiments, the adverse events are It is a mental disorder characterized by anxiety, dissociation, euphoria, insomnia, or a combination thereof. In this embodiment, adverse events include renal impairment such as frequent urination and urinary tract disorders. Further embodiments In this state, adverse events include nasal discomfort, oropharyngeal pain, pharyngeal irritation, or a combination thereof. These include respiratory, thoracic, and mediastinal disorders. In other embodiments, adverse events include skin problems such as excessive sweating. The adverse event is skin and subcutaneous tissue damage. In a further embodiment, the adverse event is disorientation.

[0027] Anxiety can manifest as agitation, anticipatory anxiety, fear, nervousness, irritability, nervousness, and panic attacks. This includes tension, or a combination thereof. In some embodiments, the adverse event is dynamic It is shaking. In other embodiments, the adverse event is anticipatory anxiety. In further embodiments, the adverse The event is typical anxiety. In other embodiments, the adverse event is nervousness. In further embodiments, the adverse event is fear. In other embodiments, anxiety is irritability. Yes. In further embodiments, the adverse event is nervousness. In yet another embodiment, the adverse event An elephant is a panic attack. In a further embodiment, anxiety is tension.

[0028] "Increased blood pressure" or variations thereof include increased diastolic blood pressure, increased total blood pressure, and increased systolic blood pressure. In addition, hypertension, or a combination thereof, may occur. In some embodiments, adverse events In a further embodiment, the adverse event is an increase in diastolic blood pressure. In other embodiments, the adverse event is an increase in systolic blood pressure. In further embodiments, The adverse event is hypertension.

[0029] Disorientation can manifest in particular as a result of medication, affecting time, place, or identity. This includes transient states of confusion. A person skilled in the art can identify a patient's disorientation. It will be possible.

[0030] Dissociation, that is, a sensation detached from space and / or time, includes delusional perception, depersonalization, and Derealization disorder, loss of sense of reality, double vision, paresthesia, coldness, heat, sensation of changes in body temperature, hallucinations, hearing Awareness hallucinations, visual hallucinations, auditory hypersensitivity, illusions, eye discomfort, oral sensory abnormalities, paresthesia, oral paresthesia Senses, pharyngeal paresthesia, photophobia, altered time perception, tinnitus, blurred vision, visual impairment, or a combination thereof. Combinations are included. In some embodiments, the adverse event is delusional perception. Other implementations Morphologically, the adverse event is depersonalization / derealization disorder. In a further embodiment, the adverse event In other embodiments, the adverse event is a loss of sense of reality. In yet another embodiment, the adverse event is double vision. In this embodiment, the adverse event is dissociation. In a further embodiment, the adverse event is paresthesia. In other embodiments, the adverse event is a feeling of coldness. In further embodiments, the adverse event is , a feeling of heat. In another embodiment, the adverse event is the sensation of a change in body temperature. In one embodiment, the adverse event is a hallucination. In another embodiment, the adverse event is an auditory hallucination. Yes. In further embodiments, the adverse event is visual hallucination. In yet another embodiment, The adverse event is hyperacusis. In further embodiments, the adverse event is an illusion. In one embodiment, the adverse event is eye discomfort. In a further embodiment, the adverse event is oral discomfort. It is a sensory abnormality. In other embodiments, the adverse event is paresthesia. Further embodiments In this case, the adverse event is oral paresthesia. In a further embodiment, the adverse event is pharyngeal paresthesia. In other embodiments, the adverse event is photophobia. In further embodiments, the adverse event This is a change in time perception. In other embodiments, the adverse event is tinnitus. In one embodiment, the adverse event is blurred vision. In a further embodiment, the adverse event is , he has a visual impairment.

[0031] Dizziness can be classified into several types: dizziness, exertional dizziness, postural dizziness, and This includes static floating dizziness, or a combination thereof. In some embodiments, The adverse event is dizziness. In other embodiments, the adverse event is exertional dizziness. In further embodiments, the adverse event is postural dizziness. Morphologically, the adverse event is treatment-induced dizziness.

[0032] Articulation disorders include articulation disorders, language development delays, speech disorders, or combinations thereof. In some embodiments, the adverse event is dysarthria. In further embodiments, the adverse event is In one embodiment, the adverse event is language development delay. In another embodiment, the adverse event is speech disorder.

[0033] Taste disorders include taste disorders or taste dullness. In some embodiments, adverse events One adverse event is a taste disorder. In a further embodiment, the adverse event is taste dulling.

[0034] Headaches include sinus headaches, or general headaches that are not necessarily related to the sinuses. In some embodiments, the adverse event is headache. In other embodiments, the adverse event is It is a sinus headache.

[0035] "Increased heart rate" or variations thereof refers to beats per minute (bpm). This includes the increase in heart rate when measured using [the appropriate method].

[0036] Sensory impairment includes generalized hypoesthesia, oral hypoesthesia, dental hypoesthesia, or pharyngeal hypoesthesia. In some embodiments, the adverse event is sensory impairment. In other embodiments, the adverse event In a further embodiment, the adverse event is oral numbness. In a further embodiment, the adverse event is tooth numbness. In another embodiment, this is pharyngeal numbness.

[0037] Lethargy includes fatigue or lethargy. In some embodiments, the adverse event is fatigue. In other embodiments, the adverse event is lethargy.

[0038] Nasal discomfort includes nasal scabs, nasal discomfort, nasal dryness, or nasal itchiness, or a combination of these. Combinations are included. In some embodiments, the adverse event is nasal crusting. Other embodiments In one embodiment, the adverse event is nasal discomfort. In a further embodiment, the adverse event is nasal dryness. It is dry. In yet another embodiment, the adverse event is nasal itching.

[0039] Nausea includes the sensation of an urge to vomit. Nausea can last for a short period of time, and / or Nausea can be acute or systemic. Other symptoms may include diarrhea, gas, and constipation. This may be accompanied by nausea. In some embodiments, nausea may be mild, moderate, or severe. In this embodiment, nausea is not accompanied by vomiting. A person skilled in the art would know whether the patient has nausea or not. It should be possible to identify it.

[0040] Sedation, i.e., drowsiness, includes altered states of consciousness, hypersomnia, sedation, or somnolence, or a combination of these. Combinations are included. In some embodiments, the adverse event is an altered state of consciousness. In one embodiment, the adverse event is hypersomnia. In another embodiment, the adverse event is sedation. In further embodiments, the adverse event is somnolence.

[0041] Tachycardia includes premature contractions, increased heart rate, or tachycardia. In some embodiments, The adverse event is premature contractions. In other embodiments, the adverse event is an increase in heart rate. In one embodiment, the adverse event is tachycardia.

[0042] Rotational vertigo includes rotational vertigo or postural rotational vertigo. In one embodiment, the adverse event is rotational vertigo. In another embodiment, the adverse event is postural vertigo. This is rotational vertigo.

[0043] When used in this specification, "serious adverse event," "serious side effect," and "SAE" are used interchangeably. The terms are interchangeable, and the ICH and EU guidelines regarding the monitoring of pharmacovigilance for human use Idline (ICH and EU Guidelines on Pharmacovigilance for Medicinal Products) Defined based on (Human Use). Serious adverse events can occur regardless of dose. Those skilled in the art will understand that serious adverse events are medically significant. In some embodiments, a serious adverse event is a fatal adverse event. In other embodiments, A serious adverse event is life-threatening, for example, if the subject is at the time of the serious adverse event. This includes cases where there is a risk of death. In a further embodiment, a serious adverse event may result in hospitalization. The patient requires hospitalization or extension of the current hospitalization. In further embodiments, a serious adverse event may occur. , resulting in permanent or severe physical disability or incapacity. In further embodiments, severe physical disability Adverse events are congenital abnormalities / congenital defects. In other embodiments, serious adverse events are drug-induced. It is a suspected transmission of some infectious agent through the product. In further embodiments, it is a serious harmful The event is fainting. In another embodiment, the adverse event is a feeling of spinning. In terms of administration methods, serious adverse events are a concern.

[0044] The method comprises a 4-week introductory phase and treatment sessions. When used herein, the term "introductory" is used. The "initiation period" is the period during which esketamine is first administered to the patient. In some embodiments, The introductory phase is long enough to achieve a robust and stable reduction in depressive symptoms. Suicidal thoughts Specific conditions such as MDD with concern, severe MDD, or severe MDD requiring emergency symptom management. Regarding the response to symptoms, the treatment method consists of an induction phase, meaning that the maintenance phase is not included.

[0045] During the induction period, patients receive approximately 56 mg or approximately 84 mg per induction treatment session. Administer mg of esketamine at least twice a week for 4 weeks. Administered during the induction phase. The amount of esketamine administered may be determined by the attending physician. In some embodiments, The effective dose of esketamine administered during the induction period is approximately 56 mg. In other embodiments, The effective dose of esketamine administered during the admission period is approximately 84 mg.

[0046] As discussed below, the nasal spray device, in certain embodiments, delivers a total of 28 mg of esketami. This is a single-use device that delivers the drug with two sprays (one spray per nostril). The device is medical It may be operated by the patient under the supervision of a medical professional or healthcare provider. Regarding dosage, 1 One device may be used for a 28 mg dose, or two devices may be used for a 56 mg dose. Often, or three devices may be used for an 84 mg dose. Therefore, as used herein When referring to a "treatment session," the term refers to the prescribed dosage of esketamine (for example). This refers to the duration of administration of 56 or 84 mg. Applicable to treatment sessions. In such cases, an introductory treatment session and a maintenance treatment session are included. Furthermore, the use of each device... It is preferable to have a 5-minute interval between them. Typically, time 0 is from the first intranasal device. This is defined as the time of the first intranasal spray administration into the nostril of the person. During the treatment session, the finger A fixed dose of esketamine is administered. For example, treatment with 56 mg of esketamine. A session may include two sprays from the first device and two sprays from the second device. As another example, a treatment session involving 84 mg of esketamine was administered from the first device. Two sprays from the first device (one spray into each nostril), two sprays from the second device (one spray into each nostril) This may include a spray from the first device, and two sprays from the third device (one spray into each nostril). For example, if the device does not function properly, the required dosage or amount of esketamine may not be administered. If additional equipment is needed for treatment, more equipment may be used as needed. The spray typically begins when the first spray is administered from the first device into one nostril. The treatment session ends when the last spray is administered into the nostril from the last device.

[0047] As used herein, the term "twice a week" means twice a week (7 days). This refers to the degree. For example, "twice a week" may refer to the administration of esketamine in this specification. In some embodiments, twice a week refers to the frequency of the first and second days of the week. In this embodiment, twice a week refers to the frequency of the first and third days of the week. In a further embodiment, twice a week "Times" refers to the frequency of being on the 1st and 4th days of the week. In yet another embodiment, "twice a week" refers to the frequency of being on the 1st and 4th days of the week. This refers to the frequency of occurrence on day 1 and day 5. "Day 1" refers to Sunday, Monday, Tuesday, Wednesday, It may be any day of the week, including Thursday, Friday, or Saturday. Typically, Regarding the administration of ketamine, twice a week refers to the frequency of administration on the 1st and 4th days of the week. As long as possible, take the dose as soon as possible thereafter, and continue the prescribed regimen thereafter. good.

[0048] As used herein, the term "once a week" means once a week (7 days). This refers to the degree. For example, "once a week" may refer to the administration of esketamine in this specification. In some embodiments, once a week refers to a frequency that occurs on the first day of the week. In other embodiments, once a week "Once" refers to a frequency of the second day of the week. In a further embodiment, "once a week" refers to the third day of the week. This refers to the frequency of occurrence. In further embodiments, once a week refers to the frequency of occurring on the fourth day of the week. In one embodiment, once a week refers to a frequency of the 5th day of the week. In another embodiment, once a week means This refers to a frequency that occurs on the 6th day of the week. In yet another embodiment, once a week refers to a frequency that occurs on the 7th day of the week. This refers to "Day 1," which is Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. It may be any day of the week, including [the specified day]. As long as there is an error in administration, report it as soon as possible thereafter. You may take the prescribed dose and then continue with the prescribed regimen.

[0049] At any stage during a treatment session, the patient's response to the treatment session is: This can be evaluated using the techniques described herein. This evaluation is for when the patient is ready to leave the testing area. It may be carried out until it is deemed by those skilled in the art that it has been done. Valuation may be performed before, during, or after each treatment session. Preferably, the patient's response is If the patient has experienced any adverse events, including serious adverse events, the number of such events will be determined. It is evaluated by [the following criteria]. If a patient experiences a serious adverse event, that patient will be considered an eligible patient. This is not the case. The patient must not have a treatment session for at least two consecutive treatment sessions. A severe adverse event is experienced after being monitored for at least 90 minutes (e.g., 2 hours) following the procedure. Without, and with a clinically meaningful increase in blood pressure, a clinically meaningful increase in heart rate, moderate Dissociation of a level greater than or equal to moderate to moderate sedation or disorientation, and / or moderate If the patient does not experience any of the above levels of nausea without vomiting, the patient is not a qualified patient. In other embodiments, eligible patients undergo at least two consecutive treatment sessions. After each treatment session, severe symptoms are monitored for at least 90 minutes (e.g., 2 hours). No adverse events were experienced, and there was a clinically significant increase in blood pressure and a moderate to severe level of dissociation. , moderate to high levels of sedation, moderate to high levels of dizziness, and / or moderate to high levels of vertigo. This refers to individuals who do not experience any of the higher levels of rotational vertigo. In yet another embodiment, this refers to individuals who do not experience any of the higher levels of rotational vertigo. Eligible patients will receive a post-treatment check for at least two consecutive treatment sessions. If, after being monitored for at least 90 minutes (e.g., 2 hours), the patient does not experience a severe adverse event, Furthermore, a clinically significant increase in blood pressure, a clinically significant increase in heart rate, and a moderate or greater increase in heart rate. Those who have not experienced either a moderate level of dissociation or / or a moderate or higher level of sedation. ru.

[0050] Before being designated as an eligible patient, the patient should preferably undergo at least a 90-minute treatment session. The patient will be evaluated at regular intervals during the post-monitoring period. However, there is a possibility that the patient is experiencing distress. Evaluation can be performed as needed, including when there is a possibility of a problem. Preferably, the patient's blood pressure is Measured and observed in patients with dissociative symptoms, sedative symptoms, dizziness, nausea, and / or rotational symptoms. The symptoms are evaluated. In some embodiments, after the treatment session is completed, The evaluation is performed at intervals of at least approximately 5 minutes. In other embodiments, the patient is evaluated at approximately 5, 10, and 15 minutes. The evaluation is performed at intervals of approximately 20, 25, or 30 minutes. In a further embodiment, the patient is evaluated at approximately 5 ~30, 5~25, 5~20, 5~15, 5~10, 10~30 Approximately 10-25, approximately 10-20, approximately 10-15, approximately 15-30, approximately 15-25 intervals of approximately 15-10 minutes, 20-30 minutes, 20-25 minutes, or 25-30 minutes. The patient is evaluated. Preferably, the patient receives the dose at approximately 15-minute intervals. The evaluation is based on whether the patient is harmed. The process continues as long as the event is observed. In some embodiments, the evaluation is performed for at least about 90 minutes. In other embodiments, the evaluation is performed for approximately 90 to 180 minutes, approximately 90 to 170 minutes, and approximately 90 minutes. ~160, 90~150, 90~140, 90~130, 90~13 0, approximately 90-120, approximately 90-110, approximately 90-100, approximately 100-180, approximately 100-approx. 170, approx. 100-approx. 160, approx. 100-approx. 160, approx. 100-approx. 150, approx. 100-140, 100-130, 100-120, 100-110, approx. 110-approx. 180, approx. 110-approx. 170, approx. 110-approx. 160, approx. 110-approx. 150, approx. 110-approx. 140, approx. 110-approx. 130, approx. 110-approx. 120, approx. 120-approx. 180, approx. 120-approx. 170, approx. 120-approx. 160, approx. 120-approx. 150, approx. 120-approx. 140, approx. 120-approx. 130, approx. 130-approx. 180, approx. 130-approx. 170, approx. 130-approx. 160, approx. 130-approx. 150, approx. 130-approx. 140, approx. 140-approx. 180, approx. 140-approx. 170, approx. 140-160, 140-150, 150-180, 150-170, approx. 150-160, 160-180, 160-170, or 170-180 It is carried out for several minutes. Preferably, the evaluation is carried out for approximately 90 to 120 minutes. Continued during the monitoring period. In such cases, patients are usually released from the testing facility based on clinical judgment.

[0051] Furthermore, patients, without medical intervention during all treatment sessions and before becoming eligible patients, It is desirable to tolerate esketamine and related side effects / adverse events. Therefore, patients Those who received esketamine before becoming eligible patients do not require emergency treatment.

[0052] Once a patient is designated as an eligible patient, they will continue to be monitored even after the treatment session. However, post-treatment monitoring sessions are used before patient eligibility. The duration may be shorter compared to the treatment period. In some embodiments, eligible patients undergo treatment sessions. The patient is evaluated at regular intervals after the treatment session is completed. In some embodiments, the patient is evaluated after the treatment session is completed. Afterward, the patient is evaluated at intervals of at least approximately 5 minutes. In other embodiments, the patient is evaluated at approximately 5, approximately 10 The evaluation is performed at intervals of approximately 15, 20, 25, or 30 minutes. In further embodiments, the patient Approximately 5-30, approximately 5-25, approximately 5-20, approximately 5-15, approximately 5-10, approximately 10 ~30, 10~25, 10~20, 10~15, 15~30, 15 ~25, 15~10, 20~30, 20~25, or 25~30 minutes The evaluation is performed at intervals shorter than the period required before the patient was eligible. Continue. In some embodiments, the evaluation is carried out for less than approximately 90 minutes. In other embodiments... The ratings are approximately 30-90, 30-80, 30-70, and 30-60. Approximately 30-50, approximately 30-40, approximately 40-90, approximately 40-80, approximately 40-70, Approximately 40-60, approximately 40-50, approximately 40-45, approximately 50-90, approximately 50-80, Approximately 50-70, approximately 50-60, approximately 60-90, approximately 60-80, approximately 60-70, The program will be conducted for approximately 70-90 minutes, approximately 70-80 minutes, or approximately 80-90 minutes or less. Specific implementation format In this configuration, the appropriate post-treatment session monitoring period is at least 60 minutes. Further embodiments In other embodiments, the appropriate post-treatment monitoring period is approximately 60 to less than 90 minutes. The post-session monitoring period is approximately 60 minutes.

[0053] After the patient is deemed stable following the post-treatment session monitoring period, the patient will be esc. Patients are free to leave the clinic or medical facility where they were administered the drug. However, patients In order to discharge the patient, the patient must be monitored and / or contact a medical professional. And / or it should be required that a patient monitoring form be submitted. In one embodiment, If the post-treatment session monitoring period is less than two hours, the caregiver or responsible adult must monitor the patient. To accompany the person. Preferably, a caregiver or responsible adult shall be present during the patient's treatment sessions and Be present during one or both of the post-treatment session monitoring periods. Ensure the patient is safely transported from the clinic. In addition to guaranteeing that the caregiver or responsible adult will not be able to see an adult after leaving the clinic. It may assist patients in monitoring any adverse effects caused by ketamine.

[0054] As used herein, the term “caregiver” refers to a legal term relating to the care and welfare of a patient. This refers to an adult who is responsible for the care of a child. Therefore, a caregiver is a member of the family (e.g., parent, sibling, child). (etc.) or legal guardian. The term "responsible adult" means physically and mentally This refers to an adult who can support a patient but is not legally responsible for their care. In some embodiments, a caregiver or responsible adult is present during the treatment session. To be present during the post-session monitoring period, to leave the clinic (for example, at home or residence) (To assist the patient), to monitor the patient for a set period of time after leaving the clinic, Supporting patients through remote interaction with their attending physician, or any combination thereof. Preferably, a caregiver or responsible adult should clinically assess the patient before administering esketamine. Provide your personal information to the doctor (e.g., name, relationship, contact information).

[0055] If the post-treatment session monitoring period is less than 2 hours after leaving the clinic, the caregiver or scrutinizer Adults in charge of care will participate in one or more follow-up assessments conducted between the patient and the clinician. Participation allows for the assessment of the patient's clinical condition. When used in this specification, "Follow The term "up-up evaluation" refers to monitoring the patient's response to esketamine. This refers to the interaction between the patient and the clinician. During these follow-up evaluations, the clinician The patient's physical and mental condition is assessed. In some embodiments, the clinician treats How many and what kinds of adverse events did the patient experience after the post-session monitoring period? It is possible to determine the extent of the adverse events experienced by the patient. Preferably, the clinician will determine all adverse events experienced by the patient. To document. In certain embodiments, the clinician determines that the patient has experienced Document any events such as sedation, dissociation, and / or serious adverse events. Other implementations In this situation, the clinician will determine if the patient experiences new episodes of sedation and / or dissociation after the post-treatment monitoring period. Determine whether the patient experienced the symptoms. Certain adverse events considered important may be identified by the clinician. It is written down and documented (e.g., in the relevant monitoring form). Several embodiments Therefore, the caregiver or responsible adult should arrange for an optional follow-up assessment by a clinician. This is possible. In a further embodiment, the caregiver or responsible adult can communicate with the patient and the clinician. You may participate in the follow-up evaluation.

[0056] Ideally, the first follow-up evaluation should be conducted on the same day as the treatment session. In this embodiment, this involves the clinician and patient and the next treatment session using esketamine. This is the only follow-up evaluation performed between [the patient and the doctor]. However, if clinicians require further monitoring... If deemed necessary, further follow-up evaluations will be conducted. Several embodiments The follow-up evaluation is then performed hourly or daily. In certain embodiments, the follow-up evaluation is performed hourly or daily. The follow-up evaluation is conducted daily after the initial follow-up evaluation, for example, during the follow-up session. However, after the initial follow-up evaluation, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 It continues daily for 12, 13, 14 days or more, if clinically demonstrated. Those skilled in the art would know, after the initial follow-up evaluation, how often and how many follow-up evaluations should be conducted. It will be possible to determine whether a follow-up evaluation is required. In certain embodiments, follow - The follow-up session continues daily for one day after the initial follow-up evaluation. Other embodiments The follow-up sessions will continue daily for two days following the initial follow-up assessment. In a further embodiment, follow-up sessions are held every three days after the initial follow-up evaluation. It continues for several days. In yet another embodiment, the follow-up session is the same as the initial follow-up. The assessment is continued daily for four days after the initial assessment. In further embodiments, follow-up sessions are provided. This is continued daily for 5 days after the initial follow-up evaluation. In other embodiments, follow-up The sessions continue daily for 6 days after the initial follow-up assessment. In further embodiments, Follow-up sessions will continue daily for 7 days following the initial follow-up assessment.

[0057] Interaction between patient and clinician (optionally, with caregiver or responsible adult) (Both) can be performed using various technologies available to the patient and their physician. The assessment may be conducted to evaluate the patient, including monitoring the patient's physical health. In some embodiments, the interaction between the doctor and the patient is face-to-face, In other embodiments, the procedure is performed in a hospital where esketamine is administered. The interaction between them is remote, for example, via telephone (e.g., voice and / or video). This is done by means of. In a further embodiment, the interaction between the doctor and the patient is, in particular In some embodiments, this is done remotely using other electronic means such as video conferencing. The attending physician left the esketamine administration facility for at least approximately two hours on the same day, i.e. Contact with the patient will be made approximately two hours after the post-treatment session monitoring period.

[0058] To facilitate compliance and measure patient tolerance to esketamine, This includes measurable parameters such as heart rate and blood pressure, and especially recording of any significant adverse events. Furthermore, it is necessary to complete one or more forms in order to track the patient's health status. There may be cases where this is the case.

[0059] Administration may further include a maintenance phase following the induction phase. In the maintenance phase, the first four weeks of the maintenance phase, weekly Esketamine is administered once. The frequency of subsequent administrations will be determined by the attending physician. It can be adjusted (for example, based on tolerability). In some embodiments, the dosage The frequency is once a week, that is, only one treatment session per week. In other embodiments, The administration frequency is adjusted to once every two weeks. In some embodiments, the following is administered during the maintenance phase. In other embodiments, the amount of sketamine administered during the maintenance phase is approximately 56 mg. The effective dose of Min is approximately 84 mg. Typically, at the time of the post-treatment session monitoring period, Patients, for example, those typically in the maintenance phase of treatment, may only receive treatment sessions once a week. I am receiving treatment.

[0060] During the induction phase or maintenance phase, in any one or more stages, treatment The patient's response is evaluated using the techniques described herein. This evaluation is used to assess whether the patient has recovered. It may be carried out until a suitable response to the therapeutic regimen is deemed to have been achieved by those skilled in the art. In some embodiments, the evaluation is performed using techniques known to those skilled in the art and described herein. This includes determining the mental state of the patient. In other embodiments, the evaluation includes, among other things, heart rate, cardiac Assessment of the patient's physical condition, including but not limited to rhythm, vision, hearing, blood pressure, and respiration. This includes a fixed measurement. In some embodiments, blood pressure is measured at intervals of approximately 40 minutes.

[0061] Patients must meet at least the first two treatment sessions before becoming eligible patients. The monitoring period is 90 minutes. In some embodiments, the pre-qualification monitoring period is approximately 1 It is 20 minutes. In some embodiments, before becoming an eligible patient, the patient is about 2, about 3, about 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15 After approximately 16, 17, 18, 19, or 20 treatment sessions, i.e., approximately They are monitored for 1 to 10 weeks. In other embodiments, the patient undergoes approximately two treatments before becoming eligible. The patient is monitored for approximately one week during the treatment session. In a further embodiment, the patient is an eligible patient. Before this occurs, approximately four treatment sessions, i.e., monitoring for about two weeks, are performed. In other embodiments, Patients undergo approximately 8 treatment sessions, or about 4 weeks of monitoring, before becoming eligible patients. (i.e., the introductory phase). In a further embodiment, the patient undergoes approximately 8 treatments before becoming an eligible patient. Treatment sessions, i.e., monitoring for approximately 8 weeks (i.e., a 4-week introductory period). In this embodiment, the patient undergoes approximately 12 treatment sessions, i.e., before becoming an eligible patient. They will be monitored for approximately 6 weeks. In a further embodiment, the patient will be monitored approximately 16 times before becoming an eligible patient. The treatment sessions, which involve monitoring for approximately 8 weeks, are followed by treatment.

[0062] When evaluating a patient's physical condition, many physical parameters can be measured. In some embodiments, the attending physician may determine if adverse events caused by the treatment session occur. It is possible to determine whether or not an adverse event is present or present to a certain degree. Generally, adverse events are optional and may require medical intervention. This is a severe adverse event. When used herein, the term "adverse event" refers to a severe adverse event. This refers to the physical response following a treatment session to tamine. In some embodiments, adverse events The elephant exhibited dissociation, disorientation, increased blood pressure, increased heart rate, nausea (without vomiting), vomiting, and sedation. One or more of the following: intoxication, vertigo, hypoesthesia, anxiety, dizziness, or lethargy. Above. In other embodiments, the adverse event is dissociation. In further embodiments, the adverse event In a further embodiment, the adverse event is an increase in blood pressure. In other embodiments, the adverse event is nausea. In further embodiments, the adverse event is Vomiting. In other embodiments, the adverse event is moderate to severe nausea without vomiting. In further embodiments, the adverse event is sedation. In even further embodiments, the adverse event is , intoxication. In another embodiment, the adverse event is rotational vertigo. In one embodiment, the adverse event is sensory numbness. In another embodiment, the adverse event is anxiety. In further embodiments, the adverse event is dizziness. In yet another embodiment, the adverse event is The event is lethargy. In other embodiments, adverse events include, among other things, increased blood pressure and heart rate. Increased symptoms, dissociation, nausea without moderate to severe vomiting, sedation, dizziness, and / or episodes. It is a type of vertigo.

[0063] In other embodiments, a shorter post-treatment session monitoring period is observed in any subsequent treatment session. Before becoming an eligible patient (for example, less than 90 minutes), the patient must have at least two treatment sessions. After the procedure, the patient will be monitored for at least 90 minutes. Even after the procedure, no serious adverse events were experienced, and there was no clinically significant increase in blood pressure. Meaningful increase in heart rate, moderate to severe dissociation, moderate to severe sedation, moderate Severe or greater levels of dizziness, moderate or greater levels of nausea without vomiting, and / or moderate If the patient does not experience any of the following levels of rotational vertigo, the patient should receive the following treatment. In treatment, a shorter post-treatment session monitoring period (e.g., less than 90 minutes, preferably) is preferred. The patient will be eligible in approximately 60 minutes. As stated herein, the pre-qualification monitoring period is until the patient is eligible. The first eight weeks in which you do not experience any serious adverse events or any of the following adverse events. It is possible to include more than the first two treatment sessions, such as the initial two treatment sessions. Critical: Clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate to severe increase. Dissociation at a moderate level, moderate to moderate level of sedation, moderate to moderate level of dizziness, moderate Nausea without vomiting at the above levels, and / or moderate to severe levels of rotational vertigo. In this case as well, typically, the conditions for the above adverse events are met after two consecutive treatment sessions. The pre-qualification review monitoring period must be met without encountering any of the listed adverse events. The more treatment sessions there are, the less likely the patient is to experience them in the next treatment session. The rate increases further. Following a monitoring period after a treatment session of less than 90 minutes, eligible patients are generally If a medical professional determines that the eligible patient is clinically stable and ready for discharge They will be released after making a decision.

[0064] At any point during esketamine treatment, i.e., during or after a treatment session, If a patient experiences a serious adverse event, or any of the following adverse events, Disqualification due to shortened monitoring sessions: clinically significant increase in blood pressure, clinically significant Increased heart rate, moderate to severe disorientation, moderate to severe sedation, and / Or nausea without vomiting at a moderate or greater level, or any combination thereof. Patients who are disqualified must stay for a full two hours or more during the post-treatment monitoring period. It is necessary. In certain embodiments, the patient will have an upcoming treatment session of less than two hours. A follow-up monitoring period is prohibited. In other embodiments, the patient is determined by the attending physician. It is possible to attempt to qualify for a post-treatment session monitoring period of less than two hours. For example, if a patient is unsuitable for 4, 6, 8, 10, or 12 treatment sessions. If no symptoms are present, the physician may, at his discretion, administer the medication within 2 hours as described herein. Patients can be re-eligible for the full monitoring period.

[0065] When used herein, unless otherwise specified, the term "clinically" (independently, (or used to modify the term "meaningful") is a mark of the U.S. Food and Drug Administration. This means that it is meaningful to conduct similar research for market approval by quasi- or EMEA. A clinically meaningful increase in blood pressure and / or a clinically meaningful increase in heart rate is defined as follows: , which can be determined by clinical judgment. In some embodiments, an increase in blood pressure is systolic, This could be an increase in diastole, or a combination of both. For example, 20 mm from baseline. An increase of 15 mmHg or more in systolic blood pressure and / or an increase of 15 mmHg or more in diastolic blood pressure from baseline. An increase of 4 from baseline can be considered clinically significant. In other cases, 4 An increase in systolic blood pressure of 0 mmHg or more and / or dilation of 25 mmHg or more from baseline. An increase in blood pressure can be considered clinically significant. In further examples, 180 mm A systolic blood pressure of 110 mmHg or higher and / or a diastolic blood pressure of 110 mmHg or higher is clinically significant. It may be considered that: Furthermore, an increase in heart rate of 20 bpm or more from baseline and / or 1 A heart rate of 00 bpm or higher can be considered clinically significant. In other cases, An increase in heart rate of 15 bpm or more above the baseline can be considered clinically significant. Cut.

[0066] A person skilled in the art would know from experience and from one or more of the tools used to make such an evaluation. The above tools will allow for easy measurement of adverse events in patients. For example, clinical Clinician-Administered Dissociative States Scale (CADSS) ) is a technique used to measure current dissociative symptoms, and therefore, during treatment It can be used to assess dissociative symptoms. The CADSS consists of 23 subjective items. The three components are: depersonalization (items 3-7, 20, and 23), and loss of reality (items 1, 2) , 8-13, 16-19, and 21), as well as memory loss (items 14, 15, and 22) They can be categorized. Participant responses are coded on a 5-point scale (0 = not at all ~ 4 = extremely Therefore, a higher CADSS value indicates a worse dissociation state, and a lower CADS value indicates a worse dissociation state. The S value indicates a mild state of dissociation.

[0067] To measure sedation induced by a treatment session, a person skilled in the art may use a modified wakefulness / Observer's Assessment of Alertness / Sedation Scale (Modified Observer's Assessment of Alertness / Sedation Scale) The tion scale (MOAA / S) can be used. The MOAA / S score is such that 0 = no pain response to the stimulus. "None" response (corresponding to the ASA continuum for general anesthesia) ~5 = name spoken in a normal tone This is the range that responds easily to the previous state (corresponding to the ASA continuum of arousal and minimal sedation). Each nasal cavity On the day of administration, MOAA / S will be performed every 15 minutes from before administration until 1.5 hours after administration. If the score is 3 or less at any point during the 1.5-hour interval after administration, the score will be raised to 4. MOAA / S is administered every 5 minutes until the target is reached (at this point, t = 1.5 hours after administration). (The frequency can be resumed at 15-minute intervals.) However, if the subject is t = post-administration + If a target does not have a score of 5 or higher within 1.5 hours, that target should continue to be monitored. For subjects with a score of 4, the evaluation must be repeated every 15 minutes. Furthermore, for subjects with a score of 3 or lower, the evaluation must be repeated every 5 minutes until a score is obtained. Yes. In some embodiments, the MOAA / S results are recognized by the American Society of Anesthesiologists (AAA). Defined by the continuum of the Society of Anesthesiologists (ASA). This may correlate with the level of sedation achieved.

[0068] The Clinical Global Assessment of Discharge Readiness ess, CGADR) are also used in conjunction with other parameters to assess the subject's current clinical status. This is a clinician assessment of readiness to discharge patients from the testing facility, which can measure the following: "The subjects are selected based on their overall clinical condition (e.g., sedation, blood pressure, and other adverse events)." Answer "yes" or "no" to the question, "Do you think you are ready to send them to the hospital?" CGADR is administered 1 or 1.5 hours after administration on each day of intranasal administration. If the answer is not "yes" in the next 1.5 hours, until a "yes" answer is obtained, or clinical When indicated, the procedure was repeated every 15 minutes until the subject was referred to appropriate medical care. If the patient is eligible, CGA should be administered approximately 15 minutes before the end of the post-treatment session monitoring period. A discharge assessment (or similar discharge preparation assessment) is performed, and 45 minutes after administration (post-treatment session) the patient says "Yes If not "yes", the assessment will continue until a "yes" response is achieved, or until clinically demonstrated This is repeated every 15 minutes until the subject, if present, is referred to appropriate medical care.

[0069] In the case of adverse events, including those for which there is no standard method for assessing severity, a person skilled in the art Severity is determined using the general category descriptors "mild," "moderate," or "severe." Grade evaluation is possible. Grade "Mild" means easily acceptable and minimally invasive. This is related to patients who are aware of symptoms that produce pleasure and do not interfere with their daily lives. Grade "moderate" or "severe" means that the condition significantly impairs normal activities. Used for patients experiencing significant discomfort. Grade "severe" indicates extreme pain and significant discomfort. Patients experiencing functional impairment or incapacity, thereby interfering with their normal daily activities. It is used.

[0070] Typically, eligible patients are those who have resolved adverse events during the post-eligibility treatment session follow-up period. It does not require medical intervention and / or medical observation. At that time, the term "medical intervention" refers to the need for medical professionals to care for a patient. In particular, it helps with blood tests, respiratory support, cardiac function support, and reducing adverse events or the symptoms of adverse events. This may include one or more of the following: administration of drugs, emergency treatment, etc. When used in writing, the term "medical observation" refers to close monitoring of a patient by a medical professional. To refer to. Monitoring may be visual, and may involve interaction with the patient, at the discretion of the patient. This may consist of measuring the patient's response to questions, or determining whether medical intervention is necessary. To determine this, in particular, heart rate, heart rhythm, vision, hearing, blood pressure, and respiration are measured. This may include testing.

[0071] As disclosed herein, eligible patients may undergo adverse events during the post-treatment session monitoring period. The risk of developing the disease in elephants is low, and therefore, the same amount of time is not required for monitoring. In one embodiment, an eligible patient does not require medical intervention in any previous treatment session. In other embodiments, an eligible patient is clinically relevant or does not exhibit significant side effects that are of concern based on clinical judgment. As disclosed herein, the conventional post-treatment monitoring period requires approximately 1.5 to 2 hours of monitoring by a medical professional. This period allows the medical professional to evaluate adverse events and determine whether the patient has encountered mild adverse events or no adverse events. Doing so provides greater confidence that no serious adverse events will occur after administration and enables the identification of eligible patients who require a shorter post-treatment monitoring period. For example, if a patient has a dose adjustment ranging from 56 mg to 84 mg, the effect of administration on AE is small, but it is noted that the patient may be recommended for re-eligibility for a shorter post-treatment monitoring period. Typically, elderly patients are more likely to exhibit adverse events related to blood pressure changes and are more likely to have difficulty predicting blood pressure changes, so elderly patients are not eligible for a shorter post-treatment monitoring period. One of ordinary skill in the art will be able to determine whether an adverse event has been "resolved" using the skills of the art. In some embodiments, an adverse event is resolved when all or substantially all of the symptoms related to the adverse event have dissipated. In other embodiments, when a patient can function normally, i.e., can function after esketamine administration in the same manner as before esketamine administration, the adverse event is resolved. As disclosed herein, typically, a patient has severe adverse events and the following adverse events within the range of having a dose adjustment from 56 mg to 84 mg, the effect of administration on AE is small, but it is noted that the patient may be recommended for re-eligibility for a shorter post-treatment monitoring period. Typically, elderly patients are more likely to exhibit adverse events related to blood pressure changes and are more likely to have difficulty predicting blood pressure changes, so elderly patients are more likely to exhibit adverse events related to blood pressure changes and are more likely to have difficulty predicting blood pressure changes, so elderly patients are not eligible for a shorter post-treatment monitoring period.

[0072] One of ordinary skill in the art will be able to determine whether an adverse event has been "resolved" using the skills of the art. In some embodiments, an adverse event is resolved when all or substantially all of the symptoms related to the adverse event have dissipated. In other embodiments, when a patient can function normally, i.e., can function after esketamine administration in the same manner as before esketamine administration, the adverse event is resolved. That is, when the patient can function after esketamine administration in the same manner as before esketamine administration, the adverse event is resolved. As disclosed herein, typically, a patient has severe adverse events and the following adverse events

[0073] As disclosed herein, typically, a patient has severe adverse events and the following adverse events Without experiencing any of the above, two consecutive treatment sessions are required: clinically Meaningful increase in blood pressure, clinically meaningful increase in heart rate, moderate to severe dissociation, moderate Sedation of a moderate to severe level, dizziness of a moderate to severe level, vomiting of a moderate to severe level. Nausea without vomiting, and / or moderate to severe vertigo. In some embodiments, The patient becomes eligible after at least the first three consecutive treatment sessions. In that embodiment, the patient is at least about 3, about 4, about 5, about 6, about 7, about 8, about 9, about After 10, approximately 11, approximately 12, or more treatment sessions, you will become eligible. In one embodiment, the patient becomes eligible after approximately four treatment sessions. In another embodiment, the patient The patient becomes eligible after approximately 8 treatment sessions. In a further embodiment, the patient is approximately 3 to 8 12, approximately 3-11, approximately 3-10, approximately 3-9, approximately 3-8, approximately 3-7, approximately 3-8 , approximately 3-7, approximately 3-6, approximately 3-5, approximately 3-4, approximately 4-12, approximately 4-11, approximately 4 to approximately 10, approximately 4 to approximately 9, approximately 4 to approximately 8, approximately 4 to approximately 7, approximately 4 to approximately 8, approximately 4 to approximately 7, approximately 4 to approximately 6, approximately 4-5, approximately 5-12, approximately 5-11, approximately 5-10, approximately 5-9, approximately 5-8 , approximately 5-7, approximately 5-6, approximately 6-12, approximately 6-11, approximately 6-10, approximately 6-9, Approximately 6-8, approximately 6-7, approximately 7-12, approximately 7-11, approximately 7-10, approximately 7-9, approximately Suitable after approximately 7-8 weeks, 8-12 weeks, 9-11 weeks, 9-10 weeks, or 10-11 weeks. It becomes a rank.

[0074] Some of the quantitative expressions used herein are not modified by the term "approximately". Whether the term "about" is explicitly used or not, as indicated herein. All amounts indicated mean the actual values shown, including approximations based on experimental and / or measurement conditions of such shown values, and are meant to refer to approximations of such shown values that would be reasonably inferred based on ordinary skill in the art, which is understood. It is understood that this also means

[0075] As used herein, unless otherwise indicated, the term "esketamine" refers to the (S)-enantiomer of ketamine, i.e., the compound of formula (I):

[0076]

Chem.

[0077]

Chem.

[0078]

Chem.

[0079] ​​​​It contains less than % by weight of the (R)-enantiomer of ketamine. In further embodiments, Based on the weight of the ketamine sample, the amounts were approximately 10, 9, 8, 7, 6, 5, and 4. , 3, 2, 1, 0.5, 0.1, 0.005, or less than 0.001% by weight of ketamine ( It contains the R)-enantiomer. In yet another embodiment, esketamine is esketamine Based on the weight of the sample, approximately 0.001 to 10% by weight of ketamine (R)-enan It contains thiomer. In further embodiments, esketamine is used in esketamine samples. Based on the weight, approximately 0.001 to approximately 10%, approximately 0.001 to approximately 5%, approximately 0.001 to approximately 1. Approximately 0.001 to approximately 0.5, approximately 0.001 to approximately 0.1, approximately 0.1 to approximately 5, approximately 0.1 to approximately 1. Approximately 0.1 to 5, or approximately 0.5 to 5% by weight of esketamine (R)-enantiomate - Contains.

[0080] The term "esketamine" is also a term that can be easily selected by those skilled in the art. It may also include the salts that are tolerated. "Medically tolerated salts" are non-toxic and biologically acceptable. Esketamine is tolerable or otherwise biologically suitable for administration to the subject. It is intended to mean salt. Generally, G.S. Paulekuhn, "Trends in Active Pharmaceutical Ingredient Sal t Selection based on Analysis of the Ora nge Book Database”, J.Med.Chem.,2007,50:6 665-72, SMBerge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts,Properties,Selectio n,and Use,Stahl and Wermuth,Eds.,Wiley-V. See CH and VHCA, Zurich, 2002. Medicinally acceptable. Examples of salts include those that are pharmacologically effective and do not cause excessive toxicity, irritation, or allergic reactions. This salt is suitable for administration to patients.

[0081] Other examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, and sulfites. , bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyro Phosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, pr Ropionate, decantate, caprylate, acrylate, formate, isobutyrate, capro Salts, heptanes, propiolates, oxalates, malons, succinates, sucroses Phosphates, sebacinates, fumarates, maleates, butin-1,4-diates, hex Syn-1,6-diote, benzoate, chlorobenzoate, methylbenzoate, dinitro Benzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, Xylene sulfonate, phenyl acetate, phenylpropionate, phenyl butyrate, Ethanol, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfone Salts, propane sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates Examples include esterates and mandelates. In particular, the salts of esketamine are hydrochlorides.

[0082] In certain embodiments, esketamine is administered intranasally. In other embodiments, esketamine is administered intranasally. Tamine is administered intranasally as its corresponding hydrochloride. In further embodiments, Esketa Min is the corresponding hydrochloride in a 16.14% wt / vol solution (14% wt / vol esketami It is administered intranasally as a base (equivalent to a nucleotide).

[0083] In a particular embodiment, esketamine is administered at a concentration of 161.4 mg / mL in water at a pH of 4.5. Esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg / m² L of ethylenediaminetetraacetic acid (EDTA), and 1 It is administered intranasally as a solution containing 0.5 mg / mL of citrate. In other embodiments, Ketamine is administered intranasally and delivered via intranasal delivery to water at a pH of 4.5, 161.4 ml. g / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.1 2 mg / mL ethylenediaminetetraacetic acid (EDTA) and 1.5 mg / mL citric acid A 100 μL solution containing is administered. In a further embodiment, esketamine is administered as a nasal spray. It is delivered into the nasal cavity using a pump, and this pump dispenses 161.4 mg in water with a pH of 4.5. Esketamine hydrochloride at a concentration of 140 mg / mL (equivalent to 140 mg / mL of esketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg / mL of citric acid Deliver a 100 μL solution containing the substance.

[0084] Generally, one pump from a nasal spray device dispenses approximately 50 μL to 200 μL (approximately 60 μL). Approximately 70 μL, approximately 80 μL, approximately 90 μL, approximately 100 μL, approximately 110 μL, approximately 120 μL, approximately 130μL, approx. 140μL, approx. 150μL, approx. 160μL, approx. 170μL, approx. 180μL The esketamine solution (containing approximately 200 μL) is configured to be delivered into the target nostril. This is also acceptable. Therefore, two pumps will deliver approximately 100 μL to approximately 400 μL to the target. .

[0085] In certain embodiments, patients requiring treatment with a therapeutically effective dose of esketamine are depressed. The patient is suffering from an episode of illness (e.g., major depressive disorder). In other embodiments Patients who require treatment are those who have suffered an episode of depression (e.g., major depressive disorder). Furthermore, episodes of depression (e.g., major depressive disorder) are associated with at least two oral antihistamines. The patient is not responding to medication (i.e., the patient is taking at least two oral antidepressants). (Not responding to treatment).

[0086] At the end of the induction phase, the treating physician will evaluate the patient and determine whether to administer any subsequent treatments, such as a "maintenance phase." The dosage and frequency can be optimized. The frequency of intranasal treatment during subsequent administrations, such as during the maintenance phase, is The frequency of administration should be reduced from at least twice a week during the induction phase to once a week for at least four weeks. It is expected that the dose will be reduced. In some embodiments, subsequent administrations, such as during the maintenance phase, will be less. Each lasts approximately 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, and 1 week. 1 week, approximately 12 weeks, approximately 13 weeks, approximately 17 weeks, approximately 18 weeks, approximately 19 weeks, approximately 20 weeks, Approximately 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or 2 years In some embodiments, esketamine administration during the maintenance phase lasts for at least 6 months. In other embodiments, esketamine administration during the maintenance phase lasts for at least one year. In further embodiments, the frequency of administration during the maintenance phase may be once a week or once every two weeks, These are combinations of those. In yet another embodiment, the frequency of esketamine administration during the maintenance phase The degree and effective dose are the minimum frequency and amount necessary to treat depression.

[0087] Subsequent administration, such as during the maintenance period, may include longer durations depending on the patient's condition. In that embodiment, these longer periods include indefinite periods, at least about 3 years, and about 4 years. It can be one year, approximately 5 years, approximately 6 years, approximately 7 years, approximately 8 years, approximately 9 years, approximately 10 years, or even more than approximately 10 years. For example, in the case of a patient diagnosed with TRD, treatment may be indefinite. Other implementations In this embodiment, the treatment frequency is reduced to every other week. In a further embodiment, the treatment frequency is every three weeks. The frequency is reduced to once a month. In another embodiment, the treatment frequency is reduced to once a month. The patient is patient The condition is maintained as planned until remission is achieved, the response is maintained, or treatment fails. The patient achieves remission or responds to weekly treatment for at least four weeks. If maintenance is required, the frequency of intranasal therapy sessions will be every other week, based on the severity of depressive symptoms. The dose can be reduced to a manageable level, and in some patient populations, the treatment frequency is as described above. The frequency can be reduced to once every three or four weeks.

[0088] The maintenance period described herein refers, for example, to long-term remission of depression (e.g., 1 (including remission of one or more symptoms), social and / or social conditions to the usual or pre-symptomatic level. Or further treatment as indicated by improvement in occupational functioning or other known measures of depression. Those skilled in the art will understand that treatment can be continued until it is no longer necessary.

[0089] The amount of esketamine administered during the maintenance phase is the same as the amount of esketamine achieved during the induction phase. This is the amount that maintains a mechanically steady state. In some embodiments, it is about 56 mg or about 84 mg g of esketamine is administered to the patient during the maintenance phase. For example, approximately 56 mg of esketamine. For certain patients taking this medication, the dosage may be increased to approximately 84 mg if depressive symptoms begin to worsen. It may be added, thereby stabilizing the patient. Alternatively or additionally, the patient may be administered every other week. If you are receiving treatment and those symptoms begin to worsen, esketamine is administered once a week. The response can be maintained during the maintenance phase. Again, at any point during the maintenance phase, the patient's response can be maintained. It can be re-evaluated.

[0090] One or more times (for example, twice) in any of the periods described herein. If the dose of esketamine is not administered, based on the administration frequency regimen, The next dose may be scheduled. If more than two doses are not administered, a clinical judgment is made. Accordingly, adjustments to the dosage or frequency of esketamine may be necessary.

[0091] Furthermore, the methods described herein include, but are not limited to, one or more therapeutically effective doses of antimicrobial agents. This includes adjunctive therapy with medication. Preferably, adjunctive therapy is administered during the induction phase, maintenance phase, or both. Yes. In some embodiments, adjunctive therapy is administered during the induction phase. In other embodiments, adjunctive therapy is administered. Therapy is in the maintenance phase. In a further embodiment, adjunctive therapy is between the induction and maintenance phases. In certain embodiments, esketamine is one or two or more as described herein. In combination with the above antidepressants, preferably in combination with 1 to 3 antidepressants, more preferably Alternatively, it may be administered in combination with one or two antidepressants. In other embodiments, Eske Tamin, in combination with one or more antidepressants as described herein, further comprises 1 It may be administered in combination with one or more atypical antipsychotics. Antidepressants are, This should be at least approximately two hours after the execution of the treatment session described in the manual. Such administration is desirable to minimize side effects. In some embodiments, antidepressants are used. The medication should be administered at least 3, 4, 5, 6, 7, or 8 hours after the treatment session. In other embodiments, the antidepressant is administered in doses of approximately 3 to 8, 3 to 7, 3 to 6, and 3 to 5. , 3-4, 4-8, 4-7, 4-6, 4-5, 5-8, 5-7, 5 It is administered for approximately 6, 6 to 8, 6 to 7, or 7 hours.

[0092] The timing of adjuvant therapy is determined by the attending physician. In some embodiments, adjuvant therapy is administered. The therapy is administered at least 3 hours after the induction or maintenance treatment session. Other embodiments So, adjunctive therapy is at least 3, 4, 5, 6, and 7 of the initial treatment sessions. Approximately 8, 9, 10, 11, 12, 18, or 24 hours later. Further implementation In this scenario, adjunctive therapy is administered in approximately 3-12, 3-11, and 3-1 sessions of the initial treatment phase. 0, approximately 3-9, approximately 3-8, approximately 3-7, approximately 3-6, approximately 3-5, approximately 3-4, approximately 4 ~approximately 12, approximately 4~approximately 11, approximately 4~approximately 10, approximately 4~approximately 9, approximately 4~approximately 8, approximately 4~approximately 7, approximately 4~ Approximately 6, approximately 4-5, approximately 5-12, approximately 5-11, approximately 5-10, approximately 5-9, approximately 5- 8, approximately 5-7, approximately 5-6, approximately 6-12, approximately 6-11, approximately 6-10, approximately 6-9 , approximately 6-8, approximately 6-7, approximately 7-12, approximately 7-11, approximately 7-10, approximately 7-9, Approximately 7-7, approximately 8-12, approximately 8-11, approximately 8-10, approximately 8-9, approximately 9-12, Approximately 9-11, 9-10, 10-12, 10-11, and 11-12 hours later In other embodiments, adjunctive therapy is performed for at least 3, 4, or 5 of the maintenance therapy sessions. , 6, 7, 8, 9, 10, 11, 12, 18, or 24 hours later. In further embodiments... Adjunctive therapy is performed in approximately 3-12, 3-11, and 3-10 maintenance treatment sessions. Approximately 3-9, approximately 3-8, approximately 3-7, approximately 3-6, approximately 3-5, approximately 3-4, approximately 4- 12, approximately 4-11, approximately 4-10, approximately 4-9, approximately 4-8, approximately 4-7, approximately 4-6 , approximately 4-5, approximately 5-12, approximately 5-11, approximately 5-10, approximately 5-9, approximately 5-8, Approximately 5-7, approximately 5-6, approximately 6-12, approximately 6-11, approximately 6-10, approximately 6-9, approximately 6-approx. 8, approx. 6-approx. 7, approx. 7-approx. 12, approx. 7-approx. 11, approx. 7-approx. 10, approx. 7-approx. 9, approx. 7 ~approximately 7, approximately 8~approximately 12, approximately 8~approximately 11, approximately 8~approximately 10, approximately 8~approximately 9, approximately 9~approximately 12, approximately 9 ~Approximately 11, approximately 9-10, approximately 10-12, approximately 10-11, and approximately 11-12 hours later. ru.

[0093] As used herein, the terms “adjunctive therapy” and “adjunctive treatment” refer to esketamine. By administering it in combination with one or more antidepressants, patients requiring treatment This means the treatment of the person, and esketamine and antidepressants are administered by any suitable means. It is administered. In some embodiments, esketamine is used in combination with 1 to 5 antidepressants. It is administered with dimen. In other embodiments, esketamine is administered with 1, 2, 3, 4, or 5 types It is administered as part of a regimen using antidepressants. In other embodiments, esketamine is administered as one or It is administered in a regimen using two antidepressants. In a further embodiment, esketamine is It is administered using a regimen that includes the antidepressant currently being administered to the patient. In other embodiments, Esketamine is administered in regimens with different antidepressants. Further embodiments Esketamine was administered in a regimen using an antidepressant that had not been previously given to the patient. In yet another embodiment, esketamine is used with antidepressants previously administered to the patient. They are administered in the regimen. When esketamine and antidepressants are administered in separate dosage forms, each The number of doses administered per day for a compound may be the same or different, and is more typical. It differs. Antidepressants are prescribed by the attending physician and / or by their label. It may be administered as described herein, and esketamine is administered as described herein. Typically, the patient is under concurrent treatment with both antidepressants and esketamine, and Both are administered according to their respective prescribed dosing regimens.

[0094] Esketamine and antidepressants may be administered via the same or different routes of administration. Examples of preferred methods of administration include oral, intravenous (iv), intranasal (in), and intramuscular (im) administration. This includes, but is not limited to, subcutaneous (sc), percutaneous, oral, or rectal methods. In one embodiment, esketamine is administered intranasally.

[0095] As used herein, unless otherwise specified, the term “antidepressant” refers to a drug for depression. This refers to any medicine that can be used for treatment. A preferred example is mo Noamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin Noradrenergic reuptake inhibitors, noradrenergic and specific serotonin Examples include, but are not limited to, agonists or atypical antipsychotics. Other examples Examples include monoamine oxidases such as phenelzine, tranylcypromine, and moclobemide. Inhibitors; imipramine, amitriptyline, desipramine, nortriptyline, doxep Tricyclic antidepressants such as protriptyline, trimipramine, clomipramine, and amoxapine Depressants; tetracyclic antidepressants such as maprotiline; acyclic antidepressants such as nomifensin; trazodone Triazolopyridines such as fluoxetine, sertraline, paroxetine, citalophramide Serotonin reuptake inhibitors such as citalopram, escitalopram, and fluvoxamine. Drugs; serotonin receptor antagonists such as nefazadone; venlafaxine, milnaci Serotonins such as plan, desvenlafaxine, duloxetine, levomilunacipran, etc. Noradrenergic reuptake inhibitors; such as mirtazapine • Specific serotonergic drugs; norepinephrine such as reboxetine and edivocketine Reuptake inhibitors; atypical antipsychotics such as bupropion; Kava Kava, Western Otto Natural products such as cypress; nutritional supplements such as s-adenosylmethionine; and thyroid stimulants. Neuropeptides such as hormone-releasing hormones; neurokinin receptor antagonists, etc. Examples include compounds that target neuropeptide receptors, and hormones such as triiodothyronine. These are some examples, but are not limited to these. In some embodiments, the antidepressant is imipramide. N, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline Trimipramine, Maprotiline, Amoxapine, Trazodone, Bupropion, Clorox Mipramine, fluoxetine, duloxetine, escitalopram, citalopram, cell Traline, Paroxetine, Fluvoxamine, Nefazadone, Venlafaxine, Milnaci Plan, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemi Do, Kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone These are releasing hormones, neurokinin receptor antagonists, or triiodothyronine. Preferably, the antidepressant is fluoxetine, imipramine, bupropion, or venlafaxine. The group is selected from syn and sertraline.

[0096] Antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors) Serotonin reuptake inhibitors, serotonin-noradrenergic reuptake inhibitors, noradrenergic Sex-specific serotonergic drugs, norepinephrine reuptake inhibitors, natural products, nutritional supplements Foods, neuropeptides, compounds targeting neuropeptide receptors, hormones, and the foregoing The therapeutic effective dose / dosage level and drug regimen of the pharmaceuticals listed can be easily determined by those skilled in the art. This can be determined. For example, the therapeutic dosage and regimen of a drug approved for sale may be It is generally available, for example, on packaging labels, standard medication guidelines, and physical ian's Desk Reference(Medical Economics C (Available online at the company or http: / / www.pdrel.com) These are listed in standard medication references or other sources.

[0097] As used herein, the term “antipsychotic drug” includes the following, but is not limited to the following: It is not limited to them. (a) Typical or conventional antipsychotics, e.g., phenothiazines (e.g., chlorpromazines) Lomazine, Thioridazine, Fluphenazine, Perphenazine, Trifloperazine, Levome Promazine (levomepromazin), thioxanthenes (e.g., thiothixene, flupen) Thixol), butyrophenones (e.g., haloperidol), dibenzoxazepines ( For example, roxapine), dihydroindrones (for example, morindone), substituted benzamides Drugs (e.g., sulpiride, amisulpride), and others; (b) Atypical antipsychotics and mood stabilizers, e.g., paliperidone, clozapine, risperidone Lidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, peros Pyrone, blonanserin, certindol, ORG-5222 (Organon), etc. And others, for example, sonepiprazole, aripiprazole, nemonapride, SR-31 742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia ), NE-100 (Taisho), divalproate (mood stabilizer) etc.

[0098] In this embodiment, the "atypical antipsychotic drug" is aripiprazole, quetiapine, or olanza Selected from the group consisting of pin, risperidone, and paliperidone. In another embodiment, Atypical antipsychotics include aripiprazole, quetiapine, olanzapine, and risperidone. Selected from the group consisting of n, preferably atypical antipsychotics include aripiprazole, que The drug is selected from the group consisting of chiapine and olanzapine.

[0099] Unresponsiveness to a given set of appropriate antidepressants can be determined retrospectively or anticipatoryly. Those skilled in the art will recognize this. In the embodiment, the unresponsiveness to a suitable set of antidepressants At least one is determined anticipatoryly. In another embodiment, a suitable set of antidepressants At least two of the unresponsive ones are determined in advance. In another embodiment, a suitable series At least one of the non-responses to antidepressants is determined retrospectively. In another embodiment, At least two unresponsive patients to an appropriate set of antidepressants are in a current depressive episode. It will be determined retroactively.

[0100] "At least two oral antidepressants" or "at least two different oral antidepressants" are the primary It is administered to the patient in an appropriate dose, which may be determined by the attending physician. Similarly, antidepressants are primarily It is administered for a suitable duration determined by the attending physician.

[0101] When used herein, unless otherwise specified, terms such as "to treat" and "treatment" are used. , for the purpose of addressing diseases, conditions, or disorders, the subject or patient (preferably a mammal, y Preferably encompasses the management and care of humans, and the prevention of the onset of symptoms or complications. For the relief of symptoms or complications, or for the eradication of disease, condition, or disability, as specified herein This includes the administration of the compounds listed.

[0102] When used herein, the term “therapeutic effective dose” is used by researchers, veterinarians, physicians, or other Histological system, including relief of symptoms of the disease or disorder being treated, as requested by clinicians. The amount of active compounds or pharmaceuticals that elicit a biological or pharmaceutical response in animals or humans. It tastes good. In some embodiments, the antidepressant is administered in a therapeutically effective dose determined by the attending physician. It is used. In other embodiments, esketamine is used in a therapeutically effective dose.

[0103] As used herein, the term “composition” refers to a composition containing a specific component in a specific amount. Matter, and any organism resulting directly or indirectly from a combination of specific amounts of specific components. It shall include the finished product.

[0104] In some embodiments, the induction period is when the patient's MADRS score is 5% above baseline. It can be said that the process is complete when it is reduced to 0% or more, or from approximately 20% to approximately 13%. In the embodiment, the patients' MADRS scores were approximately 19, 18, 17, 16, and 15. It may be approximately 14, or even approximately 13. Patients with a MADRS score of 12 or less are in remission. If deemed stable for four weeks, the condition should be transitioned to or maintained in the maintenance phase.

[0105] Pharmaceutical composition A preferred pharmaceutical composition contains esketamine hydrochloride as an active ingredient, and conventional pharmaceutical composition According to the combined technique, the pharmaceutical carrier is thoroughly mixed with water, and this carrier is administered. It can take on a wide variety of forms depending on the desired form of dispensing. Suitable carriers are well known in the art. The explanation is from The Handbook, published by the American Pharmaceutical Association and the British Pharmaceutical Association. It can be found in ok of Pharmaceutical Excipients. ru.

[0106] The method for formulating pharmaceutical compositions was published by Marcel Dekker, Inc. Pharmaceutical Dosage For ms:Tablets,Second Edition,Revised and Ex panded, Volumes 1-3; Pharmaceutical, edited by Avis et al. Dosage Forms:Parental Medications,Vol. Umes 1-2; and Pharmaceutical Do (edited by Lieberman et al.) sage Forms:Disperse Systems,Volumes 1-2, It is mentioned in many publications such as the ones listed above.

[0107] One preferred aqueous formulation of esketamine comprises water and esketamine, wherein esketamine is Based on the total volume of the pharmaceutical composition, the concentration is approximately 25 mg / mL to approximately 250 mg / mL, preferably. Approximately 55 mg / mL to approximately 250 mg / mL, or approximately 100 mg / mL to approximately 250 mg / It exists in an amount in the range of mL, or any amount or range within that range. Preferably, Min is in an amount ranging from approximately 150 mg / mL to approximately 200 mg / mL, or any amount within that range. It exists in a range of approximately 150 mg / mL to approximately 17 It is present in an amount within the range of 5 mg / mL, or any amount or range within that range. More preferably Esketamine is present in amounts ranging from approximately 160 mg / mL to approximately 163 mg / mL, for example, approximately It is present in an amount of 161.4 mg / mL.

[0108] Another preferred aqueous formulation of esketamine comprises water and esketamine, where esketamine is Based on the total volume of the pharmaceutical composition, the range is approximately 100 mg / mL equivalent to approximately 250 mg / mL equivalent. It is present in a certain amount, or in any amount or range within that amount. Preferably, esketamine is or an amount in the range of approximately 125 mg / mL equivalent to approximately 180 mg / mL equivalent, or any of the amounts within that range. It is present in a quantity or range. More preferably, esketamine is present in about 140 mg / mL equivalent. In amounts within the range of approximately 160 mg / mL equivalent, or any amount or range within that range, for example, It is present in an amount of approximately 140 mg / mL equivalent.

[0109] The pharmaceutical compositions preferred for use in this specification are preferably aqueous formulations. When used, unless otherwise specified, the term "aqueous" means that the main liquid component of the formulation is water. This means that, preferably, water is about 80% by weight of the liquid component of the pharmaceutical composition. More than %, more preferably more than approximately 90% by weight, more preferably more than approximately 95% by weight, more It makes up approximately 98% by weight.

[0110] In a pharmaceutical composition suitable for use in this specification, the water content of the composition is the total weight of the composition. Based on the quantity, 85±14% by weight, more preferably 85±12% by weight, and even more preferably The weight is within the range of 85±10% by weight, most preferably 85±7.5% by weight, and especially 85±5% by weight. That is the case.

[0111] In a pharmaceutical composition suitable for use in this specification, preferably, the water content of the composition is Based on the total weight of the composition, 90±14% by weight, more preferably 90±12% by weight, and further More preferably 90±10% by weight, most preferably 80±7.5% by weight, and especially 90±5% by weight. It is within the range of %.

[0112] In another pharmaceutical composition for use herein, the water content of the composition is the total weight of the composition. Based on the quantity, 95±4.75% by weight, more preferably 95±4.5% by weight, and even more preferably More preferably 95±4% by weight, even more preferably 95±3.5% by weight, and most preferably 9 The weight is within the range of 5±3% of the weight, and especially within the range of 95±2.5% of the weight.

[0113] In another pharmaceutical composition for use herein, the water content of the composition is the total weight of the composition. Based on the amount, 75-99.99% by weight, more preferably 80-99.98% by weight, and further More preferably 85-99.95% by weight, and even more preferably 90-99.9% by weight. Most preferably, the amount is in the range of 95 to 99.7% by weight, and more preferably, 96.5 to 99.5% by weight.

[0114] In another pharmaceutical composition for use herein, the composition comprises one or more stimulants. It further comprises a buffer and / or a buffer system (i.e., a conjugate acid-base pair).

[0115] As used herein, the term "buffering agent" means that when added to an aqueous formulation, the said This refers to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts the pH of the formulation. It shall be assumed that the buffering agent can adjust the pH of the aqueous formulation in any direction (more acidic, more acidic). It will be recognized that the pH can be adjusted (towards a more basic or more neutral pH). Furthermore, buffering agents are medically acceptable.

[0116] Suitable examples of buffering agents that may be used in the aqueous formulations described herein include citric acid and phosphorus. Sodium dihydrogen acid, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, sucrose Examples include citric acid, tartaric acid, malic acid, lactic acid, and fumaric acid, but are not limited to these. Preferably, the buffering agent or buffering system is NaOH, citric acid, sodium dihydrogen phosphate, and It is selected from the group consisting of disodium hydrogen phosphate.

[0117] In the embodiment, the buffering agent is an esketamine hydrochloride pharmaceutical composition (for example, as described herein). The pH of the aqueous formulation is set to a pH within the range of approximately pH 3.5 to approximately pH 6.5, or any amount within that range. Alternatively, it is selected to adjust to a range. Preferably, the buffer is esketamine hydrochloride. The pH of the composition is set to a range of approximately pH 4.0 to approximately pH 5.5, or any amount or range within that range. A range, more preferably in the range of approximately pH 4.5 to approximately pH 5.0, or any amount within that range. Selected to adjust to the range.

[0118] Preferably, the concentrations of the buffering agent and buffering system, preferably NaOH, are sufficient for buffering. It is adjusted to provide the necessary functions.

[0119] In this embodiment, the mixture consists of esketamine hydrochloride, water, and a buffer or buffering system, preferably NaOH. A pharmaceutical composition containing the buffer or buffer system is provided, and the pH is approximately pH 4.0 to approximately pH 6.0 A sufficient amount to obtain a formulation having a pH within the range, or any amount or range within that range. To exist.

[0120] The pharmaceutical compositions described herein may optionally contain preservatives.

[0121] When used in this specification, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" are used. The term is preferably used to protect against microbial degradation or growth, usually medical This refers to any substance added to a drug composition. In this regard, the growth of microorganisms is typically They play an important role. In other words, preservatives serve the primary purpose of preventing microbial contamination. One aspect is that any microbial influence on the active ingredients and excipients is also considered. In some cases, it is desirable to avoid it, that is, to prevent microbial decomposition.

[0122] Typical examples of preservatives include benzalkonium chloride, benzethonium chloride, and benzoic acid. Sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridin Nium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxyl Lenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, f Phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, pro Pyrene glycol, sodium propionate, thimerosal, methylparaben, ethyl phosphate Lavender, propylparaben, butylparaben, isobutylparaben, benzylparaben, Examples include, but are not limited to, sorbic acid and potassium sorbate.

[0123] The esketamine hydrochloride content is sufficiently high, and due to its preservative properties, the desired shelf life or If the stability during use can be achieved by the presence of the drug itself, the medical It is preferable that the drug composition is completely free of preservatives. Preferably, under these circumstances The concentration of esketamine hydrochloride is at least 120 mg / mL equivalent, preferably about 120 mg / mL equivalent to approximately 175 mg / mL equivalent, or any amount or range within that range. More preferably, an amount in the range of approximately 125 mg / mL equivalent to approximately 150 mg / mL equivalent, or Any amount or range within that range, for example, approximately 126 mg / mL equivalent or approximately 140 mg / mL equivalent That is the case.

[0124] When used in this specification, "penetration agent," "penetration enhancer," and The term "penetrant" refers to the active ingredient in a pharmaceutical composition (e.g., esketamine). This refers to any substance that increases or promotes the absorption and / or bioavailability of hydrochloride salts. Furthermore, after nasal administration, the active ingredient of the pharmaceutical composition (e.g., esketamine hydrochloride) is absorbed. To increase or promote the absorption and / or bioavailability of salts (i.e., through mucous membranes) (Increases or promotes the absorption and / or bioavailability of the active ingredient).

[0125] Suitable examples include tetradecyl maltoside, sodium glycolate, and tauro. Taursodeoxycholic acid (TUDCA), lecithin, etc. Chitosan (and its salts), as well as benzalkonium chloride, sodium dodecyl sulfate, dodecyl Sodium urethrate, polysorbate, laureth-9, oxytoxyl, deoxycol Examples of surfactants include sodium phosphate and polyarginine, but are not limited to these. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0126] Penetrating agents, for example, increase membrane fluidity and create transient hydrophilic pores within epithelial cells. Any mechanism including reducing the viscosity of the mucus layer or opening the tight junctions. It can act through the mechanism. Some penetrating agents (e.g., bile salts and fusidic acid derivatives) are Furthermore, it inhibits enzyme activity in the membrane, thereby improving the bioavailability of the active ingredient. It is possible.

[0127] Preferably, the penetrating agent meets one or more of the following general requirements, more preferably The options are selected to satisfy all requirements. (a) Absorption of the active ingredient (preferably nasal absorption), preferably temporary and / or reversible It is effective in increasing the number of cases. (b) It is pharmacologically inactive. (c) Non-allergenic, non-toxic, and / or non-irritating. (d) It is very potent (effective in small amounts). (e) Compatible with other components of the pharmaceutical composition. (f) It is odorless, colorless, and / or tasteless. (g) It is permitted by the regulatory authorities. (h) It is inexpensive and available in high purity.

[0128] In one embodiment, the penetrating agent penetrates without causing nasal irritation (absorption of esketamine hydrochloride and Selected to increase / or bioavailability. In another embodiment, the penetrating agent is Selected to improve the absorption and / or bioavailability of esketamine hydrochloride, and further, It is selected to enhance uniform drug efficacy.

[0129] In the embodiment, the pharmaceutical composition comprises esketamine and water, and in this specification, the pharmaceutical composition The product does not contain antimicrobial preservatives, and the pharmaceutical composition contains a penetration enhancer, preferably TUDCA. It contains.

[0130] In another embodiment, the pharmaceutical composition comprises esketamine and water, and in this specification, The pharmaceutical composition does not contain antimicrobial preservatives, and the pharmaceutical composition contains tauroursodeoxycholic acid (T It further contains UDCA, with TUDCA concentration ranging from approximately 1.0 mg / mL to approximately 25.0 mg / mL. A range, or any amount or range within that range, preferably about 2.5 mg / mL to about 15 mg The range of / mL, or any amount or range within that range, preferably about 5 mg / mL to about 10 It exists in a concentration within the range of mg / mL, or any amount or range within that range. Another embodiment In this embodiment, TUDCA is present at a concentration of approximately 5 mg / mL. A is present at a concentration of approximately 10 mg / mL.

[0131] The pharmaceutical compositions used herein may include one or more additional excipients, for example, It further contains humectants, surfactants, solubilizers, thickeners, colorants, antioxidants, etc. It's fine if you do that.

[0132] Examples of suitable antioxidant components, when used, include the following: namely, sulfurous acid. Salt; ascorbic acid; sodium ascorbate, calcium ascorbate, or as Potassium corbate and other ascorbic acid salts; ascorbyl palmitate; fumaric acid; e ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol Gallate salts such as propyl gallate, octyl gallate, or dodecyl gallate. Vitamin E; and one or more of the mixtures thereof, but these include Not limited to. Antioxidant components provide long-term stability to liquid compositions. Antioxidant components The addition of can help enhance and ensure the stability of the composition, after 6 months at 40°C. It also stabilizes the composition. A suitable amount of antioxidant component, if present, is equal to the total weight of the composition. The amount is approximately 0.01% by weight to approximately 3% by weight, preferably approximately 0.05% by weight to approximately 2% by weight.

[0133] Solubilizers and emulsifiers are generally less soluble in liquid carriers than active ingredients or other excipients. It may be included to promote uniform dispersion. Examples of suitable emulsifiers, when used, For example, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose Examples include, but are not limited to, carbomers, carbomers, and mixtures thereof. Examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, and tre Halos, benzyl benzoate, ethanol, trisaminomethane, cholesterol, trie Thanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate Examples include thorium and mixtures thereof.

[0134] Preferably, the solubilizer contains glycerin. The solubilizer or emulsifier is generally contained in the carrier. It is present in an amount sufficient to dissolve or disperse the active ingredient, namely esketamine. If a sizing agent or emulsifier is included, the typical amount is about 1% by weight to about 80% by weight of the total weight of the composition. Weight %, preferably about 20% to about 65% by weight, more preferably about 25% to about 55% by weight It is a percentage.

[0135] Suitable isotonic agents, when used, include sodium chloride, glycerin, and D-mannine. Examples include thor, D-sorbitol, glucose, and mixtures thereof. The preferred amount of the isotonic agent is typically about 0.01% by weight to about 15% by weight of the total weight of the composition. Amount %, more preferably about 0.3% by weight to about 4% by weight, more preferably about 0.5% by weight to about It is 3% by weight.

[0136] For example, to increase the nasal retention time, a suspension or thickener may be added to the pharmaceutical composition. This is also good. Preferred examples include hydroxypropyl methylcellulose and carmellose sodium. Um, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt, Examples include gellan gum, poloxamer, polyvinylpyrrolidone, and xanthan gum. However, it is not limited to these.

[0137] Advantageously, esketamine may be administered as a single daily dose, or as a total daily dose. It may be administered in divided doses two, three, or four times a day, preferably twice a day. Typically, divided doses should be administered over shorter intervals. In some embodiments... The divided doses are taken approximately 20 minutes apart, 15 minutes apart, 10 minutes apart, 5 minutes apart, and 4 minutes apart. It is administered within a minute, approximately within 3 minutes, approximately within 2 minutes, approximately within 1 minute, or shorter. Additionally, with flexible dosing regimens, patients may receive medication daily, twice a week, once a week, every other week, or once a month. It may be administered multiple times. For example, one dose of esketamine may be administered on day 1, and another dose of esketamine may be administered. Either the dose of is administered on the second day, or one dose of esketamine is administered on the first day, and esketamine is administered on the second day. Another dose of esketamine is administered on day 3, or one dose of esketamine is administered on day 1. Then, another dose of esketamine is administered on day 4, or one dose of esketamine is administered on day 1. It is administered to the eyes, and another dose of esketamine is administered on the fifth day. Furthermore, esketamine, Preferably, in an intranasal form via local application of a suitable intranasal vehicle such as a nasal spray pump. It will be administered.

[0138] nasal device Typical nasal spray devices are described in U.S. Patent No. 6,321,942 and U.S. Patent Application Publication No. 2. Disclosed in No. 020-0009081(A1), all of which are incorporated herein by reference. It is included. For example, a disposable sprayer for discharging a continuous partial discharge as a spray. The methods disclosed herein can be used to carry out the methods disclosed herein. Typically, such The device allows for the spraying of medication into both of the patient's nostrils in two consecutive strokes. The container may be ready for immediate use, even if the drug is discharged from the medium container. Good. The device typically separates the first discharge stroke from the second discharge stroke. This prevents the media container from being completely emptied in a single motion. The device is single-use Discarded after use, this two-part straw allows for precise and reliable dispensing of individual portions. It can take the form of a disposable pump.

[0139] In one embodiment, the nasal spray device sprays a total of 28 mg of esketamine twice (into the nostrils) This is a single-use device that delivers the medication with a single spray. The device is administered to the patient under the supervision of a medical professional. It may be operated in this way. Regarding the dosage, one device may be used for a 28 mg dose, or two devices may be used. The device may be used for a 56 mg dose, or three devices may be used for an 84 mg dose. Furthermore, it is preferable to have a 5-minute interval between the use of each device. As described in Example 2. Thus, time 0 is the administration of the first intranasal spray from the first intranasal device into one nostril. Defined as time.

[0140] manner Applicable form 1. A method for treating depression in human patients who require treatment for depression, The method has an introductory phase and treatment sessions, the introductory phase has a duration of 4 weeks, and the method , For the initial treatment session, approximately 56 mg or approximately 84 mg of esketamine will be administered to the patient. The drug is administered intranasally, and the induction treatment sessions are performed twice a week during the induction period. And, before any treatment session, the patient had a systolic blood pressure of less than 140 mmHg and 1 Having a diastolic blood pressure of less than 10 mmHg, After at least the first two treatment sessions, adverse events should be reported for at least 90 minutes. This includes monitoring the patient after each treatment session, and ensuring the patient is present for any two consecutive treatment sessions. Even after the treatment session, the patient did not experience any severe adverse events, Clinically significant increase in blood pressure, Moderate to severe level of dissociation, Moderate to high level of sedation, Moderate to severe levels of dizziness, and If you do not experience any of the adverse events of moderate to severe vertigo, The patient will have a post-treatment monitoring period of less than 90 minutes in the next treatment session. How to become an eligible patient.

[0141] Apparatus 2. The patient undergoes at least the first 3, 4, 5, 6, 7, or 8 treatment sessions. The method according to embodiment 1, wherein the patient becomes an eligible patient after the examination.

[0142] Applicable aspect 3. The post-treatment session monitoring period for eligible patients is at least 60 minutes, as in Applicable aspect 1 or The method described in section 2.

[0143] Apparatus 4. Before the treatment session, the patient's systolic blood pressure is less than 140 mmHg and 110 mmHg. If the patient does not have a diastolic blood pressure of less than mHg, the treatment session will be rescheduled, aspect 1~ The method described in any one of the three methods.

[0144] Embodiment 5. The patient does not currently have poorly controlled hypertension, according to any one of claims 1 to 4. Method of description.

[0145] Appearance 6. The patient has not taken any drugs or substances that promote sedation or an increase in blood pressure. Method 1 through 5.

[0146] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the patient is under 65 years of age.

[0147] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the depression is major depressive disorder.

[0148] Appearance 9. The depression is major depressive disorder with suicidal ideation or severe major depressive disorder. The method described in aspect 8.

[0149] 10. The method involves administering approximately 56 mg or 84 mg of esketamine per maintenance treatment session. The subsequent maintenance phase further includes intranasal administration of the drug to the patient, and the maintenance phase treatment session The treatment is performed once a week during the first four weeks of the maintenance phase, and then once a week or every other week thereafter. The method according to any one of embodiments 1 to 9, which is modified.

[0150] Embodiment 11. The method according to Embodiment 10, wherein the depression is major depressive disorder.

[0151] Embodiment 12. The method according to Embodiment 11, wherein the depression is treatment-resistant depression.

[0152] Appropriate 13. During the induction and maintenance phases, one or more antidepressants are administered in therapeutically effective doses. The method according to any one of embodiments 1 to 12, including adjunctive therapy.

[0153] Appearance 14. One or more antidepressants are administered during any induction or maintenance treatment session. The method according to embodiment 13, wherein the drug is administered at least 3 hours later.

[0154] Applicable aspect 15. In the following treatment session, eligible patients will receive approximately 56 mg or approximately 84 mg of E. Sketamine was administered intranasally, and the patient was monitored for less than 90 minutes during the post-treatment session monitoring period. After a medical professional determines that each patient is clinically stable and ready for discharge The method according to embodiment 1, which is released to

[0155] The following examples are provided to aid in understanding the present invention and are not included herein. The purpose is to limit the invention described in the "claims" in any sense. It was not done, nor should it be interpreted in that way. [Examples]

[0156] Example 1 Esketamine is a colorless, transparent intranasal solution of esketamine hydrochloride in a nasal spray pump. Supplied as (16.14 wt / vol[w / v], 14% w / v esketamine) (Equivalent to a base). The solution is 0.12 mg / mL of ethylenediaminetetraacetic acid (ED) in water for injection. TA) and 161.4 mg / m³ of citric acid (pH 4.5) are combined with 1.5 mg / mL of citric acid. It consists of L-grade esketamine hydrochloride (equivalent to 140 mg of esketamine base). The solution is administered via the nose. It is supplied in a spray pump, and the pump dispenses 16.14 mg of esketami per 100 μL of spray solution. The esketamine hydrochloride (14 mg) is delivered. Each individual nasal spray pump (device) It contains a total of 28 mg (i.e., enough for two sprays).

[0157] Example 2 Data were pooled from adult patients (18-64 years old) with TRD. Patients had recurrent episodes. Alternatively, a single episode (2 years or more) of MDD (DSM-5), depression assessed by 3 or more clinicians. Symptom item scores, and total Montgomery-Asberg Depression Rating Scale (Montgomery) scale scores of 2 or more items. - The patient had an Åsberg Depression Rating Scale (MADRS) score. Furthermore, depressive symptoms are present in the current depressive episode, with a commercially available O of 1 or more and 5 or less. The patient does not respond to appropriate AD testing. Non-response persists for more than 4 weeks during the screening phase. This was further confirmed by prospective studies of different OADs.

[0158] A. Test Design Simply put, Trial 1 was a double-blind, placebo-controlled relapse prevention trial, and in this trial... After 4 months of treatment using ESK in combination with FDA-approved OAD, the condition stabilized. Depressive symptoms in patients with TRD who showed either remission or a stable response. ESK vs. placebo nasal spray in delaying relapse (both used in combination with FDA-approved OAD) The effectiveness was compared. Trial 2 was an open-label, multicenter trial, and in this trial, participants had TRD. The long-term safety and efficacy of ESK in combination with FDA-approved OAD in patients were evaluated.

[0159] The analysis compared two doses of ESK (56) approved by the FDA for use in patients with TRD. The dosage was limited to mg and 84 mg. Patients received OAD in addition to the induction phase (weeks 1-4). ESK (56 or 84 mg) is administered twice a week, and once a week during the optimization phase from week 5 to 8. Then, during the 12-week optimization phase and the remainder of the maintenance phase, the medication is administered either once a week or every other week. (According to the severity of depressive symptoms [MADRS total score ≤ / >12] and tolerability) (Individualized).

[0160] B. Safety Evaluation Patients are monitored for at least 90 minutes after ESK administration in each treatment session, and thereafter at the clinician's discretion. The quantity allowed me to leave the clinical facility. I monitored and reported AEs, and performed clinical tests and physical examinations. Safety assessments, including those mentioned above, were conducted throughout the entire study. AEs reported by clinicians were based on clinical judgment. These were classified as mild, moderate, or severe (Table 1).

[0161] [Table 1]

[0162] Vital signs, Clinician-Managed Dissociative State Scale (CADSS), and modified wakefulness / sedation. Observer assessment of the scale (MOAA / S) is performed at baseline and throughout all treatment sessions. Evaluated (before administration, 40 minutes after administration, 1 hour after administration [unless voluntarily reported by the patient]) [Vital signs only] (1.5 hours later). Regular blood pressure (BP) readings during each treatment session. A cerebrospinal fluid sample was taken, and an elevated level was reported as an adverse event (AE) based on the clinician's judgment. CADSS was used. The dissociative symptoms that occurred during treatment were evaluated using 23 questions, each rated on a 5-point scale (0 = ). Coded as (not at all, 1=mild, 2=moderate, 3=severe, 4=extreme), total score 0 ~92 is obtained. A total CADSS score of 4 or higher in 11A indicates the presence of dissociative symptoms. OAA / S evaluates sedation that occurred during treatment, ranging from 0 = no response to painful stimuli to 5. =This score range represents the ability to easily respond to a name spoken in a normal tone. Any decrease in MOAA / s (score less than 5) indicated some degree of sedation. BP abnormalities A significant increase is defined as a systolic blood pressure of 180 mmHg or higher, which is 20 mmHg or more above baseline. , and / or diastolic blood pressure of 105 mmHg or higher and 15 mmHg or higher than baseline. It was defined as a case.

[0163] C. Analysis of the relationship between early AEs and AE recurrence This analysis includes all treatments in which patients received ESK (either open-label or blinded). A compression was included. The occurrence and severity of AEs were evaluated within the following time frame: Month 1 (Week 1 and Weeks 2-4), Month 2 (Weeks 5-8), Months 3-6, and Months 6-12 Eye. The severity of AEs reported by clinicians was 0 (no AE), 1 (mild), 2 (moderate), and It was scored as 3 (severe). To examine AEs in individual patients over time. Only patients who received at least one ESK dose during the following periods, for each respective period The data was included in the analysis between weeks. Therefore, the patient data was (i) the patient had at least once every 2-4 weeks. If ESK administration is received, (ii) the patient receives at least one ESK at weeks 5-8. If SK administration is received, it is retained at 2-4 weeks, and (iii) the patient does not need to have an SK injection once every 3-6 months. If the above ESK administration is received, it is retained at 5-8 weeks, and (iv) patients at 6-12 months If ESK has been administered once or more times, it is retained for 3 to 6 months.

[0164] Five of the most commonly reported occurrences during ESK plus OAD therapy The symptoms (dissociation, dizziness, nausea, sedation, and rotational vertigo) were evaluated, and each of them was assessed by... The incidence rate was 5% or more and at least twice that of racebo plus OAD. 14 BP We also investigated the increase in [the number of cases].

[0165] Weeks 1 and 4 are set a priori as indicator weeks because they mark the start and end of the implementation period. These indicators, the frequency of AEs reported during the week and the highest reported severity, will be used in future analysis. It functions as a stratification variable for examining the severity of recurrence and AE recurrence within a time frame. Ta.

[0166] Medication is administered to treat an emergency AE or to prevent the (re)occurrence of an AE. The number of patients was identified, and their potential role in influencing AE recurrence rates was investigated.

[0167] The data was summarized using descriptive statistics.

[0168] D. Results Of the 953 patients, 25 were excluded from all analyses, and of those 25, 21 were at the testing facility. This was due to concerns regarding the implementation (Figure 1). Sensitivity analysis including these excluded patients was performed. It was confirmed that this does not affect the overall conclusions of the study. Therefore, the dataset This included 928 patients in weeks 1-4, 918 patients in weeks 5-8, and 3-6 months The study included 595 patients in the first month and months 6-12. This included those attributable to adverse events (AEs). The reason why the patient was previously reported to have stopped and was excluded from subsequent timeframes within this analysis is: The randomization was primarily defined by the protocol for placebo in Trial 1. The average patient The average age of the patients was 46, and approximately two-thirds of the patients were female (Table 2).

[0169] [Table 2]

[0170] (i) Association between the frequency of AE occurrence in the first week and subsequent recurrence The higher the frequency of AEs occurring during the first week of treatment across the examined AEs, The percentage of patients experiencing relapses increases (Table 3).

[0171] [Table 3-1]

[0172] [Table 3-2]

[0173] [Table 4]

[0174] The percentage of dissociation reported by clinicians between weeks 2 and 4 across the entire patient population was 16.1%. In contrast, among patients who reported two dissociations in the first week, 86.5% (64 out of 74) Among patients who reported one dissociation per week, 48.2% (41 out of 85 patients) reported one dissociation per week. In patients who did not report any dissociation during the first week, the figure was 5.6% (44 out of 790). (Figure 2). AEs, dissociation, and sedation reported and investigated by each clinician based on a standardized scale. Regarding the percentage of static or increasing BP, the same general pattern (increasing frequency in week 1) The recurrence rate increased with age, which was observed (Figures 3A and 3B).

[0175] These results also show the size of the group most or least likely to experience AE recurrence. It also provides insights into the following: for example, the recurrence rate of all AEs reported by clinicians. The lowest group (the group in which no adverse events were reported in week 1) was the highest percentage of patients. This constitutes a minimum of 78% of the sample (Table 3). These percentages reflect the clinical significance recognized by clinicians. The percentage was low based on measurements of dissociation and sedation, which did not explain consciousness (4% of patients, respectively). (Not reported in 3% and 62% of cases during the first week).

[0176] (a) Increased blood pressure If elevated blood pressure is reported as an adverse event (AE) in the first week, recurrence may occur during the induction period (weeks 2-4). The likelihood of this occurring increased. Subsequently, in patients who experienced an increase in blood pressure twice in the first week, all The likelihood of recurrence is high at that point, and in patients who experienced it once in the first week, recurrence occurred over a period of 3 to 6 months. The likelihood of developing it increased. In patients whose blood pressure did not increase in the first week (95.7%), the subsequent During all subsequent post-administration monitoring periods, an increase in blood pressure was reported in less than 4% of patients. Blood pressure at week 4. The frequency of increases in blood pressure is more closely related to relapses in subsequent treatment sessions than the frequency of increases in blood pressure during the first week. It was related to the connection.

[0177] (b) evil intentions Of the patients who did not report nausea in the first week (86.0%), less than 6% experienced nausea after subsequent doses. Nausea was reported during the monitoring period. The frequency of nausea at week 4 is added to the predictive value at month 2. And nothing is added after that.

[0178] (c) Vomiting Participants who experienced vomiting once in the first week were more likely to vomit during the subsequent period. Of the eight participants who vomited twice in the first week, only one received voluntary related prophylactic or acute treatment. Although they received the treatment, none of them experienced vomiting during the subsequent period.

[0179] (d) dissociation Dissociation / perceptual changes include distortions of time and space, as well as illusions, loss of reality, and depersonalization. These symptoms include: the patient perceives these symptoms in relation to himself, his thoughts and feelings, and his surroundings. Patients who did not report dissociation in the first week Of the participants (83.2%), dissociation occurred in less than 10% of those who participated in the introductory period. Over 50% of patients who experienced two eye dissociations experienced an AE (external vascular event) dissociation between 3 and 6 months. The frequency of AEs in week 4 was higher than the incidence in week 1, indicating a recurrence of dissociation in subsequent treatment sessions. It seems to predict possibilities more accurately.

[0180] (ii) Correlation between the severity of a given AE experienced in the early stages of treatment and the severity of AE in the later stages of treatment. The ability to test whether the severity in week 1 or week 4 helps predict the severity thereafter is However, this was limited due to the small number of patients whose AEs were characterized as moderate or severe. For all AEs reported by clinicians, observation after the onset of the event in either week 1 or week 4. During the study period, fewer than five patients experienced severe relapses. These included dissociation, vertigo, and rotational vertigo. In the case of clinician-reported adverse events (AEs) other than nausea, observation is performed either at week 1 or week 4 after the onset. During the period, fewer than 10 patients experienced moderate relapses.

[0181] Despite the highest reported severity of AEs in week 1 or week 4, relapses were severe. The severity tended to be mild to moderate. Patients who did not report a given AE in the first week and A There was no consistent difference in the mean severity of recurrent AEs compared to patients with mild E. Regarding dissociation reported by clinicians, in patients with moderate or severe AE in the first week... In this context, the average relapse severity score was 1.5 for both at weeks 2-4, and 1.5 at week 5- At 8 weeks, the values ​​are 1.3 and 1.8; at 3-6 months, they are 1.4 and 1.2; and at 6-12 months... At the first month, the figures were 1.5 and 1.6 (1 in all timeframes for patients without dissociation in the first week). (Compared to .3).

[0182] A maximum CADSS total score of 14 or less (this generally indicates mild to moderate reported AEs) In patients with the following characteristics (corresponding to the range), there was no clear difference in the severity of relapse ( The average individual score across various follow-up timeframes was 1.2 to 1.4, where 1 = mild (Degree and 2 = moderate). Maximum CADSS total score is 15-24 and 24-42. The mean individual CADSS scores in patients across various follow-up timeframes The average score was 1.3-2.1, with fewer than 3 patients having a maximum CADSS score above 42. Despite the highest MOAA / S being reported in either week 1 or week 4, (most Low score = 0 [indicates the most severe sedation], high score = 5 [no sedation]), then average Relapses were mild (except for one patient with a mean relapse score of 3.25). (A 3.5~4.0).

[0183] (iii) At the end of the induction period (week 4) vs. week 1 for indications related to relapse rate or severity Comparison of the incidence of eye AEs The recurrence of adverse events (AEs) after 4 weeks is more closely related to the frequency of AEs at 4 weeks than to the frequency of AEs at 1 week. If no AE occurred in either week 1 or week 4, the prognosis for those conditions was... There was little difference in efficacy between weeks. This is because clinicians reported dissociation, sedation, and The increase in BP is shown in Figure 2. The relationship with other AEs is dissociation, sedation, and This includes the percentage based on the measurement of increased BP, and follows a similar pattern (Figures 3A to 3F). The difference in the latter was relatively small.

[0184] (iv) Effects of administration and concomitant medications Flexible dosing (ESK 56 or 84 mg) was permitted in the trial, and the individual patient's dose was determined. Because the dosage may vary within the administration time frame, patients should follow the most frequent dose during each period. Stratified. The low-dose effect was most pronounced in dissociation and dizziness. (Figures 4A-4I) The effect of dose on the AE recurrence rate is greater than the effect of the AE frequency in week 1. It was on a much smaller scale.

[0185] Proactive or symptomatic management of potential or observed AEs should be carried out within their respective timeframes. Because there were four or fewer patients who received preventative or symptomatic treatment for this AE, the observations were... The impact on the pattern was likely minimal (Table 4).

[0186] [Table 5]

[0187] In cases of dissociation, only three patients received symptomatic medication (alprazolam, lorazepam) throughout the trial period. While one patient received zepam, the other two patients received prophylactic drug administration (lorazepam) at all intervals. They received Pam, diazepam. Regarding blood pressure, two patients received symptomatic treatment (L) in weeks 2-4. While one person received sartan (captopril), the other two received symptomatic treatment between weeks 5 and 8. Patients who have received symptomatic medication for blood pressure two or more times are... Furthermore, no symptomatic medication for blood pressure was administered after the 8th week. In one patient, the symptoms persisted from the 2nd to the 4th week. Prophylactically, propranolol was administered between weeks 5 and 8. Four patients experienced worsening symptoms between weeks 2 and 4. One of the patients received medication for the heart (ondansetron), and during the following two periods... They received medication, and two of them each received symptomatic medication during an additional period. The medication was administered. Two patients received symptomatic medication (betahistamine) for dizziness during weeks 2-4. No patients who underwent the test subsequently received treatment for dizziness.

[0188] (v) Time to onset of adverse event The time to the onset of adverse events experienced by patients in Example 2 was analyzed. Tables 5-11 show the following: The following includes summaries of specific adverse events categorized by the maximum time to onset during the periods below. (i) Each time an AE occurs in the first week, it occurs during sessions 3-8 of the induction phase (Table 5) (ii) During the optimization period for each occurrence of AE in the first week (Table 6), (iii) during the occurrence of AE in the fourth week During the optimization period for each birth cycle (Table 7), (iv) each occurrence of AE in the first week, during the 3rd to 6th month of the maintenance period. (Table 8), (v) Each occurrence of AE at 4 weeks during the maintenance phase from 3 to 6 months (Table 9), (vi) A For each occurrence of E in the first week, the maintenance phase is considered from months 6 to 12 (Table 10), and (vii) 4 weeks of AE. For each period, the maintenance phase is from 6 to 12 months (Table 11).

[0189] [Table 6-1]

[0190] [Table 6-2]

[0191] [Table 6-3]

[0192] [Table 7-1]

[0193] [Table 7-2]

[0194] [Table 8-1]

[0195] [Table 8-2]

[0196] [Table 9-1]

[0197] [Table 9-2]

[0198] [Table 10-1]

[0199] [Table 10-2]

[0200] [Table 11-1]

[0201] [Table 11-2]

[0202] [Table 12-1]

[0203] [Table 12-2]

[0204] Tables 12-16 show the clinical data from Week 1 to 12 months using data from Example 2. Blood pressure reported by the attending physician (Table 12), dissociation reported by the clinician (Table 13), dizziness (Table 1) 4) The incidence of sedation (Table 15) and rotational vertigo (Table 16) is recorded. These data This indicates that adverse events, particularly dissociation and increased blood pressure, generally peak at 40 minutes.

[0205] [Table 13]

[0206] [Table 14]

[0207] [Table 15]

[0208] [Table 16]

[0209] [Table 17]

[0210] E. Discussion This trial indicates a high frequency of the given adverse event (AE) occurring during early post-administration monitoring of ESK treatment. It has become clear that the likelihood of recurrence increases during subsequent post-administration monitoring sessions. Yes. One of the most commonly reported adverse events was treated once or twice during the first week of treatment. Patients who experience this are more likely to suffer a recurrence of the same adverse event (AE) compared to patients who do not. Five of the most common adverse events (AEs) associated with TRD ESK + oral antidepressant treatment (dissociation, dizziness) If dizziness, nausea, sedation, or rotational vertigo occurs more frequently during the first week of treatment, then... The likelihood of recurrence increases after the initial episode. Dissociation, dizziness, nausea, sedation, rotational vertigo, and The reported severity of elevated blood pressure was mostly mild, both for the initial occurrence and recurrence. The severity was low, and there were very few severe cases. Clinicians reported dissociation, dizziness, nausea, and The incidence of sedation was highest in the first week of treatment with ESK + oral antidepressant, and then decreased thereafter. .

[0211] For each AE other than dissociation as defined by CADSS, the majority of patients report the AE in the first week. Because they did not disclose, they were stratified into the group with the lowest risk of recurrence (dissociation as defined by CADSS). (43% of patients belonged to this group.)

[0212] If an AE occurs in week 1 and week 4, the recurrence of the AE after week 4 (end of the introductory period) is... The frequency of the same AE was more closely correlated in week 4 than in week 1. In week 1 and week 4, A If none of E occurred, it did not provide different insights. A in weeks 1 and 4 The predictive utility for both E frequencies was generally strong during the first six months. The incidence of specific AEs in week 1 or week 4 is far higher than that of ESK doses, with a much higher risk of future AE recurrence. The frequency of AEs occurring during the post-administration monitoring period in the first week was a prognostic indicator. It best predicts the recurrence of AEs in the remaining subsequent treatment sessions (weeks 2-4), and generally... Predicts a lower recurrence rate of AEs afterward.

[0213] Among participants who did not spontaneously report an AE in the first week, the incidence of that AE was observed through testing. It was lower than the overall ratio in each subsequent time slot. Furthermore, given AE in week 1 If absent, the moderate dose effect observed in some AEs is due to the frequent occurrence of those AEs. It is almost non-existent due to recurrence. During the post-administration monitoring period, a given AE was reported in week 1. If not present, less than 10% of participants experienced adverse events (AEs) after subsequent treatment sessions. An exception is dizziness occurring between 3 and 6 months [11.6%].

[0214] The recurrence rate generally decreases over time.

[0215] Difference between formally measured dissociation, sedation, and abnormally elevated blood pressure (BP) and the percentage reported by clinicians. This is clear. These measurement approaches are inherently calibrated against various standards, Clinicians are encouraged to report adverse events (AEs) that are clinically important or that they are deemed worthy of treatment. Although it had been done, formal measurements showed deviations from the generally accepted standard of "normal" values. It simply detects the difference. Therefore, it is not surprising, but clinician reports... However, formal measurements revealed a higher percentage. Therefore, the same fundamental relationship exists between initial tolerability and later tolerability across measurement modalities. The person in charge was observed.

[0216] This trial showed that the recurrence rate was lower in patients who had not previously experienced the same adverse event. However, the recurrence rate of dissociation, sedation, and elevated blood pressure, as objectively measured, is never zero. It did not reach that point. Therefore, BP should be administered at least 40 minutes after ESK administration. Furthermore, evaluations should be made as needed based on clinical judgments, and patients should undergo sedation and dissociation before discharge. We need to monitor the situation for two hours to confirm that the issue has been resolved.

[0217] Example 3: Reduced monitoring procedure This embodiment summarizes the procedure for reduced monitoring as described herein.

[0218] Clinicians administering esketamine and implementing reduced monitoring for eligible patients should: All requirements, including but not limited to these, should be followed. • Maintain records showing that processes / procedures are implemented and followed. This includes measures related to reducing the monitoring of eligible patients. • All monitoring within 7 calendar days after administration of any dose, with less than the minimum 2-hour monitoring requirement. For eligible patients, submit the appropriate form to the clinician.

[0219] A. Considerations for identifying eligible patients Use the following criteria to identify patients who may be suitable for reduced monitoring: • The patient is enrolled in the option to become an eligible patient and reduced monitoring will be initiated. At that point, at least eight previous esketamine treatment sessions (i.e., beyond induction therapy) (receiving) • Patients will receive treatment sessions at least once a week once reduced monitoring is initiated. doing • The patient has received all esketamine treatment in any previous treatment session, including the following: The session and associated side effects were tolerated without requiring medical intervention, including emergency treatment. - No clinically significant increases in blood pressure or heart rate were observed. -Only mild dissociation is observed. -Only mild sedation or disorientation is observed. -Only mild nausea is observed, without vomiting. - No other clinically relevant side effects of concern based on clinical judgment. • Patients have currently uncontrolled hypertension associated with either cardiovascular or endocrine complications. I do not have it. - The patient is to be with the patient after the treatment session, and at least on that day. Two hours later, at an agreed time, the patient will be contacted by the clinician for a telephone assessment to evaluate the patient's clinical condition. The participant must have an adult caregiver / responsible adult who agrees to participate with them. - Adult caregivers / responsible adults can arrange follow-up phone assessments. I agree to provide the information (name, relationship, contact information) as described above.

[0220] B. Informed consent from patients and adult caregivers / responsible adults Informed consent includes the following: • Patients and / or clinicians include, but are not limited to, the following: patients and caregivers / responsible parties. Review the potential risks associated with supervising a responsible adult for less than two hours: - Ensure that patients and caregivers / responsible adults are aware of the potential risks. In urgent cases, I agree to administer and monitor the drug within 2 hours. This information needs to be documented by the healthcare provider. - If the patient's condition does not improve after the monitoring period, the patient and adult caregiver / responsible adult should Or, if you have any other related health problems, follow the instructions provided by your clinician. I agree to that. - Adult caregivers / responsible adults should, after the treatment session has ended, At least two hours after the end, an agreed-upon follow-up phone call with the clinician on the same day. I agree to stay with the patient until the evaluation is complete.

[0221] C. Instructions for the day of administration The reduced monitoring treatment option is available to eligible patients treated with esketamine at a medical institution. This is applicable only to home administration and monitoring of esketamine, and is not performed in that context.

[0222] Guidance on the day of administration (i) While the patient is in the medical facility • The relevant forms are completed by the clinician monitoring the patient at the healthcare facility. • Clinicians continue to monitor patients based on clinical judgment until they are clinically stable. To determine whether a patient is clinically stable, clinicians may observe the patient during treatment sessions. Confirm that the following clinical criteria are met: - No clinically significant increases in blood pressure or heart rate were observed. -Only mild dissociative symptoms were observed and resolved. -Only mild sedation was observed and resolved. - No other clinically relevant side effects of concern based on clinical judgment. Based on the clinical judgment of the clinician, if the patient is not ready for early discharge, the medical Medical facilities will accommodate patients for a full two hours or longer, if necessary. • After being monitored for at least one hour but less than two hours, the patient is clinically stable. If it is determined that this is the case, it must be documented. • Before discharge, the clinician must stay with the patient for at least 2 hours after the end of the treatment session. Shortly after, I agreed to participate with the patient in a telephone assessment conducted by HCP on the same day. Ensure that an adult caregiver / responsible adult is present. • Clinicians should ensure that the patient and adult caregiver / responsible adult have left the healthcare facility. When intervention is necessary, the patient and adult caregivers will be provided according to the healthcare institution's processes and procedures. Provide instructions to responsible adults.

[0223] After the HCP-monitored treatment session has ended: • Patients who were deemed clinically stable and discharged within 2 hours of esketamine administration. In order for the clinician to follow up on the patient's clinical condition after the treatment session has ended, At least two hours afterward, at the agreed time, the patient and the adult caregiver / responsible adult should be brought in. To intertwine. • During the caregiver / patient telephone assessment, the clinician will start the assessment after the treatment session has ended. Specifically ask if the patient has any new sedation or dissociation. The clinician will then... Document it in the system. • If the patient or adult caregiver / responsible adult reports a clinically relevant adverse event, The clinician should determine whether treatment for the adverse event is necessary, or whether a follow-up telephone evaluation should be conducted the following day. We need to determine whether scheduling it is appropriate. • If the patient requires medical intervention, the patient and the adult caregiver / responsible adult should contact the emergency room. This may include, but may also include, calling 911 to seek medical services, as suggested by a clinician. Follow the instructions provided. - All serious adverse events must be reported in any form. - All other non-serious adverse events (other than dissociation or sedation) related to esketamine or manufacturing Complaints about product quality must be reported. • Clinicians must submit all forms for all patients within 7 calendar days after administering all doses. ru. • After getting some rest, the patient should refrain from potentially dangerous activities such as driving a car or operating machinery until the next day. I agree not to engage in it. • If the patient fails to comply with all the necessary elements, the clinician may decide to discontinue future treatment sessions. We agree to cease reducing surveillance in [location].

[0224] D. Theoretical basis for the proposed elements (i) Determining which patients may be suitable candidates By requiring the patient to have received at least eight previous treatment sessions, The tolerability profile of those patients in subsequent administration sessions can likely be predicted. It is thought that...

[0225] In addition to requiring that the patient has no history of poorly controlled hypertension, the following requirements must be met. The case involves the patient not having any clinically significant problems in previous treatment sessions. Adding reliability: No clinically significant increase in blood pressure or heart rate is observed, mild resolution. Only mild sedation or disorientation was observed, and there was no vomiting. Only self-limiting nausea was observed, and clinical judgment indicated no other clinically relevant side effects of concern. It has no effect.

[0226] (ii) Duration of monitoring after administration The current proposal states that the duration of the post-administration monitoring period should be based on clinical stability as determined by clinical judgment. However, all patients should be monitored for at least one hour after administration.

[0227] Therefore, if no significant clinical problems are observed, at least eight treatment sessions have been previously performed. In established patients who have received the treatment, a minimum duration of one hour may cause the patient to dissociate, sedate, or hematoma. If you experience an increase in pressure, these events should begin within the first hour after administration. It is guaranteed that the patient will be able to monitor clinically. Subsequently, based on the current proposal, the monitoring period will be until the patient is able to monitor clinically. It will continue until it is determined.

[0228] If a patient is not ready for early discharge, the patient will be discharged completely if clinically necessary. You can stay for two hours or longer.

Claims

1. A method for treating depression in a human patient who requires treatment for depression, the method However, it has an introductory phase and treatment sessions, and the introductory phase has a duration of 4 weeks, and the method The law, For the aforementioned introductory treatment session, approximately 56 mg or approximately 84 mg of esketamine is administered to the patient. The drug is administered intranasally to the patient, and the induction treatment sessions are performed twice a week during the induction period. This is performed at a frequency such that, prior to each treatment session, the patient has a blood glucose level of less than 140 mmHg. Having a systolic blood pressure and a diastolic blood pressure of less than 110 mmHg, After at least the first two treatment sessions, adverse events should be reported for at least 90 minutes. During the period, including monitoring the patient after each treatment session, and if the patient is any After two consecutive treatment sessions, the patient did not experience any severe adverse events, Clinically significant increase in blood pressure, Clinically significant increase in heart rate, Moderate to severe level of dissociation, Moderate to severe levels of sedation or disorientation, and If you do not experience any of the following adverse events: moderate to severe nausea without vomiting, The aforementioned patient, in the next treatment session, had a post-treatment session monitoring period of less than 90 minutes. How to become a qualified patient.

2. The patient has undergone at least the first three, four, five, six, seven, or eight treatment sessions. The method according to claim 1, wherein the patient becomes an eligible patient after the procedure.

3. The method according to claim 1 or 2, wherein the patient becomes an eligible patient after eight treatment sessions. 。

4. Claims 1 to 3, wherein the post-treatment session monitoring period for the eligible patient is at least 60 minutes. The method described in any one of the items.

5. Prior to the treatment session, the patient's systolic blood pressure was less than 140 mmHg and 110 mmHg. If the patient does not have a diastolic blood pressure of less than g, the treatment session is rescheduled, claim 1. The method described in any one of items (4) above.

6. The patient does not currently have poorly controlled hypertension, as described in any one of claims 1 to 5. The method.

7. Claim 1: The patient has not taken any drugs or substances that promote sedation or an increase in blood pressure. The method described in any one of items ~6.

8. The method according to any one of claims 1 to 7, wherein the patient is under 65 years of age.

9. The method according to any one of claims 1 to 8, wherein the depression is major depressive disorder.

10. The claim states that the depression is major depressive disorder with suicidal ideation or severe major depressive disorder. The method described in item 8.

11. The above method involves administering approximately 56 mg or approximately 84 mg of esketamine per maintenance treatment session. The treatment further includes a subsequent maintenance phase, which involves intranasal administration to the patient. The treatment is performed once a week during the first four weeks of the maintenance period, and thereafter once a week or every other week. The method according to any one of claims 1 to 10, which is adjusted in a single step.

12. The method according to claim 11, wherein the depression is major depressive disorder.

13. The method according to claim 12, wherein the depression is treatment-resistant depression.

14. During the induction and maintenance phases, supplemental use of one or more antidepressants in therapeutically effective doses. The method according to any one of claims 1 to 13, including auxiliary treatment.

15. If one or more of the aforementioned antidepressants are administered after any induction or maintenance treatment session The method according to claim 14, wherein the administration is performed at least three hours later.

16. In the following treatment session, the eligible patient will receive approximately 56 mg or approximately 84 mg of es. Ketamine was administered intranasally, and the patient was monitored for less than 90 minutes during the post-treatment session monitoring period. A healthcare professional determines that the eligible patient is clinically stable and ready for discharge. The method according to claim 1, wherein the person is released after the person is released.

17. Esketami for use in the treatment of depression in human patients who require treatment for depression The treatment comprises an introductory phase and treatment sessions, and the introductory phase lasts for four weeks. It has a duration, and For the aforementioned introductory treatment session, approximately 56 mg or approximately 84 mg of esketamine is administered to the patient. The drug is administered intranasally to the patient, and the induction treatment sessions are performed twice a week during the induction period. This is performed at a frequency such that, prior to each treatment session, the patient has a blood glucose level of less than 140 mmHg. Having a systolic blood pressure and a diastolic blood pressure of less than 110 mmHg, After at least the first two treatment sessions, adverse events should be reported for at least 90 minutes. During the period, including monitoring the patient after each treatment session, and if the patient is any After two consecutive treatment sessions, the patient did not experience any severe adverse events, Clinically significant increase in blood pressure, Clinically significant increase in heart rate, Moderate to severe level of dissociation, Moderate to severe levels of sedation or disorientation, and If you do not experience any of the following adverse events: moderate to severe nausea without vomiting, The aforementioned patient, in the next treatment session, had a post-treatment session monitoring period of less than 90 minutes. To become a qualified patient, esketamine.

18. The patient has undergone at least the first three, four, five, six, seven, or eight treatment sessions. The method according to claim 17, wherein the patient becomes an eligible patient after the examination.

19. The patient becomes eligible after eight treatment sessions, according to claim 17 or 18. Esketamine.

20. Claim 17 - The post-treatment session monitoring period for the eligible patient is at least 60 minutes. Esketamine as described in any one of item 19.

21. Prior to the treatment session, the patient's systolic blood pressure was less than 140 mmHg and 110 mmHg. If the patient does not have a diastolic blood pressure of less than g, the treatment session is rescheduled, claim 1. Esketamine as described in any one of items 7 to 20.

22. The patient does not currently have poorly controlled hypertension, according to any one of claims 17 to 21. Esketamine as described.

23. Claim 1: The patient has not taken any drugs or substances that promote sedation or an increase in blood pressure. Esketamine as described in any one of items 7 to 22.

24. The esketami according to any one of claims 17 to 23, wherein the patient is under 65 years of age. hmm.

25. The depression is major depressive disorder, according to any one of claims 17 to 24. Ketamine.

26. The claim states that the depression is major depressive disorder with suicidal ideation or severe major depressive disorder. Esketamine as described in item 24.

27. The above method involves administering approximately 56 mg or approximately 84 mg of esketamine per maintenance treatment session. The treatment further includes a subsequent maintenance phase, which involves intranasal administration to the patient. The treatment is performed once a week during the first four weeks of the maintenance period, and thereafter once a week or every other week. An esketamine according to any one of claims 17 to 26, which is prepared in a single dose.

28. The esketamine according to claim 27, wherein the depression is major depressive disorder.

29. The esketamine according to claim 28, wherein the depression is treatment-resistant depression.

30. During the induction and maintenance phases, supplemental use of one or more antidepressants in therapeutically effective doses. Esketamine according to any one of claims 17 to 29, including adjunct therapy.

31. If one or more of the aforementioned antidepressants are administered after any induction or maintenance treatment session The esketamine according to claim 30, which is administered at least three hours later.

32. In the following treatment session, the eligible patient will receive approximately 56 mg or approximately 84 mg of es. Ketamine was administered intranasally, and the patient was monitored for less than 90 minutes during the post-treatment session monitoring period. A healthcare professional determines that the eligible patient is clinically stable and ready for discharge. The method according to claim 17, wherein the person is released after the person has been released.

Images