Treatment methods for depression

Abstract

The present disclosure is directed to a method of treating depression in a human patient in need thereof, whereby certain patients may be eligible for a shortened monitoring period following a treatment session. The method is based on an analysis of adverse events and provides treatment options to the patient and healthcare provider.

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 balance of risk - benefit equilibrium 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.

[0004] Not all patients are 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 about how the drug's AE profile changes over time and the degree of a patient's tolerance early in the treatment process, providing insight into how AEs may manifest as the treatment progresses.

[0005] Esketamine (ESK) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist approved for use in combination with Food and Drug Administration-approved oral antidepressants (OADs) for the treatment of adults with treatment-resistant major depressive disorder (TRD). In this art, it is necessary to adapt treatment protocols for patients who respond well to esketamine during treatment. [Overview of the Initiative] [Means for solving the problem]

[0006] In some embodiments, this disclosure relates to a method for treating depression in a human patient requiring treatment for depression, the method comprising an induction phase and treatment sessions, the induction phase having a duration of 4 weeks. Prior to any treatment session, the patient has a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg. The method comprises intranasal administration of approximately 56 mg or approximately 84 mg of esketamine per induction treatment session, the induction treatment sessions being performed twice a week during the induction phase. After at least the first two treatment sessions, the patient is monitored for adverse events for at least 90 minutes. If a patient does not experience any severe adverse events after any two consecutive treatment sessions, and does not experience any clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate to severe dissociation, moderate to severe disorientation, moderate to severe sedation, moderate to severe dizziness, moderate to severe nausea without vomiting, and / or moderate to severe vertigo, the patient is eligible for a post-treatment monitoring period of less than 90 minutes in the next treatment session. In some aspects, depression may be major depressive disorder, major depressive disorder with suicidal ideation, or treatment-resistant depression. For example, the method is suitable for treating severe major depressive disorder when emergency symptom management is required.

[0007] The method is applicable to patients who do not currently have poorly controlled hypertension, who are not taking sedatives or blood pressure-raising drugs or substances, and / or patients under 65 years of age.

[0008] In other embodiments, the method further comprises a subsequent maintenance phase, which includes intranasal administration of approximately 56 mg or approximately 84 mg of esketamine to the patient per maintenance treatment session, the maintenance treatment sessions being performed once a week for the first four weeks of the maintenance phase, and thereafter adjusted to once a week or 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] This line graph shows the percentage of esketamine treatment participants experiencing adverse events, based on the incidence of increased blood pressure reported by clinicians during weeks 1 and 4. [Figure 3A] This line graph shows the percentage of participants in esketamine treatment who experienced adverse events based on the incidence of dissociation according to CADSS at weeks 1 and 4. [Figure 3B] This line graph shows the percentage of participants in esketamine treatment experiencing adverse events, based on the incidence of adverse events at weeks 1 and 4, for MOASS-based sedation. [Figure 3C] This line graph shows the percentage of participants in esketamine treatment who experienced adverse events, based on the frequency of blood pressure increases measured at weeks 1 and 4. [Figure 3D] This line graph shows the percentage of participants in esketamine treatment who experienced adverse events, based on the frequency of dizziness reported by clinicians during weeks 1 and 4. [Figure 3E] This line graph shows the percentage of esketamine treatment participants experiencing adverse events, based on the incidence of nausea reported by clinicians at weeks 1 and 4. [Figure 3F] This line graph shows the percentage of participants in esketamine treatment who experienced adverse events, based on the incidence of rotational vertigo reported by clinicians at weeks 1 and 4. [Figure 4A] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the esketamine nasal spray dose, for dissociation reported by clinicians. [Figure 4B] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the esketamine nasal spray dose, as reported by clinicians. [Figure 4C] This line graph shows the percentage of patients treated with esketamine who experienced adverse events based on the dose of esketamine nasal spray, with regard to the increase in blood pressure reported 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 addressing patients at risk of rare adverse events are disclosed, and a shorter post-treatment session (post-administration) monitoring period is disclosed for eligible patients. Monitoring and releasing patients over a shorter period saves time and resources. Part of developing esketamine administration instructions is to understand the occurrence of adverse events that may exist in specific patient populations, for which special precautions may be necessary for that class of patients. Thus, the method considered herein facilitates clinician-patient conversations about the likelihood of recurrence of specific AEs during upcoming ESK treatment sessions, thereby promoting treatment compliance and determining the treatment most likely to be acceptable to the patient. This method is also useful in structuring the clinician's thinking about the strategies that may be most relevant to managing a given patient in upcoming administration sessions. In doing so, patient treatment is personalized.

[0011] The higher the frequency of adverse events (AEs) in patients during the first two treatment sessions (e.g., the first week of treatment), the higher the percentage of patients who experienced relapses. Similar patterns of AEs were observed at week 4, and the week 4 pattern was more predictive of subsequent AEs. For example, the clinician-reported rate of dissociation between weeks 2 and 4 for the entire patient population was 16.1%, compared to 86.5% (64 out of 74 patients) for patients who reported two dissociations in week 1, 48.2% (41 out of 85 patients) for patients who reported one dissociation in week 1, and 5.6% (44 out of 790 patients) for patients who reported no dissociations in week 1. For all AEs reported by clinicians surveyed, at least 78% of patients were associated with the category with the lowest relapse rate, i.e., those who did not report any AEs in week 1. The severity of all serious AEs also decreased after long-term drug administration (e.g., 4, 8, or 12 weeks). Therefore, based on the accumulated data on AEs, it is possible to stratify patients in relation to various frequencies of AE recurrence. The practical implications of these findings are that, using patient stratification linked to knowledge of AE occurrence data, patients can be stratified into different groups, and eligible patients with a low frequency of AEs should request a shorter monitoring period for AEs before receiving a physician's assessment for relief.

[0012] The methods described herein are intended for the treatment of human patients in need of treatment for depression (i.e., major depressive disorder (MDD), treatment-resistant depression (TRD), major depressive disorder with suicidal ideation (MDSI)), or severe major depressive disorder. The methods preferably enable certain patients, i.e., eligible patients, to have a shorter post-treatment session (post-administration) monitoring period and to be able to leave the treatment facility earlier than ineligible patients or periods that may have been established as conventional monitoring periods (or conventional product labels). Typically, such patients are considered clinically stable based on clinical judgment.

[0013] As used herein, unless otherwise specified, the terms "subject" and "patient" refer to a human being who is the subject of treatment, observation, or experiment. Preferably, the patient is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the patient is an adult. As used herein, the term "adult" refers to a human being who is less than about 65 years old as used herein. In other embodiments, the term "adult" refers to a human patient who is 18 years old to about 64 years old. As used herein, the term "elderly" refers to those over 65 years old.

[0014] As used herein, the term "depression" (also referred to as depressive disorder) includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, midlife depression, late-life depression, depression due to identifiable stress factors, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, major depressive disorder is accompanied by features of melancholy or distress due to anxiety. In further embodiments, the depression is treatment-resistant depression. In some embodiments, the depression is major depressive disorder accompanied by suicidal ideation.

[0015] As is known in the art, a patient exhibits five or more symptoms that are changes from previous functioning during the same two-week period, and there must be a presence of a depressed mood and / or loss of interest / pleasure, and the patient is considered to have major depressive disorder when excluding symptoms clearly attributable to another physical illness. 1. Depressed mood: Most of the day, almost every day, either self-aware (e.g., feeling sad, empty, hopeless) or observable by others (e.g., appearing to be crying), and in children and adolescents, it can be an irritable mood 2. Loss of interest / pleasure: Marked decrease in interest / pleasure in all (or almost all) activities, most of the day, almost every day, either self-aware or observable by others 3. Weight loss or gain: Significant weight loss (without dietary therapy) or weight gain (more than 5% change in weight per month), or decreased or increased appetite on a nearly daily basis. In children, there is a possibility that weight may not increase as expected. 4. Insomnia or excessive sleep: almost every day 5. Psychomotor disturbances or stillness: Observable by others almost daily (not merely subjective restlessness or slowness) 6. Fatigue: or a decline in energy, almost daily. 7. Feelings of worthlessness or excessive / inappropriate guilt almost daily: The guilt may be delusional and not merely self-reproach or guilt about being ill. 8. Decreased concentration: You may experience difficulty making decisions almost every day, and this may be noticeable to yourself or others. 9. Thoughts of death / suicide, recurring thoughts about death (not just fear of death), repeated suicidal thoughts without a specific plan, or suicide attempts or specific plans for suicide.

[0016] To be diagnosed with MDD, the following criteria must also be met: 1. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. 2. The episode is not caused by the physiological effects of a substance or another medical condition. 3. The episode is not better described by schizoaffective disorder, schizophrenia, schizophrenia-like disorder, delusional disorder, or other identified and unidentified schizophrenia spectrum and other psychotic disorders. 4. No history of manic or hypomanic episodes.

[0017] Major depressive disorder can be classified as mild, moderate, or severe. In some embodiments, MDD is mild. In other embodiments, MDD is moderate. In further embodiments, MDD is severe. As used herein, “mild MDD” applies to patients who have few or no symptoms beyond those necessary to make a diagnosis, whose symptoms are distressing but manageable, and whose symptoms result in mild impairment in social or occupational functioning. Mild MDD may be a single episode (DSM ICD-10F32.0) or recurrent episodes (DSM ICD-10F33.0). “Moderate MDD” applies to patients who have a number of symptoms, symptom intensity, and / or functional impairment that falls between those designated as “mild” and those designated as “severe.” Moderate MDD may be a single episode (DSM ICD-10F32.1) or recurrent episodes (DSM ICD-10F33.1). "Severe MDD" applies to patients whose number of symptoms significantly exceeds those required to make a diagnosis, whose symptoms are severely distressing, whose symptoms significantly interfere with social and occupational functioning, and who require emergency symptom management. In some embodiments, severe MDD may be a single episode (DSM ICD-10F32.2) or recurrent episodes (DSM ICD-10F33.2).

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

[0019] As used herein, the term “treatment-refractory or treatment-resistant depression” and the abbreviation “TRD” are defined as major depressive disorder in patients who have not responded adequately to at least two different antidepressants, preferably two to five, in a current depressive episode. Such patients may require emergency treatment for severe depression or a severe depressive episode. In other embodiments, TRD is defined as major depressive disorder in patients who have not responded to at least two oral antidepressants in appropriate doses and durations in a current depressive episode.

[0020] As used herein, “suicide” means “the act of taking one’s own life.” See http: / / en.wikipedia.org / wiki / Suicide - cite_note-7. Suicide includes attempted suicide or non-lethal suicidal behavior, which is self-inflicted with a desire to end one’s own life but does not result in death. Attempted suicide is a sequence of self-initiated actions by an individual who, at the outset, anticipates that the series of actions will lead to their own death.

[0021] As used herein, “suicidal ideation” refers to thoughts or an abnormal preoccupation with suicide, or thoughts of ending one's own life or a desire to no longer live, but not necessarily involving any active attempt to commit suicide. The range of suicidal ideation is broad, from transient to chronic and progressing to detailed planning, role-playing, and failed attempts, which may be intentionally constructed to fail or be discovered, or fully intended to result in death. In some embodiments, a patient is classified as having “suicidal tendencies” if the patient has an average baseline MADRS total score of approximately 38 or higher. In other embodiments, a patient is classified as having suicidal tendencies if the patient has an average baseline BBSS score of 22 or higher. In further embodiments, a patient is classified as having suicidal tendencies if the patient has a score of 6 or higher on the SIBAT clinical global assessment of suicide risk. In yet another embodiment, a patient has one or more of these scores. "Suicidal ideation with intent" includes thoughts (even momentarily) about one's own injury, pain, or harm, which can be identified through questioning of a patient in consideration of the scales / tools disclosed herein, and which involve at least some degree of intent or awareness that the result may be death; or thoughts about suicide (i.e., about killing oneself and having the will to act in accordance with the thought of killing oneself).

[0022] Prior to any treatment session described herein, for safety reasons, the patient should have a systolic blood pressure of less than approximately 140 mmHg and a diastolic blood pressure of less than approximately 110 mmHg, preferably less than approximately 100 mmHg, and more preferably less than approximately 90 mmHg. In some embodiments, when systolic blood pressure is considered normal, the patient has a systolic blood pressure of approximately 140 mmHg, approximately 138 mmHg, approximately 135 mmHg, 130 mmHg, 125 mmHg, 120 mmHg, 115 mmHg, 100 mmHg, 110 mmHg, 90 mmHg, or less. In a further embodiment, the systolic blood pressure is approximately 90–135, approximately 90–130, approximately 90–120, approximately 90–110, approximately 90–100, approximately 100–135, approximately 100–130, approximately 100–120, approximately 100–110, approximately 110–135, approximately 110–130, approximately 110–120, approximately 120–135, or approximately 130–135 mmHg. In another embodiment, the patient's diastolic blood pressure is less than approximately 110 mmHg. In yet another embodiment, if the diastolic blood pressure is considered normal, the patient's diastolic blood pressure is approximately 110, 100, 105, 100, 90, 80, 70, 60, or less than 50 mmHg. In further embodiments, the patient's diastolic blood pressure is approximately 50–110, 50–100, 50–90, 50–80, 50–70, 50–60, 60–110, 60–100, 60–90, 60–80, 60–70, 70–110, 70–100, 70–90, 70–80, 80–110, 80–100, 80–90, 90–110, or 90–100 mmHg. If the patient does 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 does not currently have uncontrolled hypertension prior to or after administration of esketamine. As used herein, the terms “hypertension” or “hypertension” are interchangeable and refer to patients with stage 2 hypertension, i.e., a systolic pressure of about 140 mmHg or greater. Typically, “uncontrolled” hypertension is understood to mean that the systolic blood pressure cannot be lowered to below about 140 mmHg even by using medication, engaging in exercise, following a special diet, limiting alcohol, losing weight, smoking, or eliminating other factors known to contribute to hypertension. In some embodiments, hypertension is associated with cardiovascular comorbidities, endocrine comorbidities, or a combination thereof.

[0024] Prior to eligibility for a shortened post-treatment session monitoring period, the patient, or in some embodiments, the caregiver, provides informed consent to the methods described herein. By doing so, the patient understands the implications of the treatment methods, including any possible adverse events. In some embodiments, informed consent is documented, i.e., includes the creation of a form agreeing to one or more guidelines regarding the disclosed methods. In other embodiments, informed consent includes verbal agreement to one or more guidelines regarding the methods described herein. Generally, the patient is aware of the potential risks associated with monitoring for less than two hours. In particular, the patient is aware of the potential risks and, if eligible, agrees to proceed with the administration of esketamine and monitoring for less than two hours. In some embodiments, the patient agrees to follow instructions provided by the clinician if the patient is unwell or has any other relevant health problems after the post-treatment session monitoring period. In other embodiments, the caregiver or responsible adult agrees to stay with the patient after the treatment session has ended, after the post-treatment monitoring period has ended, and until an agreed-upon follow-up assessment, i.e., a telephone call with the clinician, is made, preferably for at least two hours after the end of the treatment session, or at the latest, throughout the day. In further embodiments, the clinician provides instructions to the patient and the caregiver or responsible adult in accordance with the healthcare institution's processes and procedures in case the patient requires medical intervention after the patient and the adult caregiver / responsible adult have left the clinic. In yet another embodiment, if the patient requires medical intervention, the patient agrees to follow the instructions provided by the clinician.

[0025] However, the attending physician may use clinical judgment when deciding whether to prescribe certain concomitant medications due to their potential effects on patients taking esketamine. For example, certain concomitant / contraindicated medications, opioids, and alcohol may produce adverse effects such as sedation that may affect a patient's ability to become or remain an eligible patient. Therefore, limiting, minimizing, or eliminating the administration of such concomitant / contraindicated medications, opioids, and alcohol may help to qualify and maintain a patient as an eligible patient for the treatment methods described herein. In some embodiments, concomitant medications may promote dizziness, sedation, i.e., a sedative effect, or an increase in blood pressure. In other embodiments, concomitant medications may include, but are not limited to, central nervous system depressants (e.g., benzodiazepines, opioids, alcohol), psychostimulants (e.g., amphetamines, methylphenidate, modaphanil, almodafinil), and monoamine oxidase inhibitor (MAOI) inhibitors. Examples of benzodiazepines include diazepam (Zetran), estazolam (Prosom(Pro)), quazepam (Doral(Pro)), alprazolam (Niravam(Pro)), diazepam (Diazepam Intensol), alprazolam (Alprazolam Intensol(Pro)), clorazepate (Tranxene), alprazolam (Xanax XR(Pro)), clonazepam (KlonopinWafer), chlordiazepoxide (Librium(Pro)), oxazepam (Serax), alprazolam (Xanax(Pro)), and lorazepam (Lorazepam). Examples include Intensol (Pro), flurazepam (Dalmane), clonazepam (Klonopin (Pro)), diazepam (Valium (Pro)), triazolam (Halcion (Pro)), lorazepam (Ativan (Pro)), chlorazepic acid (Tranxene T-Tab (Pro)), temazepam (Restoril (Pro)), chlorazepic acid (Tranxene SD), midazolam (Versed), midazolam (Nayzilam (Pro)), and midazolam (Seizalam).

[0026] The terms “adverse event,” “side effect,” and “AE” are used interchangeably herein and refer to an undesirable medical occurrence. An adverse event is any undesirable and unintended sign, symptom, or disease that is temporally related to the method herein. In some embodiments, an adverse event is not related to the method herein. In other embodiments, an adverse event is related to the method herein. An adverse event includes any occurrence that is a new onset or worsening in severity or frequency from a baseline state, or an abnormal outcome of a diagnostic procedure, including abnormal clinical laboratory findings. In some embodiments, an adverse event is a cardiac dysfunction such as tachycardia. In other embodiments, an adverse event is an ear and inner ear disorder such as vertigo. In further embodiments, an adverse event is a gastrointestinal disorder such as constipation, diarrhea, dry mouth, nausea, or vomiting, or a combination thereof. In yet another embodiment, an adverse event is a general disorder / administration site condition such as an abnormal sensation, dizziness, or a combination thereof. In yet another embodiment, an adverse event is an increase in blood pressure. In yet another embodiment, an adverse event is a clinically significant increase in heart rate. In other embodiments, adverse events include neurological disorders such as dizziness, dysarthria, dysgeusia, headache, hypoesthesia, lethargy, mental disorders, sedation, or tremor, or a combination thereof. In further embodiments, adverse events include mental disorders such as anxiety, dissociation, euphoria, insomnia, or a combination thereof. In yet another embodiment, adverse events include renal and urinary disorders such as frequent urination. In yet another embodiment, adverse events include respiratory, thoracic, and mediastinal disorders such as nasal discomfort, oropharyngeal pain, pharyngeal irritation, or a combination thereof. In other embodiments, adverse events include skin and subcutaneous tissue disorders such as excessive sweating. In yet another embodiment, adverse events include disorientation.

[0027] Anxiety includes agitation, anticipatory anxiety, fear, phobias, nervousness, irritability, squeakiness, panic attacks, tension, or a combination thereof. In some embodiments, the adverse event is agitation. In other embodiments, the adverse event is anticipatory anxiety. In yet another embodiment, the adverse event is ordinary anxiety. In yet another embodiment, the adverse event is nervousness. In yet another embodiment, the adverse event is fear. In other embodiments, the anxiety is irritability. In yet another embodiment, the adverse event is squeakiness. In yet another embodiment, the adverse event is panic attacks. In yet another embodiment, the anxiety is tension.

[0028] "Increased blood pressure" or variations thereof include increased diastolic blood pressure, increased total blood pressure, increased systolic blood pressure, hypertension, or a combination thereof. In some embodiments, the adverse event is increased diastolic blood pressure. In further embodiments, the adverse event is increased total blood pressure. In other embodiments, the adverse event is increased systolic blood pressure. In yet another embodiment, the adverse event is hypertension.

[0029] Disorientation includes, in particular, transient states of confusion regarding time, place, or identity as a result of medication. Those skilled in the art will be able to identify disorientation in a patient.

[0030] Dissociation, that is, sensations detached from space and / or time, includes delusional perception, depersonalization / derealization disorder, derealization, diplopia, paresthesia, coldness, heat, sensation of body temperature change, hallucinations, auditory hallucinations, visual hallucinations, hyperacusis, illusions, eye discomfort, oral paresthesia, paresthesia, oral paresthesia, pharyngeal paresthesia, photophobia, altered temporal perception, tinnitus, blurred vision, visual impairment, or combinations thereof. In some embodiments, the adverse event is delusional perception. In other embodiments, the adverse event is depersonalization / derealization disorder. In yet another embodiment, the adverse event is derealization. In yet another embodiment, the adverse event is diplopia. In yet another embodiment, the adverse event is dissociation. In yet another embodiment, the adverse event is paresthesia. In other embodiments, the adverse event is coldness. In yet another embodiment, the adverse event is heat. In yet another embodiment, the adverse event is the sensation of body temperature change. In yet another embodiment, the adverse event is hallucinations. In other embodiments, the adverse event is auditory hallucinations. In yet another embodiment, the adverse event is visual hallucinations. In yet another embodiment, the adverse event is auditory hypersensitivity. In yet another embodiment, the adverse event is illusion. In other embodiments, the adverse event is eye discomfort. In yet another embodiment, the adverse event is oral paresthesia. In yet another embodiment, the adverse event is paresthesia. In yet another embodiment, the adverse event is oral paresthesia. In yet another embodiment, the adverse event is pharyngeal paresthesia. In other embodiments, the adverse event is photophobia. In yet another embodiment, the adverse event is altered time perception. In yet another embodiment, the adverse event is tinnitus. In yet another embodiment, the adverse event is blurred vision. In yet another embodiment, the adverse event is visual impairment.

[0031] Dizziness includes dizziness, exertional dizziness, postural dizziness, treatment-induced 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. In yet another embodiment, the adverse event is treatment-induced dizziness.

[0032] Dysarthria includes dysarthria, language development delay, speech disorders, or a combination thereof. In some embodiments, the adverse event is dysarthria. In further embodiments, the adverse event is language development delay. In other embodiments, the adverse event is speech disorders.

[0033] Taste disorders include taste disorders or taste hypoesthesia. In some embodiments, the adverse event is taste disorder. In further embodiments, the adverse event is taste hypoesthesia.

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

[0035] "Increased heart rate" or variations thereof includes an increase in heart rate measured in beats per minute (bpm).

[0036] Sensory impairment includes oral hypoesthesia, dental hypoesthesia, or pharyngeal hypoesthesia. In some embodiments, the adverse event is sensory impairment. In other embodiments, the adverse event is oral hypoesthesia. In yet another embodiment, the adverse event is dental hypoesthesia. In yet another embodiment, the adverse event is pharyngeal hypoesthesia.

[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 crusting, nasal discomfort, nasal dryness, or nasal itching, or a combination thereof. In some embodiments, the adverse event is nasal crusting. In other embodiments, the adverse event is nasal discomfort. In yet another embodiment, the adverse event is nasal dryness. In yet another embodiment, the adverse event is nasal itching.

[0039] Nausea includes the sensation of an urge to vomit. Nausea can be short-lived or prolonged, and / or acute or systemic. Nausea may be accompanied by other symptoms, among others, such as diarrhea, gas, or constipation. In some embodiments, nausea may be mild, moderate, or severe. In other embodiments, nausea may not be accompanied by vomiting. Those skilled in the art will be able to determine whether a patient has nausea.

[0040] Sedation, or drowsiness, includes altered states of consciousness, hypersomnia, sedation, somnolence, or a combination thereof. In some embodiments, the adverse event is an altered state of consciousness. In further embodiments, the adverse event is hypersomnia. In other embodiments, the adverse event is sedation. In yet another embodiment, 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 increased heart rate. In further embodiments, the adverse event is tachycardia.

[0042] Rotational vertigo includes rotational vertigo or postural rotational vertigo. In some embodiments, the adverse event is rotational vertigo. In other embodiments, the adverse event is postural rotational vertigo.

[0043] As used herein, the terms “serious adverse event,” “serious side effect,” and “SAE” are interchangeable and defined in accordance with the ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 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 was at risk of death at the time of the serious adverse event. In further embodiments, a serious adverse event requires hospitalization or extension of the current hospitalization of a hospitalized patient. In yet another embodiment, a serious adverse event results in persistent or significant physical disability or incapacity. In yet another embodiment, a serious adverse event is a birth defect / birth abnormality. In another embodiment, a serious adverse event is a suspected transmission of some infectious agent through the drug. In a further embodiment, the serious adverse event is syncope. In yet another embodiment, the adverse event is spinning. In yet another embodiment, the serious adverse event is anxiety.

[0044] The method comprises a 4-week induction phase and treatment sessions. As used herein, the “induction phase” refers to the period during which esketamine is first administered to the patient. In some embodiments, the induction phase is long enough to achieve a robust and stable reduction of depressive symptoms. For certain indications, such as MDD with suicidal ideation, severe MDD, or severe MDD requiring emergency symptom management, the treatment method consists of an induction phase only, i.e., does not include a maintenance phase.

[0045] During the induction period, patients receive approximately 56 mg or 84 mg of esketamine per induction treatment session, at least twice a week for four weeks. The amount of esketamine administered during the induction period 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 induction period is approximately 84 mg.

[0046] As will be discussed below, the nasal spray device is a single-use device that, in certain embodiments, delivers a total of 28 mg of esketamine in two sprays (one spray per nostril). The device may be operated by the patient under the supervision of a healthcare professional or healthcare provider. With respect to dosage, one device may be used for a 28 mg dose, two devices for a 56 mg dose, or three devices for an 84 mg dose. Thus, as used herein, the term “treatment session” refers to the period of time required to administer the prescribed dose of esketamine (e.g., 56 or 84 mg). Treatment sessions include, where applicable, an induction treatment session and a maintenance treatment session. It is also preferable to have a 5-minute interval between the use of each device. Typically, time 0 is defined as the time of administration of the first intranasal spray from the first intranasal device into one nostril. During a treatment session, the specified dose of esketamine is administered. For example, a treatment session for 56 mg of esketamine may include two sprays from the first device and two sprays from the second device. As another example, a treatment session for 84 mg of esketamine may include two sprays from the first device (one spray into each nostril), two sprays from the second device (one spray into each nostril), and two sprays from the third device (one spray into each nostril). However, more devices may be used as needed, for example, if a device malfunctions and additional devices are required to administer the required dosage or amount of esketamine. A treatment session typically begins when the first spray is administered from the first device into one nostril. A treatment session ends when the last spray is administered from the last device into the nostril.

[0047] As used herein, the term “twice a week” refers to a frequency of two doses within a one-week (7-day) period. For example, “twice a week” may refer to the administration of esketamine as used herein. In some embodiments, “twice a week” refers to a frequency of one day and two days of the week. In other embodiments, “twice a week” refers to a frequency of one day and three days of the week. In further embodiments, “twice a week” refers to a frequency of one day and four days of the week. In yet another embodiment, “twice a week” refers to a frequency of one day and five days of the week. “Day 1” may be any day of the week, including Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with respect to the administration of esketamine, “twice a week” refers to a frequency of one day and four days of the week. As long as there is an overdose, the dose may be taken as soon as possible thereafter, and the prescribed regimen may be continued thereafter.

[0048] As used herein, the term “once a week” refers to a frequency of once per week (7 days). For example, “once a week” may refer to the administration of esketamine as used herein. In some embodiments, “once a week” refers to a frequency of one day per week. In other embodiments, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. In yet another embodiment, “once a week” refers to a frequency of one day per week. “Day 1” may be any day of the week, including Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. As long as there is an overdose, the dose may be taken as soon as possible thereafter, and the prescribed regimen may be continued thereafter.

[0049] At any stage during a treatment session, the patient's response to the treatment session may be evaluated using the techniques described herein. This evaluation may be carried out until a person skilled in the art deems the patient ready to leave the laboratory. Thus, such evaluations may be carried out before, during, or after each treatment session. Preferably, the patient's response is evaluated by determining the number of adverse events the patient has experienced, including serious adverse events, if any. If a patient experiences a serious adverse event, that patient is not eligible. A patient is eligible if, after being monitored for at least 90 minutes (e.g., 2 hours) after each treatment session for at least two consecutive treatment sessions, the patient has not experienced any serious adverse events and has not experienced any of the following: a clinically significant increase in blood pressure, a clinically significant increase in heart rate, a moderate or greater level of dissociation, a moderate or greater level of sedation or disorientation, and / or a moderate or greater level of nausea without vomiting. In other embodiments, eligible patients are those who, after being monitored for at least 90 minutes (e.g., 2 hours) after each treatment session for at least two consecutive treatment sessions, do not experience any severe adverse events and do not experience any of the following: clinically significant increase in blood pressure, moderate or greater dissociation, moderate or greater sedation, moderate or greater dizziness, and / or moderate or greater vertigo. In yet another embodiment, eligible patients are those who, after being monitored for at least 90 minutes (e.g., 2 hours) after each treatment session for at least two consecutive treatment sessions, do not experience any severe adverse events and do not experience any of the following: clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate or greater dissociation, and / or moderate or greater sedation.

[0050] Prior to being designated as an eligible patient, the patient is preferably evaluated at regular intervals during a post-treatment session monitoring period of at least 90 minutes. However, evaluations may be made as needed, including if the patient may be experiencing distress. Preferably, the patient's blood pressure is measured, and the patient's dissociative symptoms, sedative symptoms, dizziness symptoms, nausea, and / or vertigo symptoms are evaluated. In some embodiments, the patient is evaluated at intervals of at least approximately 5 minutes after the completion of the treatment session. In other embodiments, the patient is evaluated at intervals of approximately 5, 10, 15, 20, 25, or 30 minutes. In further embodiments, the patient is evaluated at intervals of approximately 5–30, 5–25, 5–20, 5–15, 5–10, 10–30, 10–25, 10–20, 10–15, 15–30, 15–25, 15–10, 20–30, or 25–30 minutes. Preferably, the patient receives the drug at intervals of approximately 15 minutes. The evaluation continues as long as the patient exhibits adverse events. In some embodiments, the evaluation is carried out for at least approximately 90 minutes. In other embodiments, the evaluation is performed for approximately 90 to 180 minutes, approximately 90 to 170, approximately 90 to 160, approximately 90 to 150, approximately 90 to 140, approximately 90 to 130, approximately 90 to 130, approximately 90 to 120, approximately 90 to 110, approximately 90 to 100, approximately 100 to 180, approximately 100 to 170, approximately 100 to 160, approximately 100 to 160, approximately 100 to 150, approximately 100 to 140, approximately 100 to 130, approximately 100 to 120, approximately 100 to 110, approximately 110 to 180, approximately 110 to 170, approximately 110 to 160, approximately 110 to 150, and approximately 110 to 1 The sessions are conducted for approximately 40, 110-130, 110-120, 120-180, 120-170, 120-160, 120-150, 120-140, 120-130, 130-180, 130-170, 130-160, 130-150, 130-140, 140-180, 140-170, 140-160, 140-160, 140-150, 150-180, 150-170, 150-160, 160-180, 160-170, or 170-180 minutes. Preferably, the evaluation is conducted for approximately 90 to 120 minutes.Following the monitoring period, patients are typically released from the testing site based on clinical judgment.

[0051] Furthermore, it is desirable that patients tolerate esketamine and associated side effects / adverse events without medical intervention during all treatment sessions and before becoming eligible patients. Therefore, patients should not require emergency treatment as a result of esketamine administration before becoming eligible patients.

[0052] Once a patient is designated as an eligible patient, the patient is still monitored after the treatment session. However, the post-treatment monitoring sessions may be shorter than the post-treatment monitoring period used before the patient's eligibility. In some embodiments, eligible patients are evaluated at regular intervals after the treatment session. In some embodiments, patients are evaluated at intervals of at least about 5 minutes after the completion of the treatment session. In other embodiments, patients are evaluated at intervals of about 5, about 10, about 15, about 20, about 25, or about 30 minutes. In further embodiments, patients are evaluated at intervals of about 5 to about 30, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 30, about 10 to about 25, about 10 to about 20, about 10 to about 15, about 15 to about 30, about 15 to about 25, about 15 to about 10, about 20 to about 30, about 20 to about 25, or about 25 to about 30 minutes. The assessment continues for a shorter period than required before the patient's eligibility. In some embodiments, the assessment is performed for less than approximately 90 minutes. In other embodiments, the assessment is performed for approximately 30 to less than 90 minutes, approximately 30 to approximately 80 minutes, approximately 30 to approximately 70 minutes, approximately 30 to approximately 60 minutes, approximately 30 to approximately 50 minutes, approximately 30 to approximately 40 minutes, approximately 40 to approximately 90 minutes, approximately 40 to approximately 80 minutes, approximately 40 to approximately 70 minutes, approximately 40 to approximately 60 minutes, approximately 40 to approximately 50 minutes, approximately 40 to approximately 45 minutes, approximately 50 to approximately 90 minutes, approximately 50 to approximately 80 minutes, approximately 50 to approximately 70 minutes, approximately 50 to approximately 60 minutes, approximately 60 to approximately 90 minutes, approximately 60 to approximately 80 minutes, approximately 60 to approximately 70 minutes, approximately 70 to approximately 90 minutes, approximately 70 to approximately 80 minutes, or approximately 80 to less than approximately 90 minutes. In certain embodiments, the post-eligible treatment session monitoring period is at least 60 minutes. In further embodiments, the eligible post-treatment monitoring period is approximately 60 to less than 90 minutes. In other embodiments, the post-treatment session monitoring period is approximately 60 minutes.

[0053] After the post-treatment session monitoring period, once the patient is deemed stable, the patient may freely leave the clinic or medical facility where the esketamine was administered. However, in order to discharge the patient, the patient should be required to be monitored and / or contact a healthcare professional and / or submit a patient monitoring form. In one embodiment, if the post-treatment session monitoring period is less than two hours, a caregiver or responsible adult will accompany the patient. Preferably, the caregiver or responsible adult will be present during the patient's treatment session and / or the post-treatment session monitoring period. In addition to ensuring the patient is safely transported from the clinic, the caregiver or responsible adult may assist the patient in monitoring for any adverse effects attributable to esketamine after leaving the clinic.

[0054] As used herein, the term “caregiver” refers to an adult who is legally responsible for the care and well-being of the patient. Therefore, a caregiver may be a family member (e.g., parent, sibling, child, etc.) or a legal guardian. The term “responsible adult” refers to an adult who can physically and mentally assist the patient but is not legally responsible for the patient’s care. In some embodiments, the caregiver or responsible adult may be present during treatment sessions, present during post-treatment monitoring periods, assist the patient as they leave the clinic (e.g., to their home or place of residence), monitor the patient for a predetermined period after they have left the clinic, assist the patient in remote interaction with the clinician, or any combination thereof. Preferably, the caregiver or responsible adult provides their information (e.g., name, relationship, contact information) to the clinician prior to the patient’s treatment with esketamine.

[0055] If the post-treatment session monitoring period is less than two hours after leaving the clinic, a caregiver or responsible adult may participate in one or more follow-up evaluations conducted between the patient and the clinician to assess the patient's clinical condition. As used herein, the term “follow-up evaluation” refers to interactions between the patient and the clinician to monitor the patient’s response to esketamine. During these follow-up evaluations, the clinician assesses the patient’s physical and mental condition. In some embodiments, the clinician may determine how many and what kinds of adverse events the patient has experienced after the post-treatment session monitoring period. Preferably, the clinician documents any adverse events the patient has experienced. In certain embodiments, the clinician documents any events, such as sedation, dissociation, and / or serious adverse events, that the clinician has determined the patient has experienced. In other embodiments, the clinician determines whether the patient has experienced any new onsets of sedation and / or dissociation after the post-treatment session monitoring period. Certain adverse events deemed significant are noted and documented by the clinician (e.g., on relevant monitoring forms). In some embodiments, the caregiver or responsible adult may arrange an optional follow-up assessment by the clinician. In further embodiments, the caregiver or responsible adult may participate in the follow-up assessment between the patient and the clinician.

[0056] Preferably, the first follow-up evaluation takes place on the same day as the treatment session. In some embodiments, this is the only follow-up evaluation conducted between the clinician and the patient until the next treatment session using esketamine. However, if the clinician determines that further monitoring is necessary, further follow-up evaluations are conducted. In some embodiments, follow-up evaluations are conducted hourly or daily. In certain embodiments, follow-up evaluations continue daily after the initial follow-up evaluation, for example, the follow-up session continues daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more after the initial follow-up evaluation. If clinically demonstrated, those skilled in the art will be able to determine how many follow-up evaluations are needed and at what frequency after the initial follow-up evaluation. In certain embodiments, the follow-up session continues daily for one day after the initial follow-up evaluation. In other embodiments, the follow-up session continues daily for two days after the initial follow-up evaluation. In further embodiments, the follow-up session continues daily for three days after the initial follow-up evaluation. In further embodiments, follow-up sessions are continued daily for four days after the initial follow-up evaluation. In even further embodiments, follow-up sessions are continued daily for five days after the initial follow-up evaluation. In other embodiments, follow-up sessions are continued daily for six days after the initial follow-up evaluation. In even further embodiments, follow-up sessions are continued daily for seven days after the initial follow-up evaluation.

[0057] Interactions between the patient and the clinician (optionally, with a caregiver or responsible adult) may be conducted using a variety of technologies available to the patient and the attending physician. Interactions may be conducted to assess the patient, including monitoring the patient's physical health. In some embodiments, the interaction between the physician and the patient is in person, i.e., at the hospital where the esketamine is administered. In other embodiments, the interaction between the physician and the patient is remote, e.g., by telephone (e.g., audio and / or video). In further embodiments, the interaction between the physician and the patient is conducted remotely, among other things, using other electronic means such as video conferencing. In some embodiments, the attending physician contacts the patient at least about two hours on the same day after leaving the esketamine administration facility, i.e., about two hours after the post-treatment session monitoring period.

[0058] To facilitate compliance and measure patient tolerance to esketamine, it may be necessary to complete one or more forms to track the patient's health status, including measurable parameters such as heart rate and blood pressure, and especially recording any significant adverse events.

[0059] The administration may further include a maintenance phase following the induction phase. During the maintenance phase, esketamine is administered once a week for the first four weeks of the maintenance phase. Thereafter, the frequency of administration may be adjusted as determined by the attending physician (e.g., based on tolerability). In some embodiments, the frequency of administration is once a week, i.e., only one treatment session per week. In other embodiments, the frequency of administration is adjusted to once every two weeks. In some embodiments, the amount of esketamine administered during the maintenance phase is approximately 56 mg. In other embodiments, the effective dose of esketamine administered during the maintenance phase is approximately 84 mg. Typically, at the time of the post-treatment session monitoring period, the patient, for example, a patient typically in the maintenance phase of treatment, has received only one treatment session per week.

[0060] During the induction or maintenance phase, at one or more of any stages, the patient's response to treatment is assessed using the techniques described herein. This assessment may be carried out until it is considered by those skilled in the art that the patient has achieved a satisfactory response to the treatment regimen. In some embodiments, the assessment includes determining the patient's mental state using the techniques described herein, which are known to those skilled in the art. In other embodiments, the assessment includes determining the patient's physical state, including, but not limited to, heart rate, cardiac rhythm, vision, hearing, blood pressure, and respiration. In some embodiments, blood pressure is measured at intervals of about 40 minutes.

[0061] Before becoming an eligible patient, the patient is monitored for at least 90 minutes after at least the first two treatment sessions. In some embodiments, the pre-eligibility monitoring period is approximately 120 minutes. In some embodiments, before becoming an eligible patient, the patient is monitored after approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 treatment sessions, i.e., for approximately 1 to 10 weeks. In other embodiments, the patient is monitored for approximately 2 treatment sessions, i.e., for approximately 1 week, before becoming an eligible patient. In further embodiments, the patient is monitored for approximately 4 treatment sessions, i.e., for approximately 2 weeks, before becoming an eligible patient. In other embodiments, the patient is monitored for approximately 8 treatment sessions, i.e., for approximately 4 weeks, before becoming an eligible patient (i.e., the introductory period). In a further embodiment, the patient is monitored for approximately 8 treatment sessions, i.e., approximately 8 weeks (i.e., a 4-week introductory period), before becoming an eligible patient. In yet another embodiment, the patient is monitored for approximately 12 treatment sessions, i.e., approximately 6 weeks, before becoming an eligible patient. In yet another embodiment, the patient is monitored for approximately 16 treatment sessions, i.e., approximately 8 weeks, before becoming an eligible patient.

[0062] Many physical parameters can be measured when assessing a patient's physical condition. In some embodiments, the attending physician can determine the absence or degree of adverse events caused by the treatment session. Generally, an adverse event is any severe adverse event requiring medical intervention. As used herein, the term “adverse event” refers to the physical response to esketamine after a treatment session. In some embodiments, an adverse event is one or more of the following: dissociation, disorientation, increased blood pressure, increased heart rate, nausea (without vomiting), vomiting, sedation, intoxication, vertigo, hypoesthesia, anxiety, dizziness, or lethargy. In other embodiments, the adverse event is dissociation. In further embodiments, the adverse event is increased blood pressure. In yet another embodiment, the adverse event is increased heart rate. In yet another embodiment, the adverse event is nausea. In yet another embodiment, the adverse event is vomiting. In other embodiments, the adverse event is moderate to severe nausea without vomiting. In yet another embodiment, the adverse event is sedation. In further embodiments, the adverse event is intoxication. In yet another embodiment, the adverse event is vertigo. In yet another embodiment, the adverse event is hypoesthesia. In yet another embodiment, the adverse event is anxiety. In further embodiments, the adverse event is dizziness. In yet another embodiment, the adverse event is lethargy. In yet another embodiment, the adverse events are, among other things, increased blood pressure, increased heart rate, dissociation, nausea without vomiting at a moderate to high level, sedation, dizziness, and / or vertigo.

[0063] In other embodiments, a patient is monitored for at least 90 minutes after at least the first two treatment sessions before becoming eligible for a shorter post-treatment session monitoring period (e.g., less than 90 minutes) in any subsequent treatment session. If a patient does not experience any serious adverse events after any two consecutive treatment sessions and does not experience any of the following: a clinically significant increase in blood pressure, a clinically significant increase in heart rate, a moderate or greater level of dissociation, a moderate or greater level of sedation, a moderate or greater level of dizziness, a moderate or greater level of nausea without vomiting, and / or a moderate or greater level of rotational vertigo, the patient becomes eligible for a shorter post-treatment session monitoring period (e.g., less than 90 minutes, preferably about 60 minutes) in the next treatment session. As described herein, the pre-qualification review and monitoring period may include at least the first two treatment sessions, such as the first eight, in which the patient does not experience any serious adverse events and any of the following: clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate or greater level of dissociation, moderate or greater level of sedation, moderate or greater level of dizziness, moderate or greater level of nausea without vomiting, and / or moderate or greater level of rotational vertigo. In any case, typically, the conditions for the above adverse events must be met during the pre-qualification review and monitoring period following two consecutive treatment sessions. The more treatment sessions a patient has without encountering the listed adverse events, the more likely it is that the patient will not experience them in subsequent treatment sessions. Following a post-treatment session monitoring period of less than 90 minutes, eligible patients are generally released after a healthcare professional determines that the eligible patient is clinically stable and ready for discharge.

[0064] If, at any point during esketamine treatment, i.e., during or after a treatment session, a patient experiences a serious adverse event or any of the following adverse events, the patient will be disqualified from shortening the monitoring session: clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate to severe disorientation, moderate to severe sedation, and / or moderate to severe nausea without vomiting, or any combination thereof. Therefore, a disqualified patient must stay for a full two hours or more during the post-treatment session monitoring period. In certain embodiments, the patient is prohibited from any future post-treatment session monitoring period of less than two hours. In other embodiments, the patient may attempt to qualify for any future post-treatment session monitoring period of less than two hours, as determined by the attending physician. For example, if a patient does not show any symptoms that would disqualify him for 4, 6, 8, 10, or 12 treatment sessions, the physician may, at his discretion, requalify the patient for a monitoring period of less than two hours, as described herein.

[0065] When used herein, unless otherwise specified, the term “clinically” (used independently or to modify the term “meaningful”) means having sufficient meaning to the standards of the U.S. Food and Drug Administration or similar studies for market approval under EMEA. A clinically meaningful increase in blood pressure and / or a clinically meaningful increase in heart rate may be determined by clinical judgment. In some embodiments, an increase in blood pressure may be an increase in systolic, diastolic, or a combination thereof. For example, an increase in systolic blood pressure of 20 mmHg or more above baseline and / or an increase in diastolic blood pressure of 15 mmHg or more above baseline may be considered clinically meaningful. In other examples, an increase in systolic blood pressure of 40 mmHg or more above baseline and / or an increase in diastolic blood pressure of 25 mmHg or more above baseline may be considered clinically meaningful. In further examples, a systolic blood pressure of 180 mmHg or more and / or a diastolic blood pressure of 110 mmHg or more may be considered clinically meaningful. Furthermore, an increase in heart rate of 20 bpm or more above baseline and / or 100 bpm or more above baseline can be considered clinically significant. In other cases, an increase in heart rate of 15 bpm or more above baseline can be considered clinically significant.

[0066] Those skilled in the art will be able to easily measure adverse events in patients from experience and from one or more tools used to make such assessments. For example, the Clinician-Administered Dissociative States Scale (CADSS) is a technique used to measure current dissociative symptoms and can therefore be used to assess dissociative symptoms that occur during treatment. The CADSS consists of 23 subjective items, divided into three components: depersonalization (items 3-7, 20, and 23), derealization (items 1, 2, 8-13, 16-19, and 21), and memory loss (items 14, 15, and 22). Participant responses are coded on a 5-point scale (0 = not at all ~ 4 = extremely). Therefore, higher CADSS scores indicate a worse state of dissociation, and lower CADSS scores indicate a milder state of dissociation.

[0067] To measure sedation induced by a treatment session, those skilled in the art may use the Modified Observer's Assessment of Alertness / Sedation Scale (MOAA / S). The MOAA / S score ranges from 0 = "none" response to painful stimuli (corresponding to the ASA continuum for general anesthesia) to 5 = readily responding to a name spoken in a normal tone (corresponding to the ASA continuum for alertness and minimal sedation). On each day of intranasal administration, the MOAA / S is performed every 15 minutes from before administration until +1.5 hours post-administration. If the score is 3 or less at any point during the 1.5-hour post-administration interval, the MOAA / S is performed every 5 minutes until the score reaches 4 (at this point, the frequency of every 15 minutes until t = +1.5 hours post-administration can be resumed). However, if a subject does not have a score of at least 5 at t = +1.5 hours post-administration, that subject should continue to be monitored. For subjects with a score of 4, the assessment should 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. In some embodiments, the MOAA / S results may correlate with the sedation level as defined by the American Society of Anesthesiologists (ASA) continuum.

[0068] The Clinical Global Assessment of Discharge Readiness (CGADR) is a clinician assessment of readiness to discharge from the study site, used in conjunction with other parameters to measure the subject's current clinical status. Clinicians answer "yes" or "no" to the question, "Is the subject considered ready for discharge based on their overall clinical status (e.g., sedation, blood pressure, and other adverse events)?" The CGADR is performed 1 or 1.5 hours post-administration on each intranasal administration day. If the response is not "yes" at 1.5 hours post-administration, the assessment is repeated every 15 minutes until a "yes" response is achieved, or until the subject is placed in appropriate medical care, if clinically indicated. If the patient is eligible, the CGADR (or a similar discharge readiness assessment) is performed approximately 15 minutes before the end of the post-treatment session monitoring period. If the response is not "yes" at 45 minutes post-administration (post-treatment session), the assessment is repeated every 15 minutes until a "yes" response is achieved, or until the subject is clinically indicated to be transferred 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 may use the general category descriptors “mild,” “moderate,” or “severe” to assess the severity grade. Grade “mild” is associated with patients who perceive symptoms that are easily tolerable, cause minimal discomfort, and do not interfere with daily life. Grade “moderate” or “severe” is used for patients who experience sufficient discomfort to interfere with normal activities. Grade “severe” is used for patients who experience extreme distress, resulting in significant functional impairment or incapacity, thereby interfering with normal daily activities.

[0070] Typically, eligible patients do not require medical interventions related to the resolution of adverse events during the post-qualification treatment session follow-up period, and / or medical observations. As used herein, the term “medical intervention” refers to the need for a healthcare professional to care for the patient. Medical interventions may include, among other things, one or more of the following: blood tests, respiratory support, cardiac support, administration of medications to reduce adverse events or symptoms of adverse events, and emergency treatment. Similarly, as used herein, the term “medical observations” refers to close monitoring of the patient by a healthcare professional. Monitoring may be visual, consist of patient interaction, optionally measuring the patient’s responses to questions, or include, among other things, examinations to determine whether a medical intervention is needed, such as heart rate, cardiac rhythm, vision, hearing, blood pressure, and respiration.

[0071] As disclosed herein, eligible patients have a low risk of developing adverse events during the post-treatment session monitoring period and therefore do not require the same amount of time for monitoring. In some embodiments, eligible patients do not require medical intervention in any previous treatment session. In other embodiments, eligible patients do not exhibit clinically relevant or significant side effects of concern based on clinical judgment. As disclosed herein, conventional post-treatment monitoring periods require approximately 1.5 and 2 hours of monitoring by a healthcare professional. This period allows the healthcare professional to assess adverse events and determine whether a patient has experienced a minor adverse event or not. By doing so, greater confidence is provided that serious adverse events will not occur after administration, and it becomes possible to identify eligible patients who require a shorter post-treatment session monitoring period. It is noted that patients may be recommended to be requalified for a shorter post-treatment session monitoring period, even if the effect of administration on AEs is small, within a range where the dose adjustment is, for example, from 56 mg to 84 mg. Generally, older adults are not eligible for shorter post-treatment session monitoring periods because they are more likely to experience adverse events related to blood pressure changes and because blood pressure changes are more difficult to predict.

[0072] A person skilled 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 subsided. In other embodiments, an adverse event is resolved when the patient can function normally, i.e., when the patient can function after esketamine administration as well as the patient did before esketamine administration.

[0073] As disclosed herein, typically, a patient requires two consecutive treatment sessions without experiencing any serious adverse events or any of the following: clinically significant increase in blood pressure, clinically significant increase in heart rate, moderate or greater level of dissociation, moderate or greater level of sedation, moderate or greater level of dizziness, moderate or greater level of nausea without vomiting, and / or moderate or greater level of rotational vertigo. In some embodiments, a patient becomes eligible after at least the first three consecutive treatment sessions. In some embodiments, a patient becomes eligible after at least about three, about four, about five, about six, about seven, about eight, about nine, about ten, about eleven, about twelve, or more treatment sessions. In some embodiments, a patient becomes eligible after about four treatment sessions. In other embodiments, a patient becomes eligible after about eight treatment sessions. In a further embodiment, the patients are approximately 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-8, 3-7, 3-6, 3-5, 3-4, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-8, 4-7, 4-6, 4-5, and 5-1 2. Become eligible after approximately 5-11 weeks, 5-10 weeks, 5-9 weeks, 5-8 weeks, 5-7 weeks, 5-6 weeks, 6-12 weeks, 6-11 weeks, 6-10 weeks, 6-9 weeks, 6-8 weeks, 6-7 weeks, 7-12 weeks, 7-11 weeks, 7-10 weeks, 7-9 weeks, 7-8 weeks, 8-12 weeks, 9-11 weeks, 9-10 weeks, or 10-11 weeks.

[0074] Some of the quantitative expressions expressed herein are not modified by the term “approximately.” Whether or not the term “approximately” is explicitly used, all quantities expressed herein mean the actual values ​​shown, and are understood to also mean approximations of such shown values ​​that can be reasonably estimated on the basis of ordinary skill in the art, including approximations of such shown values ​​by experimental and / or measurement conditions.

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

[0076] [ka] This refers to the compound, which is also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. "Esketamine" also refers to its salt, for example, the (S)-enantiomer of ketamine, namely formula (II):

[0077] [ka] This also includes chloride salts such as the hydrochloride salt of the compound, which is also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. In some embodiments, esketamine is the (R)-enantiomer of ketamine, i.e., formula (III):

[0078] [ka] It is substantially free of the compound.

[0079] In other embodiments, the esketamine contains less than about 10% by weight of the ketamine (R)-enantiomer, based on the weight of the esketamine sample. In further embodiments, the esketamine contains less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.005, or 0.001% by weight of the ketamine (R)-enantiomer, based on the weight of the esketamine sample. In yet another embodiment, the esketamine contains about 0.001 to about 10% by weight of the ketamine (R)-enantiomer, based on the weight of the esketamine sample. In further embodiments, the esketamine contains approximately 0.001 to 10%, 0.001 to 5%, 0.001 to 1%, 0.001 to 0.5%, 0.001 to 0.1%, 0.1 to 5%, 0.1 to 1%, 0.1 to 5%, or 0.5 to 5% by weight of the esketamine sample.

[0080] The term “esketamine” may also include other pharmaceutically acceptable salts thereof that can be readily selected by those skilled in the art. “pharmaceutically acceptable salt” is intended to mean a salt of esketamine that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See, for general information, GSPaulekuhn, “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J.Med.Chem., 2007, 50:6665-72; SMBerge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to patients without causing excessive toxicity, irritation, or allergic reactions.

[0081] Other examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, bromides (such as hydrobromide), iodides (such as hydroiodide), acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, capronates, heptaneates, propiolates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, and butin-1 Examples include 4-diote, hexine-1,6-diote, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenyl butyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. In particular, the salts of esketamine are hydrochloride salts.

[0082] In certain embodiments, esketamine is administered intranasally. In other embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt. In further embodiments, esketamine is administered intranasally as the corresponding hydrochloride salt in a 16.14% wt / volume solution (corresponding to 14% wt / volume of esketamine base).

[0083] In certain embodiments, esketamine is administered intranasally as a solution containing 161.4 mg / mL of esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL of citric acid at a pH of 4.5 in water. In other embodiments, esketamine is administered intranasally, with 100 μL of a solution containing 161.4 mg / mL of esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL of citric acid at a pH of 4.5 in water being administered via intranasal delivery. In a further embodiment, esketamine is delivered intranasally using a nasal spray pump, which delivers 100 μL of a solution containing 161.4 mg / mL of esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL of citrate at a pH of 4.5 in water.

[0084] Generally, a single pump from a nasal spray device may be configured to deliver approximately 50 μL to approximately 200 μL (including approximately 60 μL, 70 μL, 80 μL, 90 μL, 100 μL, 110 μL, 120 μL, 130 μL, 140 μL, 150 μL, 160 μL, 170 μL, 180 μL, and 200 μL) of esketamine solution to the target nostril. Thus, two pumps would deliver approximately 100 μL to approximately 400 μL to the target.

[0085] In certain embodiments, the patient requiring treatment with a therapeutically effective dose of esketamine is a patient suffering from an episode of depression (e.g., major depressive disorder). In other embodiments, the patient requiring treatment is suffering from an episode of depression (e.g., major depressive disorder), and the episode of depression (e.g., major depressive disorder) has not responded to treatment with at least two oral antidepressants (i.e., the patient has not responded to treatment with at least two oral antidepressants).

[0086] At the end of the induction phase, the treating physician can evaluate the patient and optimize the dosage and frequency of any subsequent administration phase, such as the "maintenance phase." The frequency of intranasal treatment during subsequent administration, such as the maintenance phase, is expected to be reduced for at least 4 weeks from the frequency during the induction phase (at least twice a week) to once a week. In some embodiments, subsequent administration, such as the maintenance phase, is at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years. In some embodiments, esketamine administration during the maintenance phase is at least 6 months. In other embodiments, esketamine administration during the maintenance phase is at least 1 year. In further embodiments, the frequency of administration during the maintenance phase is once a week, once every two weeks, or a combination thereof. In yet another embodiment, the frequency and effective dose of esketamine during the maintenance phase are the minimum frequency and amount necessary to treat depression.

[0087] Subsequent administrations, such as maintenance periods, may include longer durations depending on the patient's condition. In some embodiments, these longer durations may include indefinite periods and may be at least about 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 years. For example, in patients diagnosed with TRD, treatment may be indefinite. In other embodiments, the treatment frequency is reduced to every two weeks. In further embodiments, the treatment frequency is reduced to every three weeks. In yet another embodiment, the treatment frequency is reduced to once a month. Patients are maintained as scheduled until they achieve remission, maintain a response, or fail treatment. If a patient achieves remission or maintains a response with weekly treatment for at least four weeks, the frequency of intranasal treatment sessions may be reduced to a maintenance dose every two weeks based on the severity of depressive symptoms, and in some patient populations, the treatment frequency may be reduced to once every three or four weeks as described above.

[0088] Those skilled in the art will understand that the maintenance phase described herein may continue until further treatment is no longer required, for example, long-term remission of depression (including, for example, remission of one or more symptoms associated with depression), improvement in social and / or occupational functioning to the usual or pre-illness level, or as indicated by other known measures of depression.

[0089] The amount of esketamine administered during the maintenance phase is the amount that maintains the pharmacodynamic steady state of esketamine achieved during the induction phase. In some embodiments, approximately 56 mg or approximately 84 mg of esketamine is administered to the patient during the maintenance phase. For example, if a particular patient taking approximately 56 mg of esketamine begins to experience worsening of depressive symptoms, the dose may be increased to approximately 84 mg to stabilize the patient. Alternatively or additionally, if a patient is receiving treatment every other week and their symptoms begin to worsen, esketamine can be administered once a week to maintain the response during the maintenance phase. Again, the patient's response can be reassessed at any point during the maintenance phase.

[0090] If one or more doses (e.g., two) of esketamine are not administered during any of the periods described herein, the next dose will be scheduled as possible, based on the administration frequency regimen. If more than two doses are not administered, adjustments to the dose or frequency of esketamine may be necessary, according to clinical judgment.

[0091] Furthermore, the methods described herein include adjunctive therapy with one or more antidepressants in a therapeutically effective dose. Preferably, the adjunctive therapy is during the induction phase, the maintenance phase, or both. In some embodiments, the adjunctive therapy occurs during the induction phase. In other embodiments, the adjunctive therapy occurs during the maintenance phase. In further embodiments, the adjunctive therapy occurs between the induction and maintenance phases. In certain embodiments, esketamine may be administered in combination with one or more antidepressants, preferably one to three, and more preferably one to two, as described herein. In other embodiments, esketamine may be administered in combination with one or more antidepressants, as described herein, and further in combination with one or more atypical antipsychotics. The antidepressant should be administered at least about two hours after the execution of the treatment session described herein. Such administration is desirable to minimize side effects. In some embodiments, the antidepressant is administered at least about three, four, five, six, seven, or eight hours after the treatment session. In other embodiments, the antidepressant is administered for approximately 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 8, 5 to 7, 5 to 6, 6 to 8, 6 to 7, or approximately 7 hours.

[0092] The timing of adjuvant therapy is determined by the attending physician. In some embodiments, adjuvant therapy is at least 3 hours after the induction or maintenance treatment session. In other embodiments, adjuvant therapy is at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 hours after the induction treatment session. In further embodiments, adjuvant therapy is about 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-12, 5-11, 5-10, 5-9, 5-9 These are approximately 8, 5-7, 5-6, 6-12, 6-11, 6-10, 6-9, 6-8, 6-7, 7-12, 7-11, 7-10, 7-9, 7-7, 8-12, 8-11, 8-10, 8-9, 8-9, 9-12, 9-11, 9-10, 10-12, 10-11, and 11-12 hours after the maintenance therapy session. In other embodiments, adjunctive therapy is at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, or 24 hours after the maintenance therapy session. In a further embodiment, adjunctive therapy is administered during maintenance therapy sessions at approximately 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-12, 5-11, 5-10, 5-9, 5- These are approximately 8, 5-7, 5-6, 6-12, 6-11, 6-10, 6-9, 6-8, 6-7, 7-12, 7-11, 7-10, 7-9, 7-7, 8-12, 8-11, 8-10, 8-9, 9-12, 9-11, 9-10, 10-12, 10-11, 11-12, 11-12.

[0093] As used herein, the terms “adjunctive therapy” and “adjunctive treatment” mean the treatment of a patient in need of treatment by administering esketamine in combination with one or more antidepressants, and esketamine and the antidepressants are administered by any preferred means. In some embodiments, esketamine is administered in a regimen of 1 to 5 antidepressants. In other embodiments, esketamine is administered in a regimen of 1, 2, 3, 4, or 5 antidepressants. In other embodiments, esketamine is administered in a regimen of 1 or 2 antidepressants. In further embodiments, esketamine is administered in a regimen of antidepressants currently being administered to the patient. In other embodiments, esketamine is administered in a regimen of different antidepressants. In even further embodiments, esketamine is administered in a regimen of antidepressants not previously administered to the patient. In yet another embodiment, esketamine is administered in a regimen of antidepressants previously administered to the patient. When esketamine and antidepressants are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different, more typically different. Antidepressants may be administered as prescribed by the attending physician and / or as prescribed by their label, and esketamine may be administered as described herein. Typically, a patient is under concurrent treatment with both antidepressants and esketamine, both administered according to their 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, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, oral cavity, or rectal. In some embodiments, esketamine is administered intranasally.

[0095] As used herein, unless otherwise specified, the term “antidepressant” means any medicine that can be used to treat depression. Preferred examples include, but are not limited to, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin-noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic drugs, or atypical antipsychotics. Other examples include monoamine oxidase inhibitors such as phenelzine, tranylcypromine, and moclobemide; tricyclic antidepressants such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, and amoxapine; tetracyclic antidepressants such as maprotiline; acyclic antidepressants such as nomifensin; triazolopyridines such as trazodone; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine; serotonin receptor antagonists such as nefazadone; and venlafaxine, milnacipran, and desulfamethasone. Examples of antipsychotics include, but are not limited to, serotonin-noradrenergic reuptake inhibitors such as venlafaxine, duloxetine, and levomilunacipran; noradrenergic and specific serotonergic drugs such as mirtazapine; noradrenergic reuptake inhibitors such as reboxetine and edivoxetine; atypical antipsychotics such as bupropion; natural products such as kava kava and St. John's wort; nutritional supplements such as s-adenosylmethionine; and neuropeptides such as thyroid-stimulating hormone-releasing hormone; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists; and hormones such as triiodothyronine.In some embodiments, the antidepressant is imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kava kava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline.

[0096] The therapeutically effective dose / dosage levels and dosing regimens for antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin-noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic drugs, noradrenergic reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and medicinal products as described herein) can be readily determined by those skilled in the art. For example, therapeutic doses and regimens for commercially approved medicinal products are generally available and are listed, for example, on packaging labels, standard dosing guidelines, standard dosing references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / www.pdrel.com), or other sources.

[0097] As used herein, the term “antipsychotic drug” includes, but is not limited to, the following: (a) Typical or conventional antipsychotic drugs, such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifloperazine, levomepromazine), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., roxapine), dihydroindrones (e.g., morindone), substituted benzamides (e.g., sulpiride, amisulpride), etc.; and (b) Atypical antipsychotics and mood stabilizers, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, certindol, ORG-5222 (Organon), etc.; and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), divalproate (mood stabilizer), etc.

[0098] In one embodiment, the "atypical antipsychotic" is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. In another embodiment, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine, and risperidone, and preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, and olanzapine.

[0099] Those skilled in the art will recognize that non-responses to a given set of appropriate antidepressants can be determined retrospectively or anticipatoryly. In one embodiment, at least one non-response to a set of appropriate antidepressants is determined anticipatoryly. In another embodiment, at least two non-responses to a set of appropriate antidepressants are determined anticipatoryly. In yet another embodiment, at least one non-response to a set of appropriate antidepressants is determined retrospectively. In yet another embodiment, at least two non-responses to a set of appropriate antidepressants are determined retrospectively in the current depressive episode.

[0100] "At least two oral antidepressants" or "at least two different oral antidepressants" are administered to the patient in appropriate doses that may be determined by the attending physician. Similarly, the antidepressants are administered for a suitable duration that may be determined by the attending physician.

[0101] When used herein, unless otherwise specified, terms such as “treat” and “treat” encompass the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of addressing a disease, condition, or disorder, and encompass the administration of the compounds described herein for the prevention of the onset of symptoms or complications, the alleviation of symptoms or complications, or the eradication of a disease, condition, or disorder.

[0102] As used herein, the term “therapeutic dose” means the amount of an active compound or pharmaceutical product that elicits a biological or pharmaceutical response in a tissue system, animal, or human, including the relief of symptoms of the disease or disorder being treated, as determined by researchers, veterinarians, physicians, or other clinicians. In some embodiments, an antidepressant is used in a therapeutic dose determined by the attending physician. In other embodiments, esketamine is used in a therapeutic dose.

[0103] As used herein, the term “composition” includes products containing specific components in specific amounts, as well as any products resulting directly or indirectly from specific combinations of specific components in specific amounts.

[0104] In some embodiments, the induction period can be considered complete when the patient's MADRS score has decreased by more than 50% from baseline, or from about 20 to about 13. In other embodiments, the patient's MADRS score may be about 19, about 18, about 17, about 16, about 15, about 14, or about 13. Patients with a MADRS score of 12 or less are considered to be in remission and should be moved to or maintained in the maintenance phase if they remain stable for 4 weeks.

[0105] Pharmaceutical composition A preferred pharmaceutical composition contains esketamine hydrochloride as the active ingredient and is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical formulation techniques. This carrier can take a wide variety of forms depending on the desired form of the formulation for administration. Many pharmaceutically acceptable preferred carriers are well known in the art. Some descriptions of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0106] Methods for formulating pharmaceutical compositions are described in numerous publications, including *Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3* edited by Lieberman et al., published by Marcel Dekker, Inc.; *Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2* edited by Avis et al.; and *Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2* edited by Lieberman et al.

[0107] One preferred aqueous formulation of esketamine comprises water and esketamine, wherein the esketamine is present in an amount ranging from about 25 mg / mL to about 250 mg / mL, preferably about 55 mg / mL to about 250 mg / mL, or about 100 mg / mL to about 250 mg / mL, or any amount or range within that range, based on the total volume of the pharmaceutical composition. Preferably, the esketamine is present in an amount ranging from about 150 mg / mL to about 200 mg / mL, or any amount or range within that range. More preferably, the esketamine is present in an amount ranging from about 150 mg / mL to about 175 mg / mL, or any amount or range within that range. More preferably, the esketamine is present in an amount ranging from about 160 mg / mL to about 163 mg / mL, for example, in an amount of about 161.4 mg / mL.

[0108] Another preferred aqueous formulation of esketamine comprises water and esketamine, wherein the esketamine is present in an amount ranging from about 100 mg / mL equivalent to about 250 mg / mL equivalent, or any amount or range within that range, based on the total volume of the pharmaceutical composition. Preferably, the esketamine is present in an amount ranging from about 125 mg / mL equivalent to about 180 mg / mL equivalent, or any amount or range within that range. More preferably, the esketamine is present in an amount ranging from about 140 mg / mL equivalent to about 160 mg / mL equivalent, or any amount or range within that range, for example, in an amount of about 140 mg / mL equivalent.

[0109] The pharmaceutical compositions suitable for use herein are preferably aqueous formulations. As used herein, unless otherwise specified, the term “aqueous” means that the main liquid component of the formulation is water. Preferably, water constitutes more than about 80% by weight, more preferably more than about 90% by weight, more preferably more than about 95% by weight, and more preferably about 98% by weight of the liquid component of the pharmaceutical composition.

[0110] In pharmaceutical compositions suitable for use herein, the water content of the composition is in the range of 85±14% by weight, more preferably 85±12% by weight, even more preferably 85±10% by weight, most preferably 85±7.5% by weight, and particularly 85±5% by weight, based on the total weight of the composition.

[0111] In pharmaceutical compositions suitable for use herein, the water content of the composition is preferably in the range of 90±14% by weight, more preferably 90±12% by weight, even more preferably 90±10% by weight, most preferably 80±7.5% by weight, and particularly 90±5% by weight, based on the total weight of the composition.

[0112] In another pharmaceutical composition for use herein, the water content of the composition is in the range of 95±4.75% by weight, more preferably 95±4.5% by weight, even more preferably 95±4% by weight, still more preferably 95±3.5% by weight, most preferably 95±3% by weight, and particularly 95±2.5% by weight, based on the total weight of the composition.

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

[0114] In another pharmaceutical composition for use herein, the composition further comprises one or more buffers and / or buffer systems (i.e., conjugate acid-base pairs).

[0115] As used herein, the term “buffer” means any solid or liquid composition (preferably an aqueous liquid composition) that, when added to an aqueous formulation, adjusts the pH of the formulation. Those skilled in the art will recognize that a buffer can adjust the pH of an aqueous formulation in any direction (towards a more acidic, more basic, or more neutral pH). Preferably, the buffer is pharmaceutically acceptable.

[0116] Suitable examples of buffers that can be used in the aqueous formulations described herein include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, and fumaric acid. Preferably, the buffer or buffer system is selected from the group consisting of NaOH, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0117] In the embodiments, the buffer is selected to adjust the pH of the esketamine hydrochloride pharmaceutical composition (e.g., the aqueous formulation described herein) to a pH in the range of about pH 3.5 to about pH 6.5, or any amount or range within that range. Preferably, the buffer is selected to adjust the pH of the esketamine hydrochloride composition to a pH in the range of about pH 4.0 to about pH 5.5, or any amount or range within that range, more preferably to a pH in the range of about pH 4.5 to about pH 5.0, or any amount or range within that range.

[0118] Preferably, the concentrations of the buffering agent and buffering system, preferably NaOH, are adjusted to provide sufficient buffering capacity.

[0119] In the embodiment, a pharmaceutical composition is provided comprising esketamine hydrochloride, water, and a buffer or buffering system, preferably NaOH, wherein the buffer or buffering system is present in an amount sufficient to obtain a formulation having a pH in the range of about pH 4.0 to about pH 6.0, or any amount or range within that range.

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

[0121] As used herein, unless otherwise specified, the terms “antimicrobial preservative” and “preservative” preferably refer to any substance that is typically added to a pharmaceutical composition to protect against microbial degradation or growth. In this regard, microbial growth typically plays an important role; that is, preservatives serve the primary purpose of avoiding microbial contamination. In some aspects, it may be desirable to avoid any microbial influence on the active ingredients and excipients, respectively, i.e., to avoid microbial degradation.

[0122] Typical examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0123] When the esketamine hydrochloride content is sufficiently high and the desired shelf life or stability in use can be achieved by the presence of the drug itself due to its preservative properties, it is preferable that the pharmaceutical composition used herein is completely free of preservatives. Preferably, under these circumstances, the concentration of esketamine hydrochloride is at least 120 mg / mL equivalent, preferably in the range of about 120 mg / mL equivalent to about 175 mg / mL equivalent, or any amount or range within that range, more preferably in the range of about 125 mg / mL equivalent to about 150 mg / mL equivalent, or any amount or range within that range, for example, about 126 mg / mL equivalent or about 140 mg / mL equivalent.

[0124] As used herein, the terms “penetration agent,” “penetration enhancer,” and “penetrant” refer to any substance that increases or enhances the absorption and / or bioavailability of the active ingredient of a pharmaceutical composition (e.g., esketamine hydrochloride). Preferably, the penetration agent increases or enhances the absorption and / or bioavailability of the active ingredient of the pharmaceutical composition (e.g., esketamine hydrochloride) after nasal administration (i.e., increases or enhances the absorption and / or bioavailability of the active ingredient through the mucous membrane).

[0125] Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycocholate, tauroursodeoxycholic acid (TUDCA), lecithin, chitosan (and its salts), and surfactants such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxynol, sodium deoxycholate, and polyarginine. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0126] Penetrating agents may act through any mechanism, including, for example, increasing membrane fluidity, forming transient hydrophilic pores within epithelial cells, reducing the viscosity of the mucus layer, or opening tight junctions. Some penetrating agents (e.g., bile salts and fusidic acid derivatives) can also inhibit enzymatic activity in the membrane, thereby improving the bioavailability of active ingredients.

[0127] Preferably, the penetrating agent is selected to satisfy one or more, more preferably all, of the following general requirements. (a) Effective in increasing the absorption (preferably nasal absorption) of the active ingredient, preferably in a temporary and / or reversible manner. (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 is selected to increase penetration (absorption and / or bioavailability of esketamine hydrochloride) without causing nasal irritation. In another embodiment, the penetrating agent is selected to improve the absorption and / or bioavailability of esketamine hydrochloride and further to enhance uniform drug delivery efficacy.

[0129] In the embodiment, the pharmaceutical composition comprises esketamine and water, and in this specification, the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition further contains a penetration enhancer, preferably TUDCA.

[0130] In another embodiment, the pharmaceutical composition comprises esketamine and water, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and further contains tauroursodeoxycholic acid (TUDCA), wherein TUDCA is present in a concentration in the range of about 1.0 mg / mL to about 25.0 mg / mL, or any amount or range therein, preferably in the range of about 2.5 mg / mL to about 15 mg / mL, or any amount or range therein, preferably in the range of about 5 mg / mL to about 10 mg / mL, or any amount or range therein. In another embodiment, TUDCA is present at a concentration of about 5 mg / mL. In a further embodiment, TUDCA is present at a concentration of about 10 mg / mL.

[0131] The pharmaceutical compositions used herein may further contain one or more additional excipients, such as wetting agents, surfactants, solubilizers, thickeners, colorants, antioxidants, and the like.

[0132] Examples of suitable antioxidant components, when used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbates such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallates such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. Antioxidant components provide long-term stability to liquid compositions. The addition of antioxidant components can help enhance and guarantee the stability of the composition, keeping it stable even after 6 months at 40°C. A suitable amount of antioxidant component, if present, is about 0.01% to about 3% by weight, preferably about 0.05% to about 2% by weight, of the total weight of the composition.

[0133] Solubilizers and emulsifiers may be included to promote a more uniform dispersion of active ingredients or other excipients that are not generally soluble in the liquid carrier. Examples of suitable emulsifiers, when used, include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof. Examples of suitable solubilizers include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.

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

[0135] Suitable isotonic agents, when used, include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. If included, a suitable amount of isotonic agent is typically about 0.01% to about 15% by weight, more preferably about 0.3% to about 4% by weight, and more preferably about 0.5% to about 3% by weight of the total weight of the composition.

[0136] For example, a suspension or thickener may be added to the pharmaceutical composition to increase the nasal retention time. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, carmellose sodium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt, gellan gum, poloxamer, polyvinylpyrrolidone, and xanthan gum.

[0137] Advantageously, esketamine may be administered as a single daily dose, or the total daily dose may be administered in divided doses twice, three, or four times daily, preferably twice daily. Typically, divided doses need to be administered at shorter intervals. In some embodiments, divided doses are administered within about 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, or less from each other. Additionally, in flexible dosing regimens, patients may be administered daily, twice weekly, once weekly, every other week, or once monthly. For example, one dose of esketamine may be administered on day 1 and another dose on day 2, or one dose of esketamine may be administered on day 1 and another dose on day 3, or one dose of esketamine may be administered on day 1 and another dose on day 4, or one dose of esketamine may be administered on day 1 and another dose on day 5. Furthermore, esketamine is preferably administered in an intranasal form via topical use of a suitable intranasal vehicle such as a nasal spray pump.

[0138] nasal device Typical nasal spray devices are disclosed in U.S. Patent No. 6,321,942 and U.S. Patent Application Publication No. 2020-0009081(A1), both of which are incorporated herein by reference. For example, the methods disclosed herein can be carried out using a disposable sprayer for dispensing a continuous partial discharge as a spray. Typically, such a device allows the drug to be sprayed into both nostrils of a patient in two consecutive strokes. The container may be ready-to-use, from which the drug is discharged from the medium container. The device can typically separate the first discharge stroke from the second discharge stroke to prevent the medium container from being completely emptied in a single motion. The device may take the form of a two-stroke disposable pump that is discarded after single use and allows for individual partial discharges with high dosing accuracy and reliability.

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

[0140] manner Apparatus 1. A method for treating depression in human patients requiring treatment for depression, wherein the method comprises an induction phase and treatment sessions, the induction phase having a duration of 4 weeks, and the method For each induction treatment session, approximately 56 mg or 84 mg of esketamine is administered intranasally to the patient, provided that 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. This includes monitoring the patient for adverse events for at least 90 minutes after each treatment session, at least after the first two treatment sessions, and ensuring that the patient does not experience any severe adverse events after any two consecutive treatment sessions, Clinically significant increase in blood pressure, Moderate to severe level of dissociation, Moderate to high levels of sedation, Moderate to severe levels of dizziness, and If you do not experience any of the adverse events related to moderate to severe vertigo, A method for determining whether a patient is eligible for a post-treatment session monitoring period of less than 90 minutes in the next treatment session.

[0141] Embodiment 2. The method according to Embodiment 1, wherein the patient becomes an eligible patient after at least the first three, four, five, six, seven, or eight treatment sessions.

[0142] Embodiment 3. The method according to Embodiment 1 or 2, wherein the post-treatment session monitoring period for eligible patients is at least 60 minutes.

[0143] Embodiment 4. The method according to any one of Embodiments 1 to 3, wherein if the patient does not have a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg prior to the treatment session, the treatment session is rescheduled.

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

[0145] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the patient has not taken any drugs or substances that promote sedation or an increase in blood pressure.

[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] Embodiment 9. The method according to Embodiment 8, wherein the depression is major depressive disorder with suicidal ideation or severe major depressive disorder.

[0149] 10. The method according to any one of embodiments 1 to 9, further comprising a subsequent maintenance period in which the patient is intranasally administered approximately 56 mg or approximately 84 mg of esketamine per maintenance treatment session, wherein the maintenance treatment sessions are performed once a week for the first four weeks of the maintenance period, and thereafter adjusted to once a week or once every two weeks.

[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] Embodiment 13. The method according to any one of Embodiments 1 to 12, comprising adjunctive therapy using one or more antidepressants in therapeutically effective doses during the induction and maintenance phases.

[0153] Embodiment 14. The method according to Embodiment 13, wherein one or more antidepressants are administered at least 3 hours after each induction or maintenance treatment session.

[0154] Embodiment 15. The method according to Embodiment 1, wherein in the next treatment session, the eligible patient is administered approximately 56 mg or approximately 84 mg of esketamine intranasally, is monitored for less than 90 minutes during the post-treatment session monitoring period, and is released after a healthcare professional determines that the eligible patient is clinically stable and ready for discharge.

[0155] The following examples are provided to aid in understanding the present invention and are not intended to, nor should be construed to, limit in any way the invention described in the "Claims" attached to this specification. [Examples]

[0156] Example 1 Esketamine was supplied in a nasal spray pump as a colorless, clear intranasal solution of esketamine hydrochloride (16.14 wt / vol[w / v], equivalent to 14% w / v esketamine base). The solution consisted of 161.4 mg / mL of esketamine hydrochloride (equivalent to 140 mg of esketamine base) mixed with 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA) and 1.5 mg / mL of citrate (pH 4.5) in water for injection. The solution was supplied by a nasal spray pump, which delivered 16.14 mg of esketamine hydrochloride (14 mg of esketamine base) per 100 μL of spray solution. Each individual nasal spray pump (device) contained a total of 28 mg (i.e., two sprays).

[0157] Example 2 Data were pooled from adult patients (18–64 years old) with TRD. Patients had recurrent or single-episode (2 years or longer) MDD (DSM-5), three or more clinician-assessed depressive symptom item scores, and two or more total Montgomery-Åsberg Depression Rating Scale (MADRS) scores. At screening, depressive symptoms did not respond to appropriate commercially available OAD tests of 1 or greater and 5 or less in the current depressive episode. Non-response was further confirmed by prospective testing of different OADs that lasted for more than four weeks during the screening phase.

[0158] A. Test Design In short, Study 1 was a double-blind, placebo-controlled relapse prevention trial that compared the effectiveness of ESK versus placebo nasal spray (both used in combination with an FDA-approved OAD) in delaying the relapse of depressive symptoms in patients with TRD who achieved either stable remission or a stable response after 4 months of treatment with ESK in combination with an FDA-approved OAD. Study 2 was an open-label, multicenter trial that evaluated the long-term safety and efficacy of ESK in combination with an FDA-approved OAD in patients with TRD.

[0159] The analysis was limited to the two doses of ESK (56 mg and 84 mg) approved by the FDA for use in patients with TRD. Patients received ESK (56 or 84 mg) twice weekly in combination with OAD during the induction phase (weeks 1–4), once weekly during the optimization phase (weeks 5–8), and once weekly or every other week for the remainder of the 12-week optimization and maintenance phases (individualized according to the severity of depressive symptoms [MADRS total score ≤ / >12] and tolerability).

[0160] B. Safety Evaluation Patients were monitored for at least 90 minutes after ESK administration in each treatment session, after which they could leave the clinical facility at the clinician's discretion. AEs were monitored and reported, and safety assessments, including clinical laboratory tests and physical examinations, were conducted throughout the study. Clinician-reported AEs were classified as mild, moderate, or severe based on clinical judgment (Table 1).

[0161] [Table 1]

[0162] Vital signs, the Clinician-Managed Dissociative State Scale (CADSS), and the Observer-Assessed Modified Awakening / Sedation Scale (MOAA / S) were assessed at baseline and at all treatment sessions (pre-administration, 40 minutes after administration, 1 hour after administration [vital signs only unless spontaneously reported by the patient], and 1.5 hours after administration). Regular blood pressure (BP) readings were taken at each treatment session, and elevations were reported as adverse events (AEs) based on the clinician's judgment. The CADSS assessed dissociative symptoms that occurred during treatment and consisted of 23 questions, each coded on a 5-point scale (0=none, 1=mild, 2=moderate, 3=severe, 4=extreme), resulting in a total score of 0-92. A CADSS total score greater than 4 indicated the presence of dissociative symptoms. The MOAA / S assessed sedation that occurred during treatment and ranged from 0=no response to painful stimuli to 5=easily responds to a name spoken in a normal tone. Any decrease in MOAA / s from baseline (score less than 5) indicated some degree of sedation. Abnormally elevated blood pressure was defined as a systolic blood pressure of 180 mmHg or higher, which was 20 mmHg or more above baseline, and / or a diastolic blood pressure of 105 mmHg or higher, which was 15 mmHg or more above baseline.

[0163] C. Analysis of the relationship between early AEs and AE recurrence This analysis included all treatment sessions in which patients received ESK (either open-label or blinded). The incidence and severity of adverse events (AEs) were assessed within the following timeframes: Month 1 (Weeks 1 and 2–4), Month 2 (Weeks 5–8), Months 3–6, and Months 6–12. Clinician-reported AE severity was scored as 0 (no AE), 1 (mild), 2 (moderate), and 3 (severe). To examine AEs in individual patients over time, only patients who received at least one ESK dose during each of the following periods were included in the analysis for each period. Therefore, patient data is retained as follows: (i) if the patient received ESK at least once between weeks 2 and 4, it is retained in week 1; (ii) if the patient received ESK at least once between weeks 5 and 8, it is retained in weeks 2 and 4; (iii) if the patient received ESK at least once between months 3 and 6, it is retained in weeks 5 and 8; and (iv) if the patient received ESK at least once between months 6 and 12, it is retained in months 3 and 6.

[0164] The five most commonly reported in-treatment events (dissociation, dizziness, nausea, sedation, and vertigo) occurring in ESK plus OAD therapy were evaluated, each having an incidence of ≥5% and at least twice as high as placebo plus OAD. Increases in 14 blood pressure levels were also examined.

[0165] Weeks 1 and 4 were a priori set as indicator weeks because they marked the beginning and end of the introductory period. The frequency and maximum reported severity of AEs reported during these indicator weeks served as stratification variables to examine the severity of recurrence and AE recurrence in subsequent time frames.

[0166] Patients who received medication to treat an emergency AE or to prevent the (re)occurrence of an AE were 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, 21 of which were due to concerns regarding the implementation of the study site (Figure 1). Sensitivity analyses including these excluded patients were confirmed not to affect the overall conclusions of the study. Therefore, the dataset included 928 patients at weeks 1–4, 918 patients at weeks 5–8, and 595 patients at months 3–6 and 6–12. Discontinuations, including those due to adverse events, had been previously reported, and the reason patients were excluded in subsequent timeframes within this analysis was primarily the randomization defined in the protocol to placebo in Trial 1. The mean age of the patients was 46 years, 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 Across the examined AEs, the higher the frequency of AEs occurring during the first week of treatment, the higher the percentage of patients experiencing relapses (Table 3).

[0171] [Table 3-1]

[0172] [Table 3-2]

[0173] [Table 4]

[0174] For the entire patient population, the dissociation rate reported by clinicians between weeks 2 and 4 was 16.1%, compared to 86.5% (64 out of 74 patients) among those who reported two dissociations in week 1, 48.2% (41 out of 85 patients) among those who reported one dissociation in week 1, and 5.6% (44 out of 790 patients) among those who did not report any dissociations in week 1 (Figure 2). The same general pattern (increased recurrence rate as the frequency in week 1 increases) was observed for AEs and the rates of dissociation, sedation, or elevated BP reported and investigated by each clinician based on a standardized scale (Figures 3A and 3B).

[0175] These results also provide insights into the size of the groups most or least likely to experience AE recurrence. For example, for all clinician-reported AEs, the group with the lowest AE recurrence rate (those who did not report an AE in week 1) was the largest percentage of patients, comprising the smallest 78% of the sample (Table 3). These proportions were lower for proportions based on dissociation and sedation measurements, which do not account for clinicians' perception of clinical significance (not reported during week 1 in 43% and 62% of patients, respectively).

[0176] (a) Increased blood pressure If elevated blood pressure was reported as an adverse event (AE) in week 1, the likelihood of recurrence during the induction period (weeks 2-4) was higher. Subsequently, elevated blood pressure was more likely to recur at all time points in patients who experienced two elevations in week 1, and more likely to recur over months 3-6 in patients who experienced one elevation in week 1. In patients who did not experience elevated blood pressure in week 1 (95.7%), elevated blood pressure was reported in less than 4% of patients during all subsequent post-treatment monitoring periods. The frequency of elevated blood pressure at week 4 was more closely associated with recurrence in later treatment sessions than the frequency of elevated blood pressure at week 1.

[0177] (b) malice Of the 86.0% of patients who did not report nausea in the first week, less than 6% reported nausea during the follow-up monitoring period after subsequent doses. The frequency of nausea at week 4 is added to the predictive power at month 2, but not thereafter.

[0178] (c) Vomiting Participants who experienced vomiting once in the first week were more likely to vomit again in the subsequent period. However, of the eight participants who vomited twice in the first week, only one received voluntary related prophylaxis or acute treatment, and none experienced vomiting again in the subsequent period.

[0179] (d) dissociation Dissociation / perceptual alterations include distortions of time and space, as well as illusions, derealization, and depersonalization. Patients may describe these symptoms as feeling detached from themselves, their thoughts and feelings, and their surroundings. Of the patients who did not report dissociation in week 1 (83.2%), dissociation occurred in less than 10% of those patients for the remainder of the induction period. More than 50% of patients who experienced two dissociations in week 1 experienced dissociation as an AE at 3-6 months. The frequency of AEs in week 4 appears to be a better predictor of the likelihood of dissociation recurrence in later treatment sessions than the incidence in week 1.

[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 at week 1 or week 4 helps predict subsequent severity was limited due to the small number of patients whose AEs were characterized as moderate or severe. For all clinician-reported AEs except dissociation, fewer than 5 patients experienced severe relapses during either the first or fourth week observation period. For clinician-reported AEs other than dissociation, vertigo, vertigo, and nausea, fewer than 10 patients experienced moderate relapses during either the first or fourth week observation period.

[0181] Despite the highest reported severity of AEs at week 1 or week 4, relapses tended to be of mild to moderate severity. There was no consistent difference in the mean severity of recurrent AEs between patients who did not report a given AE at week 1 and patients with mild AEs. For clinician-reported dissociations, the mean relapse severity scores in patients with moderate or severe AEs at week 1 were 1.5 for both groups at weeks 2–4, 1.3 and 1.8 at weeks 5–8, 1.4 and 1.2 at months 3–6, and 1.5 and 1.6 at months 6–12 (compared to 1.3 across all timeframes for patients with no dissociation at week 1).

[0182] In patients with a maximum CADSS total score of 14 or less (which generally corresponds to a mild to moderate range of reported AEs), there were no significant differences in relapse severity (mean individual scores were 1.2–1.4 across various follow-up timeframes, with 1=mild and 2=moderate). In patients with maximum CADSS total scores of 15–24 and 24–42, mean individual CADSS scores were 1.3–2.1 across various follow-up timeframes, with fewer than three patients having a maximum CADSS score greater than 42. Despite the highest MOAA / S being reported at either week 1 or week 4 (minimum score = 0 [indicating the most severe sedation], maximum score = 5 [no sedation]), the mean subsequent relapses were mild (mean scores were 3.5–4.0, with the exception of one patient with a mean relapse score of 3.25).

[0183] (iii) Comparison of the incidence of adverse events (AEs) at the end of the induction period (week 4) versus week 1 for indications of recurrence rate or severity. The recurrence of AEs after week 4 was more closely associated with the frequency of AEs at week 4 than with the frequency of AEs at week 1. When no AEs occurred at either week 1 or week 4, there was little difference between the weeks in terms of their prognostic usefulness. This is shown in Figure 2 for dissociation, sedation, and increased BP as reported by clinicians. The relationships for other AEs, including the percentages based on measurements of dissociation, sedation, and increased BP, followed a similar pattern (Figures 3A-3F), although the differences in the latter were relatively small.

[0184] (iv) Effects of administration and concomitant medications Flexible dosing (ESK 56 or 84 mg) was permitted in the study, and since individual patient doses may vary within the dosing time frame, patients were stratified by their most frequent dose during each period. The effects of lower doses were most pronounced in dissociation and dizziness (Figures 4A-4I), but the effect of dose on AE recurrence rates was much smaller in magnitude than the effect on AE frequency at week 1.

[0185] Proactive or symptomatic management of potential or observed adverse events likely had minimal impact on the observed patterns because fewer than four patients received proactive or symptomatic treatment for each AE within each timeframe (Table 4).

[0186] [Table 5]

[0187] In the case of dissociation, only three patients received symptomatic medication (alprazolam, lorazepam) throughout the study period, while two patients received prophylactic medication (lorazepam, diazepam) at all intervals. For blood pressure, two patients received symptomatic treatment (losartan, captopril) between weeks 2 and 4, while the other two received symptomatic treatment (ramipril, enalapril) between weeks 5 and 8. No patients received symptomatic blood pressure medication in more than two periods, and no symptomatic blood pressure medication was administered after week 8. One patient received prophylactic propranolol between weeks 2 and 4 and between weeks 5 and 8. Four patients received medication for nausea (ondansetron) between weeks 2 and 4, one of whom received medication in the following two periods, and two of whom each received symptomatic medication in an additional period. Two patients received symptomatic medication (beta-histine) for dizziness during weeks 2-4, and none of the patients subsequently received treatment for dizziness.

[0188] (v) Time to onset of adverse event The time to onset of adverse events experienced by patients in Example 2 was analyzed. Tables 5-11 contain summaries of specific adverse events, categorized by the maximum time to onset, for the following periods: (i) each occurrence of an AE in week 1 during sessions 3-8 of the induction phase (Table 5), (ii) each occurrence of an AE in week 1 during the optimization phase (Table 6), (iii) each occurrence of an AE in week 4 during the optimization phase (Table 7), (iv) each occurrence of an AE in week 1 during months 3-6 of the maintenance phase (Table 8), (v) each occurrence of an AE in week 4 during months 3-6 of the maintenance phase (Table 9), (vi) each occurrence of an AE in week 1 during months 6-12 of the maintenance phase (Table 10), and (vii) each occurrence of an AE in week 4 during months 6-12 of the maintenance phase (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 describe the incidence of clinician-reported blood pressure (Table 12), clinician-reported dissociation (Table 13), dizziness (Table 14), sedation (Table 15), and vertigo (Table 16) from week 1 to 12 months, using data from Example 2. These data indicate 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 revealed that the higher the frequency of a given AE during early post-administration monitoring with ESK treatment, the higher the likelihood of recurrence in subsequent post-administration monitoring sessions. Patients who experienced one or two of the most commonly reported AEs in the first week of treatment were more likely to experience a recurrence of the same AE compared to patients who did not. The five most common AEs associated with ESK + oral antidepressant treatment for TRD (dissociation, dizziness, nausea, sedation, and vertigo) were more likely to recur after week 1 if they occurred more frequently in the first week of treatment. The reported severity of dissociation, dizziness, nausea, sedation, vertigo, and elevated blood pressure was mostly mild, with very few severe cases, for both initial occurrence and recurrence. The incidence of dissociation, dizziness, nausea, and sedation reported by clinicians was highest in week 1 of treatment with ESK + oral antidepressants and then decreased thereafter.

[0211] For each AE other than dissociation as defined by CADSS, the majority of patients did not report an AE in week 1, and were therefore stratified into the group with the lowest risk of recurrence (for dissociation as defined by CADSS, 43% of patients belonged to this group).

[0212] When adverse events (AEs) occurred in weeks 1 and 4, the recurrence of AEs after week 4 (end of induction period) was more closely associated with the frequency of the same AE in week 4 than in week 1. When neither AE occurred in weeks 1 nor 4, no different insights were provided. The predictive utility for both week 1 and week 4 AE frequencies was generally strong during the first six months. The incidence of a specific AE in week 1 or week 4 was a far more useful prognostic indicator of future AE recurrence than the ESK dose. The frequency of AEs occurring during the post-administration monitoring period in week 1 best predicted AE recurrence in subsequent treatment sessions for the remainder of the induction period (weeks 2-4) and generally predicted lower recurrence of AEs thereafter.

[0213] Among participants who did not spontaneously report an AE in week 1, the incidence of that AE was lower than the overall proportion in each subsequent time frame examined. Furthermore, when a given AE was absent in week 1, the moderate dose effect observed for some AEs was almost nonexistent due to the frequent recurrence of those AEs. During the post-treatment monitoring period, less than 10% of participants who did not report a given AE in week 1 experienced an AE after subsequent treatment sessions (with the exception of dizziness at 3–6 months [11.6%]).

[0214] The recurrence rate generally decreases over time.

[0215] The difference between formally measured dissociation, sedation, and abnormally elevated blood pressure (BP) and clinician-reported rates is clear. While these measurement approaches are inherently calibrated against various criteria, and clinicians were encouraged to report AEs deemed clinically significant or worthy of treatment, formal measurements simply detect deviations from generally accepted "normal" values. Therefore, it is not surprising that formal measurements revealed higher rates than clinician reports. However, despite these differences, the same fundamental relationship between initial and subsequent tolerability was observed across measurement modalities.

[0216] This study found a lower recurrence rate in patients who had not previously experienced the same AE; however, the recurrence rates of objectively measured dissociation, sedation, and elevated blood pressure never reached zero. Therefore, blood pressure should be assessed before ESK administration, at least 40 minutes after administration, and thereafter as needed based on clinical judgment. Patients should be monitored for 2 hours before discharge to ensure that sedation and dissociation have 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 adhere to all requirements, including, but not limited to, the following: • Maintain records demonstrating that processes / procedures are implemented and followed. This includes records related to reduced monitoring of eligible patients. • For all eligible patients who are monitored for less than the minimum 2-hour monitoring requirement within 7 calendar days after administration of any dose, 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 has previously received at least eight esketamine treatment sessions (i.e., beyond induction therapy) at the time reduced monitoring is initiated. • The patient is receiving treatment sessions at least once a week at the time reduced monitoring is initiated. The patient tolerated all esketamine treatment sessions and associated side effects in any previous treatment sessions, including the following, 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. • The patient does not have currently uncontrolled hypertension associated with either cardiovascular or endocrine complications. - The patient has an adult caregiver / responsible adult who agrees to be with the patient after treatment sessions and to participate with the patient in telephone assessments with the clinician at an agreed time at least two hours later that day to assess the patient's clinical condition. - The adult caregiver / responsible adult agrees to provide information (name, relationship, contact information) so that a follow-up telephone assessment can be arranged.

[0220] B. Informed Consent of the Patient and Adult Caregiver / Responsible Adult Informed consent includes the following: · The patient and / or clinician reviews the potential risks associated with monitoring the patient and caregiver / responsible adult for less than 2 hours, including but not limited to: - The patient and caregiver / responsible adult confirm that they understand the potential risks and consent to proceed with administration and monitoring for less than 2 hours if appropriate. Informed consent must be documented at the medical institution. - The patient and adult caregiver / responsible adult agree to follow the instructions provided by the clinician if the patient's condition does not improve after the monitoring period or if they have any other relevant health problems. - The adult caregiver / responsible adult agrees to stay with the patient after the treatment session until at least 2 hours after the end of the treatment session and until a follow-up telephone assessment agreed upon with the clinician is conducted that day.

[0221] C. Instructions on the Administration Day The reduced monitoring treatment option is only applicable to eligible patients treated with esketamine at a medical institution and is not performed for home administration and monitoring of esketamine.

[0222] Guidance on the Administration Day (i) While the patient is at the medical institution · The relevant forms are filled out by the clinician monitoring the patient at the medical institution. · The clinician continues to monitor the patient based on clinical judgment until clinically stable. To determine whether the patient is clinically stable, the clinician confirms that the following clinical criteria are met during the treatment session: - 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 clinician's clinical judgment, if a patient is not ready for early discharge, the medical institution will keep the patient for two hours or longer, if necessary. If a patient is deemed clinically stable after being monitored for at least one hour but less than two hours, this must be documented. Prior to discharge, the clinician ensures that an adult caregiver / responsible adult is present who is with the patient and agrees to participate with the patient in a telephone assessment conducted on the same day, at least two hours after the end of the treatment session. • Clinicians will provide instructions to the patient and the adult caregiver / responsible adult, based on the healthcare facility's processes and procedures, if the patient requires medical intervention after leaving the healthcare facility.

[0223] After the HCP-monitored treatment session has ended: For patients who are deemed clinically stable and discharged within two hours of esketamine administration, the clinician will contact the patient and the adult caregiver / responsible adult at an agreed time, at least two hours after the end of the treatment session, to follow up on the patient's clinical condition. During the caregiver / patient telephone assessment, the clinician will specifically ask whether the patient has experienced any new sedation or dissociation that began after the end of the treatment session. The clinician will document this on the form. • If a 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 it is appropriate to schedule a follow-up telephone assessment for the following day. • If the patient requires medical intervention, the patient and adult caregiver / responsible adult should follow the instructions provided by the clinician, which may include seeking emergency medical services and / or calling 911. - All serious adverse events must be reported in any form. - All other non-serious adverse events (other than dissociation or sedation) or product quality complaints related to esketamine must be reported. • Clinicians must submit all forms for all patients within 7 calendar days after administering all doses. The patient agrees not to engage in potentially dangerous activities, such as driving a car or operating machinery, after getting a good night's sleep until the following day. The clinician agrees to discontinue reducing monitoring in future treatment sessions if the patient fails to comply with all required elements.

[0224] D. Theoretical basis for the proposed elements (i) Determining which patients may be suitable candidates Requiring patients to have received at least eight previous treatment sessions makes it more likely that their tolerability profile in subsequent administration sessions can be predicted.

[0225] In addition to the requirement that the patient has no history of poorly controlled hypertension, the following requirements add further confidence that the patient has not had any clinically significant problems in previous treatment sessions: no clinically significant increases in blood pressure and heart rate, only mild dissociation, only mild sedation or disorientation, only mild self-limiting nausea without vomiting, and no other clinically relevant adverse events of clinical concern.

[0226] (ii) Duration of monitoring after administration The current proposal dictates 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, for established patients who have previously received at least eight treatment sessions without observing any significant clinical problems, in cases where the patient would experience dissociation, sedation, or an increase in blood pressure due to a minimum one-hour duration, it is guaranteed that those events will start within the first hour after administration. Thereafter, based on the current proposal, the monitoring period continues until the patient is clinically stable.

[0228] If the patient is not ready for early discharge, the patient may stay for a full two hours or longer if clinically necessary. The invention described in this specification may encompass the following embodiments. [1] A method for treating depression in human patients requiring treatment for depression, wherein the method comprises an induction phase and treatment sessions, the induction phase having a duration of 4 weeks, and the method For each induction treatment session, approximately 56 mg or approximately 84 mg of esketamine is administered intranasally to the patient, and 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. This includes monitoring the patient for adverse events for at least 90 minutes after each treatment session, at least after the first two treatment sessions, provided that the patient does not experience any severe adverse events after any two consecutive treatment sessions, and 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, A method for the aforementioned patient to become eligible for a post-treatment session monitoring period of less than 90 minutes in the next treatment session. [2] The method according to [1] above, wherein the patient becomes an eligible patient after at least the first three, four, five, six, seven, or eight treatment sessions. [3] The method according to [1] or [2] above, wherein the patient becomes eligible after eight treatment sessions. [4] The method according to any one of the above [1] to [3], wherein the post-treatment session monitoring period for the eligible patient is at least 60 minutes. [5] The method according to any one of the above [1] to [4], wherein, prior to the treatment session, the treatment session is rescheduled if the patient does not have a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg. [6] The method according to any one of the above [1] to [5], wherein the patient does not currently have poorly controlled hypertension. [7] The method according to any one of the above [1] to [6], wherein the patient has not taken any drugs or substances that promote sedation or an increase in blood pressure. [8] The method according to any one of the above [1] to [7], wherein the patient is under 65 years of age. [9] The method according to any one of the above [1] to [8], wherein the depression is major depressive disorder.

[10] The method according to [8] above, wherein the depression is major depressive disorder with suicidal ideation or severe major depressive disorder.

[11] The method according to any one of the above [1] to

[10] , further comprising a subsequent maintenance period in which the patient is intranasally administered about 56 mg or about 84 mg of esketamine per maintenance treatment session, wherein the maintenance treatment sessions are performed once a week for the first four weeks of the maintenance period, and thereafter adjusted to once a week or once every two weeks.

[12] The method according to

[11] above, wherein the depression is major depressive disorder.

[13] The method according to

[12] above, wherein the depression is treatment-resistant depression.

[14] The method according to any one of the above [1] to

[13] , comprising adjunctive therapy using one or more antidepressants in therapeutically effective doses during the induction and maintenance phases.

[15] The method according to

[14] above, wherein one or more of the aforementioned antidepressants are administered at least three hours after each induction or maintenance treatment session.

[16] The method according to [1] above, wherein in the subsequent treatment session, the eligible patient is administered approximately 56 mg or approximately 84 mg of esketamine intranasally, is monitored for less than 90 minutes during the post-treatment session monitoring period, and is released after a healthcare professional determines that the eligible patient is clinically stable and ready for discharge.

[17] Esketamine for use in the treatment of depression in human patients requiring treatment for depression, wherein the treatment comprises an induction phase and treatment sessions, the induction phase having a duration of 4 weeks, and For each induction treatment session, approximately 56 mg or approximately 84 mg of esketamine is administered intranasally to the patient, and 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. This includes monitoring the patient for adverse events for at least 90 minutes after each treatment session, at least after the first two treatment sessions, provided that the patient does not experience any severe adverse events after any two consecutive treatment sessions, and 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 patient becomes eligible for a post-treatment monitoring period of less than 90 minutes in the next treatment session, esketamine.

[18] The method described in

[17] above, wherein the patient becomes an eligible patient after at least the first three, four, five, six, seven, or eight treatment sessions.

[19] The esketamine described in

[17] or

[18] above, wherein the patient becomes eligible after eight treatment sessions.

[20] The esketamine according to any one of the above

[17] to

[19] , wherein the post-treatment monitoring period for the eligible patient is at least 60 minutes.

[21] If, prior to the treatment session, the patient does not have a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 110 mmHg, the treatment session is rescheduled, as described in any one of the above

[17] to

[20] .

[22] The esketamine described in any one of the above

[17] to

[21] , wherein the patient does not currently have poorly controlled hypertension.

[23] The esketamine described in any one of the above paragraphs

[17] to

[22] , wherein the patient has not taken any drugs or substances that promote sedation or an increase in blood pressure.

[24] The esketamine described in any one of the above

[17] to

[23] , wherein the patient is under 65 years of age.

[25] The esketamine described in any one of the above paragraphs

[17] to

[24] , wherein the depression is major depressive disorder.

[26] The esketamine described above

[24] , wherein the depression is major depressive disorder with suicidal ideation or severe major depressive disorder.

[27] The esketamine according to any one of the above

[17] to

[26] , wherein the method further comprises a subsequent maintenance period in which the patient is intranasally administered about 56 mg or about 84 mg of esketamine per maintenance treatment session, the maintenance treatment sessions being performed once a week for the first four weeks of the maintenance period, and thereafter adjusted to once a week or once every two weeks.

[28] The esketamine described above

[27] , wherein the depression is major depressive disorder.

[29] The esketamine described above

[28] , wherein the depression is treatment-resistant depression.

[30] Esketamine as described in any one of the above paragraphs

[17] to

[29] , including adjunctive therapy using one or more antidepressants in therapeutically effective doses during the induction and maintenance phases.

[31] The esketamine described in

[30] above, wherein one or more of the aforementioned antidepressants are administered at least three hours after each induction or maintenance treatment session.

[32] The method according to

[17] , wherein in the subsequent treatment session, the eligible patient is administered approximately 56 mg or approximately 84 mg of esketamine intranasally, is monitored for less than 90 minutes during the post-treatment session monitoring period, and is released after a medical professional determines that the eligible patient is clinically stable and ready for discharge.

Claims

1. A pharmaceutical composition for use in a method of treating depression in human patients who require treatment for depression, The aforementioned pharmaceutical composition contains esketamine, The method comprises an introduction phase, a subsequent maintenance phase, and treatment sessions, wherein the introduction phase has a duration of four weeks, and The aforementioned method, For each induction treatment session, approximately 56 mg or approximately 84 mg of esketamine is administered intranasally to the patient, 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. The subsequent maintenance phase includes intranasal administration of approximately 56 mg or approximately 84 mg of esketamine to the patient per maintenance treatment session, with the maintenance treatment sessions being performed once a week for the first four weeks of the maintenance phase, and thereafter adjusted to once a week or once every two weeks. This includes monitoring the patient for adverse events for at least 90 minutes after each treatment session, at least after the first two treatment sessions, The patient did not experience any severe adverse events after either of the two consecutive treatment sessions, and 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 No adverse events were experienced, including moderate to severe nausea without vomiting, and After the first two, three, four, five, six, seven, or eight treatment sessions, the patient becomes eligible for a post-treatment monitoring period of 60 to 90 minutes in the next treatment session. A pharmaceutical composition in which, in the subsequent treatment session, the eligible patient is administered approximately 56 mg or approximately 84 mg of esketamine intranasally, is monitored for 60 to less than 90 minutes during the post-treatment session monitoring period, and is released after a medical professional determines that the eligible patient is clinically stable and ready for discharge.

2. The pharmaceutical composition according to claim 1, wherein the patient becomes an eligible patient after eight treatment sessions.

3. The pharmaceutical composition according to claim 1 or 2, wherein the patient does not currently have poorly controlled hypertension.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient has not taken any drugs or substances that promote sedation or an increase in blood pressure.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the patient is under 65 years of age.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the depression is major depressive disorder.

7. The pharmaceutical composition according to claim 6, wherein the depression is major depressive disorder accompanied by suicidal ideation or severe major depressive disorder.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the depression is major depressive disorder.

9. The pharmaceutical composition according to claim 8, wherein the depression is treatment-resistant depression.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the method includes adjunctive therapy using one or more antidepressants in a therapeutically effective amount during the induction phase and the maintenance phase.

11. The pharmaceutical composition according to claim 10, wherein one or more antidepressants are administered at least three hours after each induction or maintenance treatment session.

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