Treatment using oxytocin

Abstract

The present disclosure relates to methods for treating and / or preventing diseases and disorders using oxytocin targeting agents, and compositions relating thereto.

Description

[Technical field]

[0001] Cross-reference to five related applications This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 303,807, filed January 27, 2022, which is incorporated by reference in its entirety. (Technical field)

[0002] The present disclosure relates to methods for treating and / or preventing diseases and disorders using oxytocin targeting agents, and compositions relating thereto. [Background technology]

[0003] It is estimated that one in twenty adults in the United States experiences a serious mental illness each year. Treatment choices for mental illness vary from person to person. Even people with the same diagnosis will have different experiences, needs, goals, and objectives for treatment. There is no "one size fits all" treatment. For severely ill patients, options and success rates for treatment may be limited, and recovery rates are low. People with serious mental illness are nearly twice as likely as the general population to develop cardiovascular and metabolic diseases, more likely to be unemployed, more likely to drop out of school, more likely to develop substance use disorders, more likely to be hospitalized, and even more likely to be incarcerated.

[0004] Thus, there is a continuing need for new therapeutic regimens for the treatment of psychiatric and other mental disorders. Summary of the Invention

[0005] Provided herein is a method for treating a condition selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenia disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome in a subject, the method comprising administering to a subject in need thereof an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and optionally an effective amount of an anti-inflammatory agent.

[0006] In some embodiments, the neuroplasticity agent is one or more of racemic ketamine, esketamine (Spravato), (R)-ketamine, (2R,6R)-hydroxynorketamine (HNK), psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT or N,N-DMT), lysergic acid diethylamide (LSD), dextromethorphan, Nudexta (a combination of dextromethorphan and quinidine), Dewdextromethorphan (AVP-786), Axam (AXS-05), dextromethadone (REL-1017), or zuranolone (SAGE-217).

[0007] Also provided herein is a method for treating postpartum or perinatal depression in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin and an effective amount of a neuroplasticity agent.

[0008] In some embodiments, the neuroplasticity agent is brexanolone or zuranolone (SAGE-217).

[0009] Also provided is a method for treating generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, or binge eating disorder in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin and an effective amount of a neuroplasticity agent.

[0010] Also provided is a method for treating chronic fatigue syndrome in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin and an effective amount of a neuroplasticity agent.

[0011] In some embodiments of the methods described herein, the treatment includes an acute phase, or a stabilization phase, and a maintenance phase, optionally, the acute phase includes administering a first dose of oxytocin prior to administering the neuroplasticity agent, and optionally followed by an anti-inflammatory agent. In some embodiments, the oxytocin, neuroplasticity agent, and / or anti-inflammatory agent are administered intranasally.

[0012] It is contemplated that the disclosed treatments will enable subjects suffering from one or more of the aforementioned diseases or disorders to stimulate and regenerate, or more rapidly stimulate and regenerate, neural connections in the brain, which will have a positive effect on mental and / or physical health. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The following description describes exemplary embodiments of the present technology, however, it should be appreciated that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0015] The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," and the like, should be read broadly and without limitation. Moreover, the terms and expressions used herein are used as terms of description and not of limitation, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or portions thereof, but is recognized to allow various modifications within the scope of the disclosed claims.

[0016] The term "about" refers to a variation of ±1%, ±3%, ±5%, or ±10% of the specified value. For example, "about 50" can include a range of 45 to 55 in some embodiments. For integer ranges, the term "about" can include one or two integers greater than and / or less than the recited integer at each end of the range. Unless otherwise indicated herein, the term "about" is intended to include values, e.g., percentages by weight, proximate the recited range that are equivalent with respect to the functionality of the individual components, compositions, or embodiments. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "cannabinoids" includes a plurality of such compounds.

[0017] As used herein, "treatment" or "treating" is an approach to obtain a beneficial or desired result, such as a clinical result. For purposes of this disclosure, a beneficial or desired clinical result includes, but is not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. For purposes of this disclosure, a beneficial or desired clinical result includes, but is not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a given disease or disorder. Preferably, treatment of a subject using the methods described herein is accompanied by no or less side effects associated with currently available treatments for the disease or condition and / or disorder, particularly for the quality of life of subjects, such as treatment-resistant subjects, subjects with severe side effects to common therapeutic agents, or subjects for whom typical standard treatments are ineffective or contraindicated. Typical standard treatments include therapies including drug therapy, physical therapy, or psychological therapy, or both.

[0018] As used herein, the term "effective amount" refers to that amount of the disclosed compound or composition that should be effective in a given treatment regime, in combination with its parameters of efficacy and toxicity, and based on the knowledge of the practitioner.As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired treatment endpoint.An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result can be obtained or achieved.

[0019] The term "neuroplastic agent" is intended to refer to a compound or substance that increases dendrite density, growth, or enhances morphology. In certain instances, an agent may impart changes in synaptic plasticity or dendritic morphology by providing increased expression of presynaptic or postsynaptic plasticity-related proteins, as well as density and / or function of axospinal synapses. Studies in both humans and animal models have demonstrated abnormal dendritic spine structure in several psychiatric disorders, including depression and other stress-related diseases. The negative effects of stress on dendritic density and organization are also believed to contribute to behavioral disorders caused by stress exposure.

[0020] Particular neuroplasticity agents are shown below in Table 1. Such agents are either commercially available or can be prepared and formulated according to published methods. [Table 1-1] [Table 1-2] [Table 1-3]

[0021] Treatment method The neuropeptide oxytocin plays an evolutionarily conserved role in mammalian social behavior. Despite the remarkable effects on social behavior in animals after intracerebroventricular drug delivery, this mode of delivery is not practical in humans. Intranasal oxytocin, which can be purchased from commercial sources, offers a non-invasive alternative to increase central oxytocin activity and has shown promise as a treatment for psychiatric disorders. For example, studies have shown that intranasal oxytocin administration improves theory of mind, memory for social cues, and increases gaze to the eye area. It is believed that intranasal oxytocin delivery may increase central oxytocin concentrations via channels surrounding trigeminal and olfactory nerve fibers, promoting increased activity at central oxytocin receptors. These findings have sparked interest in the use of intranasal oxytocin to treat psychiatric disorders characterized by social dysfunction, among others, but meta-analyses of oxytocin's effects in clinical populations have yielded mixed results to date.

[0022] Provided herein is a method for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenia disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome in a subject, the method comprising administering to a subject in need thereof an effective amount of oxytocin and an effective amount of a neuroplasticity agent.

[0023] Subjects who need the methods described herein can be identified by standard methods. Pain is determined by subject reporting it, whereas psychiatric disorders can be more subjective diagnosis. Many psychiatric tests, scales and forms have been created over the years to diagnose psychiatric disorders and assist in treatment and follow-up. These scales have demonstrated high levels of accuracy and validity, and the results can provide important clues to possible psychiatric disorders that may warrant treatment via the methods described herein.

[0024] The Major Depression Inventory (MDI) is a brief self-report mood questionnaire that allows clinicians to assess the presence of depression according to the DSM-IV. It is also used to assess the severity of depressive symptoms.

[0025] The Mood Disorder Questionnaire (MDQ), developed by Dr. Robert MA Hirschfeld and colleagues, is a screening instrument for bipolar disorder. It includes 13 yes / no questions about bipolar symptoms and two additional questions about symptom co-occurrence and functional impairment.

[0026] The Generalized Anxiety Disorder 7-item (GAD-7) was developed to diagnose generalized anxiety disorder and has been validated in 2740 primary care patients. It has a sensitivity of 89% and a specificity of 82%. It is moderately good at screening for three other common anxiety disorders: panic disorder (sensitivity 74%, specificity 81%), social anxiety disorder (sensitivity 72%, specificity 80%), and post-traumatic stress disorder (sensitivity 66%, specificity 81%).

[0027] The Clinical Global Impression Scale-CGI is a commonly used three-item observer-rated scale to measure symptom severity, overall improvement, and treatment response. Each component of the CGI is rated individually and no global score is obtained. Items 1 and 2 are rated on a 7-point scale, and item 3 is rated from 0 to 4 (treatment efficacy and treatment-related adverse events should be taken into account when rating item 3).

[0028] The Hamilton Depression Rating Scale has proven useful in determining levels of depression before, during, and after treatment. It is based on a clinician's interview with the patient and explores symptoms such as depressed mood, feelings of guilt, suicidality, sleep disorders, anxiety levels, and weight loss. The interview and scoring takes approximately 15 minutes. The assessor enters a number for each symptom construct ranging from 0 (absent) to 4 (extreme symptoms).

[0029] The Bipolar Clinical Scale or Bipolar Spectrum Diagnostic Scale (BSDS) was developed by Ronald Pies, MD, and later refined and tested by S. Nassir Ghaemi, MD, MPH, and others. The BSDS arose from Pies' experience as a psychopharmacology consultant when he was frequently called upon to manage cases of "treatment-resistant depression." In Pies' experience, most of these cases ultimately proved to be undiagnosed bipolar spectrum disorder. The BSDS questionnaire was based on questions that Pies determined would be most useful in detecting severe cases of bipolar disorder as well as patients who fall into the "softer" end of the bipolar spectrum (e.g., patients with a history of major depressive episodes who have had one or two episodes of elevated mood and energy lasting only 1-3 days and therefore do not meet DSM-IV criteria for hypomania). The BSDS was validated in its original version and showed high sensitivity (0.75 for bipolar disorder I and 0.79 for bipolar disorder II and not otherwise specified). Its specificity is high (0.85), giving this diagnostic tool great value in detecting the broad presentation of the bipolar spectrum. Ghaemi et al. determined that a score of 13 was the optimal threshold for specificity and sensitivity in detecting bipolar spectrum disorder. The BSDS has two sections. The first part contains a series of 19 statements that describe the main symptoms of bipolar spectrum disorder. Each statement is linked to a blank space that the patient is to check if they judge the statement to be an accurate description of their feelings or behavior. Each checked statement is assigned one point. The second part of the BSDS asks the patient to select the extent to which the 19 stories "fit" his or her own experience. This scale has four possibilities: "This story applies to me very much or almost perfectly" (score 6), "This story applies to me quite a bit" (score 4), "This story applies to me to some extent, but not in most ways" (score 2), and "This story does not describe me at all" (score 0).

[0030] The Hamilton Anxiety Scale (HAM-A) is a widely used interview scale that measures the severity of a patient's anxiety based on 14 parameters, including anxious mood, tension, fear, insomnia, somatic complaints, and behavior during the interview. Developed by M. Hamilton in 1959, this scale naturally predates the current definition of generalized anxiety disorder (GAD). However, it encompasses many features of GAD and may also be useful in assessing its severity. The primary value of the HAM-A is not as a diagnostic or screening tool, but as a document of the results of pharmacotherapy or psychotherapy. The interview and scoring take 15-20 minutes to complete. Each item is simply given a 5-point score ranging from 0 (absent) to 4 (severe).

[0031] The Brief Psychiatric Rating Scale (BPRS) is a tool used by clinicians or researchers to measure psychiatric symptoms such as anxiety, depression, and psychosis. Humans who have or are suspected of having schizophrenia or other psychotic disorders manifest their disorder in multiple ways. The BPRS assesses the levels of 18 symptom constructs such as hostility, distrust, hallucinations, and grandiosity. It is particularly useful for measuring the effectiveness of treatment in patients with moderate to severe psychosis. It is based on the clinician's interview with the patient and observations of the patient's behavior over the past 2-3 days. The patient's family can also provide a behavioral report. The assessor enters a number for each symptom construct, ranging from 1 (absent) to 7 (very severe). The time required to complete the interview and scoring can be as little as 20-30 minutes.

[0032] Humans taking any type of antipsychotic should be monitored for movement disorders. The AIMS (Abnormal Involuntary Movement Scale) aids in early detection of tardive dyskinesia and provides a method for ongoing monitoring. The incidence of TD has been relatively low in recent years, but prescription changes may increase the incidence. Clinicians should be aware of these possibilities and use tools that help them address any problems that are occurring as early as possible. This simple checklist takes only 10 minutes to complete and uses a five-point rating scale to record scores in seven body areas: face, lips, jaw, tongue, upper limbs, lower limbs, and trunk.

[0033] The Patient Health Questionnaire (PHQ-9) is a depression module in which each of the nine DSM-IV criteria is scored as "0" (not at all) to "3" (almost every day). It has been validated for use in primary care. It is not generally a screening tool for depression, but is used to monitor depression severity and response to treatment.

[0034] The Burns Anxiety Inventory (BAI) is an assessment tool for measuring anxiety. The Burn Anxiety Inventory is a self-report anxiety assessment tool that assesses anxiety symptoms such as worry, tension, panic, or heart rate. The higher the score, the greater the severity of anxiety.

[0035] The Geriatric Depression Scale-Short (GDS-S) is a 15-question scale developed as a basic screening measure for depression in older adults, with a score of 5 or higher indicating the need for more detailed clinical investigation.

[0036] Studies have shown that inflammation in major depressive disorder (MDD) is a factor that needs to be evaluated and understood, and is associated with increases in pro-inflammatory cytokines such as interleukin-1-beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), among others (Howren et al. Psychosom Med, 2009, 71, 171-186; Maes et al. Metab Brain Dis, 2009, 24, 27-53; Wong et al. Mol Psychiatry, 2008, 13, 800-812).

[0037] Decreases in brain-derived neurotrophic factor (BDNF), a protein of the neurotrophic family of growth factors, have been reported in various neuropsychiatric disorders. BDNF blood levels are decreased in subjects with major depressive disorder and increased after antidepressant treatment. See Binder et al., Growth Factors, 2004, 22, 123-131; Ventriglia et al., BioMed Res Int, 2013, 2013, 901082; Pezet et al., Brain Res Rev, 2002, 40, 240-249; Bjoerkholm et al., Neuropharmacology, 2016, 102, 72-79; Pandya et al., Asian J Psychiatr, 2013, 6, 22-28; Sen et al., Biol Psychiatry, 2008, 64, 527-532; Molendijk et al., Mol Psychiatry, 2014, 19, 791-800. Thus, when the brain is exposed to chronic stress and anxiety, the number of synaptic connections in certain parts of the brain decreases. It is contemplated herein that administering a neuroplasticity agent can stimulate dendritic growth, thereby restoring lost synaptic connections, strengthening existing synaptic connections, and even stimulating the growth of new neurons.

[0038] In some embodiments, the neuroplasticity agent is one or more of ketamine, esketamine, and ketamine, including but not limited to (R)-ketamine, (2R,6R)-hydroxynorketamine (HNK), psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT or N,N-DMT), lysergic acid diethylamide (LSD), dextromethorphan, Nudexta (a combination of dextromethorphan and quinidine), Dewdextromethorphan (AVP-786), Axam (AXS-05), dextromethadone (REL-1017), or zuranolone (SAGE-217).

[0039] For example, intravenous ketamine promotes new brain growth by increasing the number of synaptic connections in the brain. Chronic stress continues to stimulate the hypothalamic pituitary axis (HPA) which continues to release inflammatory cytokines. The inflammatory cytokines gain access to the brain and cause reduced production and reduced reuptake of dopamine, norepinephrine, serotonin, and BDNF. Reduced BDNF prevents normal growth, repair, and maintenance of synaptic connections of various neurons. Dopamine neurons reduce tonic release of dopamine resulting in various levels of anhedonia and depressed mood. Due to the reduced production and reuptake of serotonin, patients experience a depressed mood. Due to the reduced production and reuptake of norepinephrine, patients experience reduced focus and concentration. The most significant effect of chronic stress is the reduced dopamine and reduced reuptake, which is discussed further below.

[0040] By administering a neuroplastic agent, dendrites in the brain can be regrowth and lost connections restored. It has been determined that with IV ketamine alone, under most circumstances, a series of injections (e.g., six) can last anywhere from one month to several months (e.g., four to six months). Once the positive effects begin to fade, one booster injection is often required to sustain the positive effects for another month or more. It is contemplated by using the methods described herein that the positive effects can be extended or enhanced over ketamine alone. The methods described also provide for faster growth of dendrites and their synaptic connections with other neurons.

[0041] In some embodiments, methods are provided for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenic disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and optionally an effective amount of an anti-inflammatory agent.

[0042] In some embodiments, a method is provided for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenic disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome in a subject, comprising administering an effective amount of oxytocin and an effective amount of a neuroplasticity agent to a subject in need thereof.

[0043] In some embodiments, methods are provided for treating one of severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenic disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin and an effective amount of ketamine, including but not limited to racemic ketamine (mixture of enantiomers), esketamine, or (R)-ketamine.

[0044] Also provided herein is a method for treating postpartum or perinatal depression in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and optionally, an effective amount of an anti-inflammatory agent.

[0045] In some embodiments, the neuroplasticity agent is brexanolone or zuranolone (SAGE-217).

[0046] Also provided herein is a method for treating generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, binge eating disorder in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and optionally, an effective amount of an anti-inflammatory agent.

[0047] Also provided is a method for treating chronic fatigue syndrome in a subject, comprising administering to a subject in need thereof an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and optionally, an effective amount of an anti-inflammatory agent.

[0048] In some embodiments, the subject is a pre-adult or adolescent subject (e.g., 16-18 years old). In some embodiments, the subject is an adult, 18-65 years old. In some embodiments, the subject is an elderly subject (e.g., 65 years old or older, or 66-75 years old). In some embodiments, the subject is male. In some embodiments, the subject is female.

[0049] In some embodiments, the oxytocin is administered intravenously. In some embodiments, the oxytocin is administered intranasally. In some embodiments, the neuroplasticity agent is administered intravenously. In some embodiments, the neuroplasticity agent is administered intranasally. In some embodiments, the anti-inflammatory agent is administered intravenously, intramuscularly, or intranasally.

[0050] It should be noted that questions remain about the ideal outcome measures to be used in clinical trials to assess subject response to many of these tests. Many outcome measures currently in use, including those mentioned above, were designed to measure changes in symptoms that occur over weeks to months, rather than hours to days. For example, insomnia or changes in appetite cannot be reasonably assessed over a period of hours. However, most caregivers (e.g., physicians or therapists) use these scales, suggesting that more precise methods are needed to capture the clinical effects of these medications. Identifying unidimensional constructs that could help parse the heterogeneity of depressive symptoms could ultimately allow for the creation of more refined rating scale scores to better illuminate the connections between specific symptoms and the underlying pathophysiology (Ioline et al., Current Status 1 CNS Drugs, 2021, 35(5), 527-543; Wilkinson et al., Drug Discov Today, 2019, 24, 606-615; Ballard et al., J Affect Disord, 2018, 231, 51-57).

[0051] Major depressive disorder is typically characterized by a depressed mood accompanied by loss of interest and pleasure in almost all activities for at least two weeks.

[0052] In some embodiments, the subject exhibits one or more symptoms of depression, such as sleep disturbances, changes in energy levels or difficulty concentrating, anhedonia (inability to experience pleasure), dysphoria (state of anxiety or dissatisfaction), dissociative symptoms, externalization of anger, or aggressive symptoms.

[0053] In some embodiments, the subject further suffers from one or more of obsessive-compulsive disorder, a trauma- or stressor-related disorder, a dissociative disorder, an acute stress disorder, an adjustment disorder, an inhibited social engagement disorder, a reactive attachment disorder, a somatic symptom, a feeding or eating disorder, a sleep disorder, or a substance-related or addictive disorder.

[0054] In some embodiments, the disease or disorder is not a neuropsychiatric disease selected from the group consisting of post-traumatic stress disorder (PTSD), opioid use disorder (OUD), cocaine use disorder (CUD), unipolar postpartum depression (PPD), or a combination thereof.

[0055] Described herein is a rating scale for determining the severity of mental illness or disorder, including but not limited to major depressive disorder, called the "reward / enjoyment scale". The reward / enjoyment scale described herein (see Example 4) can be used to determine treatment methods and when to continue treating a subject in the acute or stabilization phase, as opposed to moving to a "chronic" treatment, i.e., "maintenance" phase.

[0056] In some embodiments, the method includes an acute "stabilization" phase and a "maintenance" phase.

[0057] Acute “stabilization” phase The acute "stabilization" phase typically involves a series of treatments, in which the subject receives oxytocin and a neuroplastic agent, optionally followed by an anti-inflammatory agent, one or more times per week, e.g., one, two, or three times per week, for a period of 1-6 weeks, or 1-5 weeks, or 1-4 weeks, or 1-3 weeks, or 1-2 weeks, or 2-6 weeks, or 2-5 weeks, or 2-4 weeks, or 2-3 weeks, or 3-5 weeks, or 4-5 weeks, or 3-6 weeks, or 3-5 weeks, or 3-4 weeks, or 4-5 weeks, or 4-6 weeks, or 5-6 weeks, depending on the initial severity of the illness and / or the extent of improvement of the illness. In certain embodiments, the acute "stabilization" phase lasts for about 4-5 treatments, or 2-3 weeks. The severity and extent of improvement may be determined by clinical methods known in the art, such as, but not limited to, those described herein. The more negative the patient is (-1 to -10 on the reward / enjoyment scale), the more treatment is done to get the patient into the positive zone. The amount of effort the patient puts in to apply positive coping skills (mindfulness, meditation, psychotherapy, proper diet, exercise, sleep regulation, etc.) directly correlates with their overall antidepressant response.

[0058] The "negative" zone represents various degrees of anhedonia, as well as reward or relief from thinking, saying, or doing something negative. -1 is the most negative, with -10 being the most negative in the negative zone of the reward / enjoyment scale. As patients lose synaptic connections in the brain's reward pathways, dopamine neurons become seemingly inactive, reducing the tonic release of dopamine. When enough dopamine neurons are inactive, the low-dopamine (hypodopaminergic) state causes patients to experience anhedonia, dysphoria, psychomotor slowing, and a lack of motivation to seek positive rewards. These feelings continue to worsen as the patient becomes more negative (towards -10) in the negative zone.

[0059] Patients find that they only get rewards or relief from negative thoughts, statements, or actions. They begin to seek negative rewards to relieve the anxiety they feel. Patients often create false stories to support their negative thoughts, statements, or actions. When their false stories are challenged by others, usually loved ones, patients may want to defend their false stories and further isolate themselves from others. The Negative Zone is a phenomenon that has yet to be defined in the medical literature and has been observed.

[0060] As patients lose more synaptic connections and go deeper into the negative zone, they appear to get more reward and / or relief from negative thoughts, statements, and actions. Since dopamine neurons are less active as patients continue to lose synaptic connections, it is hypothesized that patients experience more relief through upregulation (or increased proliferation) of μ-opioid receptors. There may also be an upregulation (or increased proliferation) of those dopamine receptors as the amount of dopamine released decreases. As patients go deeper into the negative zone, they become more relieved from things that cause them more emotional and even physical pain. This theory would support why people deep in the negative zone are soon relieved from non-self-injury self-injury (NSSI). This theory would also explain why people deep in the negative zone are relieved from suicidal thoughts. Thinking about suicide makes them feel like the pain and suffering is over, which makes them feel better.

[0061] It was hypothesized that the patient's own oxytocin was being released during the ketamine infusion, which was likely a key reason for how ketamine helped to alleviate anxiety given its known sedative effects on the limbic system. It was then contemplated that other rapid neuroplastic agents (i.e., psilocybin, MDMA), which also stimulate the release of oxytocin, may play a role in neurogenesis and result in reduced anxiety levels. It was then observed that administering oxytocin before ketamine treatment resulted in a much calmer and euphoric ketamine experience. The extra sedative effect was much appreciated by patients suffering from anxiety disorders. It was then observed that patients recovered from depression and anxiety much faster than with ketamine alone. It is essential that patients reach the positive zone as soon as possible. It was found that ketamine treatment alone was much slower to alleviate the effects of anxiety than patients with depression. With the addition of oxytocin treatment, patients were observed to recover from anxiety much faster than with ketamine infusion alone. Anxiety is a major cause of chronic inflammation, reducing BDNF and the ongoing loss of synaptic connections. It is contemplated that reducing anxiety by adding exogenous oxytocin will significantly reduce inflammation in the brain, thereby enhancing the neuroplastic effects from ketamine.

[0062] Oxytocin strengthens the limbic system, reinforcing what is deemed "safe" or "dangerous." This applies to people, places, and things. There are different levels of "safety" and "danger." When the limbic system detects a threat and oxytocin is present, the sense of "unsafe" is heightened, motivating the individual to avoid, fight, or flee from that person, place, or thing. When the limbic system, in the presence of oxytocin, determines that a person, place, or thing is "safe," the individual is motivated to engage with the person, place, or thing. When a person feels connected to someone and feels safe, physical contact promotes the release of additional oxytocin, which is calming and soothing. The reverse is also true. When a person deemed "unsafe" touches an individual, more oxytocin is released, increasing the individual's urge to fight or flee from the "unsafe" individual. When determining whether a patient should receive oxytocin before neuroplasticity, the patient's level of reactivity should first be evaluated by the physician. Administration of oxytocin should be avoided when dealing with highly reactive patients (i.e., acutely suicidal, homicidal).

[0063] Anti-inflammatory agents are used after neuroplastic agents to reduce the amount of inflammation present, thereby allowing neurogenesis to proceed uninhibited. Neurogenesis is enhanced by reducing the effect that inflammation has on reducing the release of BDNF. Anti-inflammatory agents, when administered with ketamine, can increase the psychedelic effect. Thus, in some embodiments, anti-inflammatory agents are administered after the psychedelic effect from the neuroplastic agents has diminished.

[0064] In some embodiments, the acute "stabilization" phase comprises administering a first dose of oxytocin prior to administering the neuroplastic agent. In some embodiments, the acute phase comprises administering a first dose of oxytocin intravenously prior to administering the neuroplastic agent intravenously. In some embodiments, the acute phase comprises administering a first dose of oxytocin intranasally prior to administering the neuroplastic agent intravenously. In some embodiments, the acute phase comprises administering a first dose of oxytocin intravenously prior to administering the neuroplastic agent intranasally. In some embodiments, the acute phase comprises administering a first dose of oxytocin intranasally prior to administering the neuroplastic agent intranasally.

[0065] In some embodiments, the acute phase comprises administering a first dose of a neuroplastic agent prior to administering oxytocin. In some embodiments, the acute phase comprises administering a first dose of a neuroplastic agent intravenously prior to administering oxytocin intravenously. In some embodiments, the acute phase comprises administering a first dose of a neuroplastic agent intranasally prior to administering oxytocin intravenously. In some embodiments, the acute phase comprises administering a first dose of a neuroplastic agent intravenously prior to administering oxytocin intranasally. In some embodiments, the acute phase comprises administering a first dose of a neuroplastic agent intranasally prior to administering oxytocin intranasally.

[0066] In some embodiments, the dose of oxytocin administered at each acute treatment is about 0.1 to about 100 international units (IU). In some embodiments, the dose of oxytocin administered at each acute treatment is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 International Units (IU). Oxytocin may be administered as a single dose (via IV or intranasal administration) or multiple doses (i.e., two or more) during each treatment.

[0067] In some embodiments, the neuroplasticity agent administered acutely is ketamine. In some embodiments, the neuroplasticity agent administered acutely is esketamine. In some embodiments, the neuroplasticity agent administered acutely is (R)-ketamine.

[0068] In some embodiments, the neuroplasticity agent administered acutely is (2R,6R)-hydroxynorketamine (HNK).

[0069] In some embodiments, the acutely administered neuroplastic agent is psilocybin.

[0070] In some embodiments, the acutely administered neuroplastic agent is 3,4-methylenedioxymethamphetamine (MDMA).

[0071] In some embodiments, the neuroplasticity agent administered acutely is N,N-dimethyltryptamine (DMT or N,N-DMT).

[0072] In some embodiments, the acutely administered neuroplastic agent is lysergic acid diethylamide (LSD).

[0073] In some embodiments, the acute phase comprises administering dextromethorphan.

[0074] In some embodiments, the neuroplasticity agent administered acutely is Nudexta (a combination of dextromethorphan and quinidine).

[0075] In some embodiments, the neuroplasticity agent administered acutely is deudextromethorphan (AVP-786).

[0076] In some embodiments, the neuroplasticity agent administered acutely is Axam (AXS-05).

[0077] In some embodiments, the neuroplasticity agent administered acutely is dextromethadone (REL-1017).

[0078] In some embodiments, the neuroplasticity agent administered acutely is zuranolone (SAGE-217).

[0079] In some embodiments, the neuroplasticity agent administered acutely is brexanolone.

[0080] In some embodiments, the dose of the neuroplastic agent administered at each acute treatment is about 0.1 to about 300 mg. In some embodiments, the dose of ketamine administered at each acute treatment is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 12 0, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg.

[0081] In some embodiments, the neuroplasticity agent comprises ketamine (e.g., racemic ketamine, esketamine, or (R)-ketamine) and is administered at least once every 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 120, 140, 160, 180, 190, 210, 220, 230, 240, 250, 260, 270, 280, 290, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 850, 860, 870 , 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg was administered intranasally, and then, optionally, 10 to 15 minutes later, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 13 The second intranasal dose is administered at a dose of 0, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or 300 mg.

[0082] In some embodiments, the acute "stabilization" phase involves treatments about twice a week, or 2-3 times a week, with each treatment spaced about 2-4 days, or 3 days, or about 72 hours apart from the previous infusion.

[0083] During the acute "stabilization" phase, oxytocin may or may not be administered with each treatment.

[0084] In some embodiments, the acute "stabilization" phase involves administering a neuroplasticity agent intravenously at a total dose of about 30-100 mg, or about 45-90 mg, or about 50-75 mg, or about 60 mg, optionally over about 45-60 minutes, or about 50 minutes.

[0085] In some embodiments, the acute "stabilization" phase involves administering ketamine (e.g., racemic ketamine, esketamine, or (R)-ketamine) intravenously at a total dose of about 30-100 mg, or about 45-90 mg, or about 50-75 mg, or about 60 mg, optionally over about 45-60 minutes, or about 50 minutes.

[0086] One meta-analysis of nine randomized placebo-controlled studies found that the antidepressant effects of (R,S)-ketamine after a single dose typically begin 40 minutes after injection, peak approximately 24 hours after injection, and lose superiority to placebo 10-12 days after injection. Other meta-analyses support these findings. See Kishimoto et al., Psychol Med, 2016, 46(7), 1459-1472; Caddy et al., Ther Adv Psychopharmacol, 2014, 4(2), 75-99; McGirr et al., Psychol Med, 2015, 45(4), 693-704; Newport et al., Am J Psychiatry, 2015, 172(10), 950-966.

[0087] In some embodiments, the methods further include administering an anti-inflammatory agent during the acute "stabilization" phase. The anti-inflammatory agent can be administered before, simultaneously with, and / or after the neuroplasticity agent.

[0088] In some embodiments, the method further comprises administering a nonsteroidal anti-inflammatory drug (NSAID) during the acute "stabilization" phase. The nonsteroidal anti-inflammatory drug (NSAID) can be administered before, simultaneously with, and / or after the neuroplasticity agent.

[0089] In some embodiments, the methods further include administering acetaminophen during the acute "stabilization" phase. The acetaminophen can be administered prior to, concurrently with, and / or after the neuroplastic agent.

[0090] In some embodiments, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered orally. In some embodiments, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered intravenously.

[0091] In some embodiments, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered at a dose of about 2-5 g / day, or about 3-5 g / day, or about 3-4 g / day, or about 2 g / day, or about 3 g / day, or about 4 g / day, or about 5 g / day.

[0092] In some embodiments, the method further comprises administering a nonsteroidal anti-inflammatory drug (NSAID), such as ketorolac (sold under the brand names Toradol® and Biorolac®, among others). In certain embodiments, ketorolac is administered intravenously. In certain embodiments, ketorolac is administered intramuscularly. In certain embodiments, ketorolac is administered intranasally. In some embodiments, ketorolac is administered at a dose of about 10 mg / day, or about 15 mg / day, or about 20 mg / day, or about 25 mg / day, or about 30 mg / day, or about 35 mg / day, or about 40 mg / day, or about 15-30 mg / day.

[0093] In the acute phase, patients may show improved scoring on one or more tests, such as those described herein. In certain embodiments, the methods described herein significantly reduce a patient's depression and / or anxiety as assessed by PHQ-9 and / or Burns Anxiety Inventory scores. In certain patients, the total score may show a lesser effect, but the patient often feels more resilient, is able to maintain some emotional coherence, and is able to "bounce back" more effectively after life stresses (e.g., breakups, moves, losses, work stress, etc.). For example, a patient who starts with a Burns Anxiety Inventory score of 51-99 (extreme anxiety or panic) before treatment (day 0) and shows a Burns Anxiety Inventory score of 21-30 (moderate anxiety) after treatment is likely to feel more resilient, even if the patient still has moderate anxiety. Thus, the acute phase may begin when the patient feels sufficient or enhanced resilience to the stressor(s), rather than an improvement in symptoms, even if the score does not reflect the stressor.

[0094] In certain embodiments, the patient's PHQ-9 score, as determined by the PHQ-9, improves by at least about 10%, at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%. In certain embodiments, the patient's PHQ-9 score, as determined by the PHQ-9, improves by at least about 10%, at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80% after Treatment 4.

[0095] In certain embodiments, the patient's Burns Anxiety Inventory score improves by at least about 20%, at least about 35%, or at least about 40%, or at least about 50%, or at least about 50%, or at least about 75%, or at least about 80%, as determined by the Burns Anxiety Inventory. In certain embodiments, the patient's Burns Anxiety Inventory score improves by at least about 20%, at least about 35%, or at least about 40%, or at least about 50%, or at least about 50%, or at least about 75%, or at least about 80%, as determined by the Burns Anxiety Inventory, after Treatment 4.

[0096] Thus, in some embodiments, the method includes only an acute "stabilization" phase. However, in some embodiments, the method further includes a "maintenance" phase. Once the patient is determined to have improved sufficiently, for example, in the positive zone, based on the patient's self-assessment score and the physician's assessment, the maintenance phase can begin.

[0097] maintenance period In some embodiments, the method includes a maintenance phase that includes one or more additional treatments, where oxytocin may or may not be administered at each treatment. The treatments may include the same or different doses and / or routes of administration of oxytocin or a neuroplastic agent as used during the acute phase. During the maintenance phase, the dose of each treatment in the maintenance phase is decreased, remains unchanged, or is increased from the previous treatment.

[0098] In some embodiments, the maintenance phase involves administering oxytocin in one or more treatments at substantially the same doses as were administered during the acute phase.

[0099] In some embodiments, the maintenance phase involves administering oxytocin in one or more treatments at a lower dose than that administered during the acute phase, hi certain embodiments, the maintenance phase involves administering oxytocin in one or more treatments at a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50% lower dose than that administered during the acute phase.

[0100] In some embodiments, the maintenance phase involves administering oxytocin in one or more treatments at a higher dose than was administered during the acute phase, hi certain embodiments, the maintenance phase involves administering oxytocin in one or more treatments at a dose that is 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 45%, or 50% higher than the dose administered during the acute phase.

[0101] In some embodiments, the dose of oxytocin administered during the maintenance period is decreased compared to the start of the maintenance phase.

[0102] Typically, the maintenance phase includes one or more treatments that involve administering a neuroplastic agent, with or without oxytocin in any given treatment.

[0103] In some embodiments, the maintenance phase comprises administering the neuroplastic agent in one or more treatments at substantially the same dose as administered during the acute phase. In some embodiments, the maintenance phase comprises administering the neuroplastic agent in one or more treatments at a lower dose than administered during the acute phase. In some embodiments, the maintenance phase comprises administering the neuroplastic agent in one or more treatments at a higher dose than administered during the acute phase.

[0104] In some embodiments, the maintenance phase involves administering the neuroplasticity agent in one or more treatments at a lower dose than was administered during the acute phase, hi certain embodiments, the maintenance phase involves administering the neuroplasticity agent in one or more treatments at a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50% lower dose than was administered during the acute phase.

[0105] In some embodiments, the maintenance phase involves administering the neuroplasticity agent in one or more treatments at a lower dose than was administered during the acute phase, hi certain embodiments, the maintenance phase involves administering the neuroplasticity agent in one or more treatments at a dose that is 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 45%, or 50% higher than was administered during the acute phase.

[0106] In some embodiments, the dose of the neuroplastic agent administered during the maintenance phase is decreased compared to the start of the maintenance phase, hi some embodiments, the dose is decreased by about 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 45%, or 50% over the maintenance phase.

[0107] In some embodiments of the maintenance phase, such as those in which the time between treatments is extended (e.g., from every 2-4 weeks to every 2-6 months), the treatment doses can be increased for one or both of the neuroplastic agent and / or oxytocin. In some embodiments, each treatment dose in the maintenance phase is increased by 5 mg, 10 mg, or 15 mg based on the patient's response from the previous treatment.

[0108] In some embodiments, the method further comprises administering an anti-inflammatory agent during the maintenance phase. The anti-inflammatory agent can be administered before, simultaneously with, and / or after the neuroplasticity agent and / or oxytocin.

[0109] In some embodiments, the method further comprises administering a nonsteroidal anti-inflammatory drug (NSAID) during the maintenance phase. The nonsteroidal anti-inflammatory drug (NSAID) can be administered before, simultaneously with, and / or after the neuroplastic agent and / or oxytocin.

[0110] In some embodiments, the method further comprises administering acetaminophen during the maintenance phase. The acetaminophen can be administered before, simultaneously with, and / or after the neuroplastic agent and / or oxytocin.

[0111] In some embodiments of the maintenance phase, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered orally. In some embodiments of the maintenance phase, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered intravenously.

[0112] In some embodiments of the maintenance phase, the anti-inflammatory agent, nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen is administered at a dose of about 2-5 g / day, or about 3-5 g / day, or about 3-4 g / day, or about 2 g / day, or about 3 g / day, or about 4 g / day, or about 5 g / day.

[0113] In some embodiments of the maintenance phase, the method further comprises administering a nonsteroidal anti-inflammatory drug (NSAID), such as ketorolac (sold under the brand names Toradol® and Biorolac®, among others).

[0114] In certain embodiments of the maintenance phase, ketorolac is administered intravenously. In certain embodiments of the maintenance phase, ketorolac is administered intramuscularly. In certain embodiments, ketorolac is administered intranasally.

[0115] In some embodiments of the maintenance phase, ketorolac is administered at a dose of about 10 mg / day, or about 15 mg / day, or about 20 mg / day, or about 25 mg / day, or about 30 mg / day, or about 35 mg / day, or about 40 mg / day, or about 15-30 mg / day.

[0116] In some embodiments, the maintenance phase involves one treatment per week for 2-4 weeks, then one treatment every 2-4 weeks for the first 6 months.

[0117] In some embodiments, the subject is isolated from human interaction. In some embodiments, the method further comprises using one or more supplemental therapies with the methods described herein. Examples of supplemental therapies include, for example, psychotherapy, participation in social support groups, and / or additional therapy with one or more additional drugs.

[0118] composition It should also be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the formulation, route of administration, activity of the particular neuroplastic agent used, age, body weight, general health, sex, diet, time of administration, rate of excretion, and the judgment of the treating physician, as well as the severity of the particular disease being treated.

[0119] Oxytocin, anti-inflammatory agents, and neuroplasticity agents can be delivered separately or together by any suitable route as a pharmaceutical composition that can include any number of excipients. Excipients that can be used include carriers, surfactants, thickeners, or emulsifiers, solid binders, dispersing or suspending agents, solubilizers, colorants, flavoring agents, coating agents, disintegrants, lubricants, sweeteners, preservatives, isotonicity agents, and combinations thereof. The selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference. In certain embodiments, the administration of oxytocin, anti-inflammatory agents, and neuroplasticity agents is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, intravitreal, or epidermal administration (e.g., injection or infusion), each independently. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intravitreal, and intrapleural injection and infusion. Alternatively, administration of one or more of the oxytocin, anti-inflammatory agent, and neuroplasticity agent can be independently performed via a parenteral route, such as a topical, epidermal, or mucosal route of administration, e.g., intranasal, oral, intravaginal, rectal, sublingual, or topical.

[0120] For administration by inhalation or intranasal route, oxytocin, anti-inflammatory agent, and neuroplastic agent can be delivered in the form of solution, suspension, emulsion, or semi-solid aerosol from pressurized pack or nebulizer, usually using propellant such as halogenated carbon derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosol, hydrocarbons such as butane, isobutene, and pentane are useful. For pressurized aerosol, the appropriate dosage form can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, can be formulated for use in inhalers and insufflators. These usually contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0121] The pharmaceutical compositions containing oxytocin and a neuroplasticity agent, optionally together with an anti-inflammatory agent, may each independently be in the form of a sterile aqueous solution or dispersion. They may also be formulated in microemulsions, liposomes, or other ordered structures suitable for high drug concentration.

[0122] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration, but will generally be that amount of the composition which produces a therapeutic effect. Generally, this amount will range from about 0.01% to about 99% of the active ingredient, or from about 0.1% to about 70%, or from about 1% to about 30% of the active ingredient in combination with a pharma- ceutically acceptable carrier, out of 100%.

[0123] The dosage regimen is adjusted to obtain the optimum desired response (e.g., therapeutic response). For example, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in unit dosage form. EXAMPLES

[0124] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the implementation of the present disclosure, and therefore can be considered to constitute specific aspects for its implementation. However, those skilled in the art should understand in light of the present disclosure that many changes can be made to the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present invention.

[0125] Example 1 For the treatment of adult male or female subjects 18-65 years of age who have been diagnosed with one or more of the following: major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymic disorder), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenia disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine headache, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome.

[0126] timing: The acute (stabilization) phase is 3-5 weeks, twice a week, depending on the severity of the initial illness. The more negative the patient is (-1 to -10 on the reward / enjoyment scale), the more treatment is given to get the patient into the positive zone. The amount of effort the patient puts in to apply positive coping skills (mindfulness, meditation, psychotherapy, proper diet, exercise, sleep regulation, etc.) directly correlates with the overall antidepressant response. The maintenance phase begins once the patient is, for example, clearly in the positive zone, based on the patient's self-assessment scores and the physician's assessment.

[0127] The chronic (maintenance) phase begins after the acute (stabilization) phase, initially once a week for 2-4 weeks, and can then transition to every other week. Once the patient maintains the gains, treatments may be required once every 2-4 weeks for the first 6 months. The physician may modify the maintenance schedule to meet the patient's needs, but treatments may be given no more than once a week. The physician may extend the treatment schedule based on the patient's ability to maintain positive coping skills and engage in psychotherapy on a regular basis (weekly is preferred). The physician may schedule treatments with a break from the usual schedule if the physician anticipates a significant stressor or group of stressors for the patient.

[0128] The acute treatment regimen is as shown in Tables 1a and 1b below. [Table 1a-1] [Table 1a-2] [Table 1a-3] [Table 1b-1] [Table 1b-2]

[0129] dose: Intranasal oxytocin is typically administered before the second drug, whether the second drug is intravenous or inhaled. Oxytocin can be administered intravenously before or after the second drug. The dose of oxytocin is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to 100 International Units (IU).

[0130] Intravenous (IV) ketamine is initially administered at a very low dose for initial treatment. 60 mg of ketamine is diluted in a 60 mL syringe containing saline. The 60 mL syringe is attached to a syringe pump with microtubing that extends to the patient's IV. The initial rate is set at 10-20 mL / hour depending on the indication for treatment. All subjects with anxiety-based disorders should be started at 10 mL / hour. Every 8-10 minutes, the clinician may increase the dose by small amounts based on the patient's tolerance to the experience. Typical dose increases are 5-10 mL / hour every 8-10 minutes up to 50 minutes.

[0131] The patient is administered at least 10-15 minutes or more as needed to recover. Post-treatment vitals must return to within 25% of the patient's pre-treatment vitals. Post-treatment vitals (heart rate, blood pressure, pulse oximetry, respiratory rate) must be within 25% of pre-treatment vitals before removing the patient monitor. The only exception to removing the monitor early is if the patient must use the bathroom before vitals return to within 25% of the patient's pre-treatment values. Wheelchair transport the patient to the bathroom and assist as needed to avoid any potential falls. Before discharging the patient, they must be reconnected to the patient monitor and meet the appropriate discharge criteria. After treatment, the patient must be driven home by a responsible adult. The patient cannot drive a car, participate in any hazardous activities, or sign any legal documents for 24 hours after treatment.

[0132] At each subsequent appointment, the ketamine dose is either decreased, unchanged, or increased from the previous therapeutic dose. Typical increases are 5 mg, 10 mg, or 15 mg based on the patient's response from the previous treatment. Once the patient achieves optimal benefit, the ketamine dose should remain the same or be decreased slightly based on the patient's comfort with the therapeutic dose.

[0133] Intranasal ketamine: Initial doses are 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to a maximum of 300 mg.

[0134] A second intranasal ketamine dose was administered 10-15 min later based on patient tolerance (as determined by the physician), which could be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, or up to 300 mg.

[0135] The first intranasal dose of ketamine treatment is a very low introductory dose to determine the patient's sensitivity to the drug. The second dose will be higher based on the patient's response to the first dose. A third low dose may be given only for the first treatment.

[0136] After the initial treatment, only two doses of intranasal ketamine are administered, spaced 10-15 minutes apart, as determined by the supervising physician. The dose of oxytocin remains constant throughout the treatment process. The dose is increased with each treatment based on the patient's overall response and tolerance to the treatment experience.

[0137] Once in the maintenance phase, patients may attend the treatment clinic for weekly intranasal oxytocin treatments.

[0138] The dosages of the other drugs listed above in combination with oxytocin will be determined by future research trials.

[0139] Example 2 Treatment for adult women aged 18-65 years who have been diagnosed with one or more of the following: postpartum depression or perinatal depression.

[0140] timing: The acute (stabilization) phase is 3-5 weeks, twice a week, depending on the severity of the initial illness. The more negative the patient is (-1 to -10 on the reward / enjoyment scale), the more treatment is given to get the patient into the positive zone. The amount of effort the patient puts in to apply positive coping skills (mindfulness, meditation, psychotherapy, proper diet, exercise, sleep regulation, etc.) directly correlates with the overall antidepressant response. The maintenance phase begins once the patient is, for example, clearly in the positive zone, based on the patient's self-assessment scores and the physician's assessment.

[0141] The chronic (maintenance) phase begins after the acute phase and may be initially once a week for 2-4 weeks, then transition to every other week. Once the patient maintains the gains, treatment may be required once every 2-4 weeks for the first 6 months. The physician may modify the maintenance schedule to meet the patient's needs, but treatment may be no more than once a week. The physician may extend the treatment schedule based on the patient's ability to maintain positive coping skills and engage in psychotherapy on a regular basis (weekly is preferred). The physician may schedule treatment with a break from the usual schedule if the physician anticipates a significant stressor or group of stressors for the patient.

[0142] The acute treatment regimen is as shown in Tables 1c and 1d below. [Table 1c] [Table 1d]

[0143] dose: Intranasal oxytocin is typically administered before the second drug, whether the second drug is intravenous or inhaled. Oxytocin can be administered intravenously before or after the second drug. The dose of oxytocin is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to 100 International Units (IU).

[0144] Intravenous (IV) ketamine is initially administered at a very low dose for initial treatment. 60 mg of ketamine is diluted in a 60 mL syringe containing saline. The 60 mL syringe is attached to a syringe pump with microtubing that extends to the patient's IV. The initial rate is set at 10-20 mL / hour depending on the indication for treatment. All subjects with anxiety-based disorders should be started at 10 mL / hour. Every 8-10 minutes, the clinician may increase the dose by small amounts based on the patient's tolerance to the experience. Typical dose increases are 5-10 mL / hour every 8-10 minutes up to 50 minutes.

[0145] The patient is administered medication in 10-15 minutes or more as needed to recover. Post-treatment vitals should return to within 25% of the patient's pre-treatment vitals. Post-treatment vitals (heart rate, blood pressure, pulse oximetry, respiratory rate) should be within 25% of pre-treatment vitals before removing the patient monitor. The only exception to removing the monitor early is if the patient must use the bathroom before vitals return to within 25% of the patient's pre-treatment values. Wheelchair transport the patient to the bathroom and assist as necessary to avoid any potential falls. Before discharging the patient, they must be reconnected to the patient monitor and meet the appropriate discharge criteria. After treatment, the patient must be driven home by a responsible adult. Patients cannot drive a car, participate in any hazardous activities, or sign any legal documents for 24 hours after treatment.

[0146] At each subsequent appointment, the ketamine dose is either decreased, unchanged, or increased from the previous therapeutic dose. Typical increases are 5 mg, 10 mg, or 15 mg based on the patient's response from the previous treatment. Once the patient achieves optimal benefit, the ketamine dose should remain the same or be decreased slightly based on the patient's comfort with the therapeutic dose.

[0147] Intranasal ketamine: Initial doses are 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to a maximum of 300 mg.

[0148] A second intranasal ketamine dose was administered 10-15 min later based on patient tolerance (as determined by the physician), which could be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, or up to 300 mg.

[0149] The first intranasal dose of ketamine treatment is a very low introductory dose to determine the patient's sensitivity to the drug. The second dose will be higher based on the patient's response to the first dose. A third low dose may be given only for the first treatment.

[0150] After the initial treatment, only two doses of intranasal ketamine are administered, spaced 10-15 minutes apart, as determined by the supervising physician. The dose of oxytocin remains constant throughout the treatment process. The dose is increased with each treatment based on the patient's overall response and tolerance to the treatment experience.

[0151] Once in the maintenance phase, patients may attend the treatment clinic for weekly intranasal oxytocin treatments.

[0152] The dosages of the other drugs listed above in combination with oxytocin will be determined by future research trials.

[0153] Example 3 Treatment for male or female subjects diagnosed with one or more of the following: generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder (PTSD), separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, or chronic fatigue syndrome.

[0154] Treatment: See Examples 1 and 2.

[0155] Route: See Examples 1 and 2.

[0156] Timing: See Examples 1 and 2.

[0157] Pre-adult subjects (under 18 years of age, e.g., 16-18 years of age) or elderly subjects (over 65 years of age, e.g., 66-75 years of age)

[0158] Dosage: The initial doses for these disorders will be much smaller. The dose progression will be much slower, based on the patient's comfort level.

[0159] For pre-adult subjects, treatment is with lower initial doses of neuroplasticity medications than for major depressive disorder (MDD).

[0160] In elderly subjects, treatment is with lower doses of the neuroplastic agent.

[0161] Example 4 The following examples show the treatment results of some patients. Table 2 shows the patient information and diagnosis at the start of treatment. [Table 2]

[0162] The following outcomes were determined using the Patient Health Questionnaire (PHQ-9) and Burn Anxiety Inventory. Below, the dose of the Burn Anxiety Inventory was the same dose as shown in the PHQ-9 data tables. In the PHQ-9 data in the tables, severity is reported as follows: EXT or ED (very difficult), VD (very difficult), SD (somewhat difficult), and ND (not difficult). The PHQ-9 questionnaire was modified only to reflect the shortened time periods between treatments in order to assess improvement during those periods.

[0163] Patient 1: Patient has had 4 different suicide attempts and 4 involuntary hospitalizations. Patient has tried over 15 antidepressants without relief. Patient presented with severe suicidality, depression, and anxiety. Current medications: Mirtazapine 15 mg once daily, Propranolol 10 mg as needed, oral contraceptives. Patient entered the positive zone after treatment 3. Patient has never felt relief so quickly. Patient experienced several difficult stressors during maintenance and has recovered well. Patient feels very stable. PHQ-9 Depression Data [Table 5] BURNS ANXIETY INVENTORY DATA [Table 6]

[0164] Patient 2: The patient had been taking sertraline 200 mg once daily for 4 years. The patient was able to wean during a stress-free period approximately 1 year prior to the current treatment. Stress caused the patient's OCD to relapse and become worse than previously experienced. The patient resumed sertraline after treatment 4. The patient entered the positive zone after treatment 6. Treatments 10-12 were on intranasal ketamine. The patient did not exceed 100 mg sertraline and was more stable after the last treatment. PHQ-9 Depression Data [Table 7] BURNS ANXIETY INVENTORY DATA [Table 8]

[0165] Patient 3: The patient had been an active alcoholic since age 18. The patient had previously been on several antidepressants without success. Meds: Seroquel 100 mg at night, Klonopin 1 mg at night, Latuda 50 mg once daily. The patient was in the positive zone after treatment 4. The patient was then started on oxytocin treatment. It is believed that the addition of oxytocin helps the patient remain sedated. The patient continued to remain sedated for 18 months. The patient was discontinued from medication and is now only taking Seroquel 50-100 mg at night. PHQ-9 Depression Data [Table 9] BURNS ANXIETY INVENTORY DATA [Table 10]

[0166] Patient 4: The patient was unable to tolerate any antidepressants (tried Zoloft without success and was on Lexapro 20mg for 1 year at the beginning of treatment). The patient was in the positive zone after treatment 5. All treatments were with intranasal ketamine and intramuscular Toradol. It was observed that higher doses were needed because some of the ketamine was dripping down the back of the throat or through the nose. Once stabilized, the patient did well emotionally and socially, and was getting all A's by the end of the school year. The patient was able to speak publicly about how ketamine saved his life and that he no longer felt suicidal. PHQ-9 Depression Data [Table 11] BURNS ANXIETY INVENTORY DATA [Table 12]

[0167] Patient 5: Patient suffered from severe depression and mild psychosis. Current medication regimen was not helping. Meds: Latuda 120 mg, Seroquel 25 mg at night. Patient entered the positive zone after treatment 5. Patient discontinued Latuda and Seroquel after treatment and is maintaining work and romantic relationship. PHQ-9 Depression Data [Table 13] BURNS ANXIETY INVENTORY DATA [Table 14]

[0168] Patient 6: The patient was only taking supplements and did not want to take any oral antidepressants. The patient entered the positive zone after treatment 2. Since the last treatment, the patient does not need anything. PHQ-9 Depression Data [Table 15] BURNS ANXIETY INVENTORY DATA [Table 16]

[0169] Patient 10: This patient had PTSD since age 17 and suffered from depression and anxiety until experiencing a new traumatic event approximately 1 year prior to treatment. Meds: Lexapro 20 mg once daily, Xanax 0.5 mg as needed. The patient's anxiety responded much more quickly to oxytocin than was seen with ketamine treatment alone. PHQ-9 Depression Data [Table 17] BURNS ANXIETY INVENTORY DATA [Table 18]

[0170] Patient 11: Patient has tried two antidepressants with no effect. Patient's current medication regimen has also not helped. Current Meds: Adderall (extended release) 30 mg once daily, as needed for focus and concentration, Adderall (immediate release) 10 mg up to 3 times daily, Lexapro 20 mg once daily, Trazodone 50 mg at night, Nexium as needed, Allegra as needed. Patient responded well and entered the positive zone after treatment 4. Patient had several significant stressors when initially entering the positive zone. Patient has not required any treatment since last treatment. PHQ-9 Depression Data [Table 19] BURNS ANXIETY INVENTORY DATA [Table 20]

[0171] Patient 14: The patient did not want to take any oral antidepressants because they had not helped in the past. The patient entered the positive zone after treatment 3. The patient felt so much better after the last treatment that he no longer needed it. PHQ-9 Depression Data [Table 21] BURNS ANXIETY INVENTORY DATA [Table 22]

[0172] Patient 15: Patient had chronic pain, depression, and anxiety. Patient on high doses of opioids wanted to taper off but had too much depression and anxiety upon weaning. Patient felt oral antidepressants had not helped in the past. Meds: Fentanyl patch 75mcg every 2 days, oxycodone 30mg tablets 3-5 times a day as needed. Patient was in the positive zone after treatment 4. PHQ-9 Depression Data [Table 23] BURNS ANXIETY INVENTORY DATA [Table 24]

[0173] Patient 16: Patient had chronic pain from a devastating car accident that caused a traumatic brain injury and an L5 burst fracture. Patient had struggled with depression since age 12. Patient was unwilling to take any oral antidepressants as they had not been successful. Meds: Spironolactone for acne. Patient was in the positive zone after treatment 2. Patient had difficulty adjusting to the positive zone but is doing much better with pain, depression, and anxiety. PHQ-9 Depression Data [Table 25] BURNS ANXIETY INVENTORY DATA [Table 26]

[0174] Patient 18: Patient was discharged from the mental health unit on the same day as the first treatment. Patient was self-harming by cutting. This patient was deep in the negative zone and did not want antidepressants. Meds: None. Patient entered the positive zone after treatment 4. Patient was started on Buspar 10mg twice daily and Lexapro 10mg once daily after treatment 2 as it was unclear if she could continue with ketamine treatment. Patient was very happy with the results and felt more resilient despite significant stressors. PHQ-9 Depression Data [Table 27] BURNS ANXIETY INVENTORY DATA [Table 28]

[0175] Patient 19: This patient has suffered from depression and anxiety since she was a teenager. Patient has tried antidepressants over the years with little relief. Current Meds: Celexa 60 mg once daily, Armor Thyroid 90 mg once daily. Patient is in the positive zone after treatment 3. Patient continues to do well and plans to wean off Celexa. PHQ-9 Depression Data [Table 29] BURNS ANXIETY INVENTORY DATA [Table 30]

[0176] Tables 3 and 4 show patient information and percentage of symptom improvement achieved using the methods described herein after treatments 3, 4, 5, and 6. Patients may be able to move from the acute "stabilization" phase to the maintenance phase in 4-5 treatments (or 2-3 weeks), but may vary based on the particular patient. [Table 3] [Table 4] * * *

[0177] Thus, while the present disclosure has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications, improvements, and variations of the disclosures disclosed herein and incorporated herein may be resorted to by those skilled in the art, and such modifications, improvements, and variations are deemed to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0178] The present disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the general disclosure also constitutes part of the present disclosure. This includes the generic specification of the present disclosure with a proviso or negative limitation removing any subject matter from that genus, regardless of whether the removed material is specifically described herein.

[0179] Additionally, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0180] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0181] While the present disclosure has been described in conjunction with the foregoing embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. A combination for use in a method for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (dysthymia), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder type 1, bipolar disorder type 2, premenstrual dysphoric disorder, schizophrenia, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, the combination comprising oxytocin, a neuroplasticity agent, and optionally, an anti-inflammatory agent.

2. The combination according to claim 1, wherein the neuroplasticity agent is one or more of racemic ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine (HNK), psilocybin, 3,4-methylenedioxymethamphetamine (MDMA), N,N-dimethyltryptamine (DMT or N,N-DMT), lysergic acid diethylamide (LSD), dextromethorphan, Nu Dexa (a combination of dextromethorphan and quinidine), Duodextromethorphan (AVP-786), Axsome (AXS-05), Dextrorphan (REL-1017), or Zuranolone (SAGE-217).

3. A combination for use in a method for treating postpartum depression or perinatal depression in a subject, the combination comprising oxytocin, a neuroplasticity agent, and an anti-inflammatory agent.

4. The combination according to claim 3, wherein the neuroplasticity agent is brexanolone or zuranolone (SAGE-217).

5. The combination according to any one of claims 1 to 4, wherein the method comprises an acute phase and a maintenance phase.

6. The combination according to claim 5, wherein the acute phase comprises administering a first dose of oxytocin before administering the neuroplasticity agent.

7. The combination according to claim 5, wherein the acute phase comprises administering a first dose of the neuroplasticity agent before administering oxytocin.

8. The combination according to any one of claims 1 to 4, wherein the oxytocin is administered intravenously.

9. The combination according to any one of claims 1 to 4, wherein the oxytocin is administered intranasally.

10. The combination according to any one of claims 1 to 4, wherein the neuroplasticity agent is administered intravenously.

11. The combination according to any one of claims 1 to 4, wherein the neuroplasticity agent is administered intranasally.

12. The combination according to any one of claims 1 to 4, wherein the dose of oxytocin is 0.1 to 100 international units (IU).

13. The combination according to claim 5, wherein the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine.

14. The combination according to claim 5, wherein the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine intravenously at a total dose of about 60 mg, optionally over 50 minutes.

15. The combination according to claim 5, wherein the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine intranasally at an initial dose of 0.1 to 300 mg, and optionally administering a second intranasal ketamine dose of 0.1 to 300 mg 10 to 15 minutes later.

16. The combination according to claim 5, wherein the acute phase is a treatment twice a week for 3 to 5 weeks.

17. The combination according to claim 5, wherein the maintenance phase comprises a treatment once a week for 2 to 4 weeks, then once every 2 weeks, or once every 2 to 4 weeks for the first 6 months.

18. The combination according to claim 17, wherein each treatment dose in the maintenance phase decreases from the previous treatment, remains unchanged, or increases.

19. The combination according to claim 17, wherein each treatment dose in the maintenance phase increases by 5 mg, 10 mg, or 15 mg based on the patient's response from the previous treatment.

20. A combination for use in a method for treating generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, binge eating disorder in a subject, the combination comprising oxytocin and a neuroplasticity agent.

21. The combination according to claim 20, wherein the subject is 16 to 18 years old or 66 to 75 years old. **Claim 22**: The combination according to claim 20, wherein the method includes an acute phase and a maintenance phase. **Claim 23** The combination according to any one of claims 20 to 22, wherein the acute phase includes administering a first dose of oxytocin before administering the neuroplastic agent. **Claim 24** The combination according to any one of claims 20 to 22, wherein the acute phase includes administering a first dose of the neuroplastic agent before administering oxytocin. **Claim 25** The combination according to any one of claims 20 to 22, wherein the oxytocin is administered intravenously. **Claim 26** The combination according to any one of claims 20 to 22, wherein the oxytocin is administered intranasally. **Claim 27** The combination according to any one of claims 20 to 22, wherein the neuroplastic agent is administered intravenously. **Claim 28** The combination according to any one of claims 20 to 22, wherein the neuroplastic agent is administered intranasally. **Claim 29** The combination according to any one of claims 20 to 22, wherein the dose of oxytocin is 0.1 to 75 international units (IU). **Claim 30** The combination according to any one of claims 20 to 22, wherein the acute phase includes administering racemic ketamine, esketamine, or (R)-ketamine. **Claim 31** The combination according to any one of claims 20 to 22, wherein the acute phase includes administering racemic ketamine, esketamine, or (R)-ketamine intravenously at a total dose of about 40 mg, optionally over 50 minutes. **Claim 32** The combination according to any one of claims 20 to 22, wherein the acute phase includes administering racemic ketamine, esketamine, or (R)-ketamine intranasally at an initial dose of 0.1 to 200 mg, and optionally administering a second intranasal ketamine dose of 0.1 to 200 mg 10 to 15 minutes later. **Claim 33** The combination according to any one of claims 20 to 22, wherein the acute phase is a treatment twice a week for 3 to 5 weeks. **Claim 34** The combination according to any one of claims 20 to 22, wherein the maintenance phase includes treatment once a week for 2 to 4 weeks, then once every two weeks, or once every 2 to 4 weeks for the first six months. **Claim 35** The combination according to claim 34, wherein each therapeutic dose during the maintenance period decreases from a previous treatment, remains unchanged, or increases.

36. The combination according to claim 34, wherein each therapeutic dose during the maintenance period increases by 5 mg, 10 mg, or 15 mg based on the patient's response from a previous treatment.

37. The combination according to any one of claims 1, 3, and 20, wherein the combination is administered in combination with an anti-inflammatory agent.

38. The combination according to any one of claims 1, 3, and 20, wherein the combination is administered in combination with a non-steroidal anti-inflammatory drug (NSAID).

39. The combination according to any one of claims 1, 3, and 20, wherein the combination is administered in combination with ketorolac.

40. A composition for use in a method for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (dysthymia), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenia spectrum disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, comprising oxytocin, wherein the composition is administered in combination with a neuroplasticity agent and optionally an anti-inflammatory agent.

41. A composition for use in a method for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (dysthymia), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder 1, bipolar disorder 2, premenstrual dysphoric disorder, schizophrenia spectrum disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, comprising a neuroplasticity agent, wherein the composition is administered in combination with oxytocin and optionally an anti-inflammatory agent.

42. A composition for use in a method for treating one or more diseases or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (dysthymia), treatment-resistant depression (TRD), disruptive mood dysregulation disorder, bipolar disorder type 1, bipolar disorder type 2, premenstrual dysphoric disorder, schizophrenia, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndrome, chronic low back pain, fibromyalgia, migraine, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, comprising an anti-inflammatory agent, characterized in that the composition is administered in combination with oxytocin and a neuroplasticity agent.

43. A composition for use in a method for treating postpartum depression or peripartum depression in a subject, comprising oxytocin, characterized in that the composition is administered in combination with a neuroplasticity agent and an anti-inflammatory agent.

44. A composition for use in a method for treating postpartum depression or peripartum depression in a subject, comprising a neuroplasticity agent, characterized in that the composition is administered in combination with oxytocin and an anti-inflammatory agent.

45. A composition for use in a method for treating postpartum depression or peripartum depression in a subject, comprising an anti-inflammatory agent, characterized in that the composition is administered in combination with oxytocin and a neuroplasticity agent.

46. A composition for use in a method for treating generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder in a subject, comprising oxytocin, characterized in that the composition is administered in combination with a neuroplasticity agent.

47. A composition for use in a method for treating generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder, separation anxiety disorder, obsessive-compulsive disorder (OCD), social anxiety disorder, body dysmorphic disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder in a subject, comprising a neuroplasticity agent, characterized in that the composition is administered in combination with oxytocin.