WO2025030142A2

WO2025030142A2 - Methods of treatment using oxytocin

Info

Publication number: WO2025030142A2
Application number: PCT/US2024/040805
Authority: WO
Inventors: Drew Grant BELNAP
Original assignee: Belnap Pharmaceuticals LLC
Current assignee: Belnap Pharmaceuticals LLC
Priority date: 2023-08-03
Filing date: 2024-08-02
Publication date: 2025-02-06
Anticipated expiration: 2026-02-03
Also published as: WO2025030142A3

Abstract

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

Description

METHODS OF TREATMENT USING OXYTOCIN

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 63/517,544, filed August 3, 2023, which is incorporated by reference in its entirety.

FIELD

BACKGROUND

It has been estimated that 1 in 20 U.S. adults experience serious mental illness each year. Treatment choices for mental health conditions will 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 severe patients, the options for treatment and success rates can be limited, and recovery rates low. People with serious mental illness are nearly twice as likely to develop cardiovascular and metabolic diseases than the general population, experience a higher rate of unemployment, are more likely to drop out of school, are more likely to develop a substance use disorder, are more likely to become hospitalized, and even are more likely to become incarcerated. As such, there is a constant demand for new therapeutic regimens for the treatment of mental illness and other psychiatric disorders.

SUMMARY

Provided herein is a method for treating one or more disease or disorders selected from anhedonia, severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, irritable bowel syndrome, post-partum depression, peripartum depression, 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, and binge eating disorder, in a subject in need thereof, comprising administering: an effective amount of oxytocin; an effective amount of a neuroplasticity agent: an effective amount of one or more additional agents selected from an omega 3 fatty acid, a drug that curbs production of inflammatory chemicals, statin, steroid, antibiotic (minocycline), a drug used to treat sleep disorders (modafinil), and N-acetyl cysteine, a disease-modifying anti-rheumatic drug (DMARD), a salicylic acid derivate, a para-aminophenol derivative, an acetic acid derivative, a propionic or heteroaryl acetic acid derivative, anthranilic acid (fenemates), a sulfonanilide derivative, a diarylheterocycle (coxibs), an enolic acid derivative (oxicams), a NK3 receptor antagonist, an antibody, antibody fragment, or a biologic agent, colchicine, corticosteroid injections, a topical NSAID (e.g. diclofenac gel), an omega-3 fatty acid, curcumin, resveratrol, boswellia extract, ginger extract, and green tea extract; and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof.

In some embodiments, the additional agent is acetylsalicylic acid (aspirin), sodium salicylate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, mesalazine/mesalamine, paracetamol/acetaminophen, indomethacin, sulindac, diclofenac, etodolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, niflumic acid, meclofenamic acid, nimesulide, celecoxib, parecoxib, rofecoxib, valdecoxib, piroxicam, tenoxicam, or meloxicam.

In some embodiments, the additional agent is a steroid. In some embodiments, the steroid is a glucocorticoid. In some embodiments, the glucocorticoid is prednisone, prednisolone, dexamethasone, betamethasone, or hydrocortisone.

In some embodiments, the disease-modifying anti-rheumatic drug (DMARD) is methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, or cyclosporine.

In some embodiments, the antibody, antibody fragment, or a biologic agent is ustekinumab, adalimumab, infliximab, etanercept, rituximab, abatacept, tocilizumab, or anakinra.

In some embodiments, the method further comprises administering a cytokine-inhibitor, polyunsaturated fatty acid, pioglitazone, minocycline, modafinil, or corticosteroid.

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

In some embodiments of the methods described herein, the treating comprises an acute, or stabilization phase, and a maintenance phase, where optionally the acute phase comprises administering a first dose of oxytocin prior to administering the neuroplasticity agent, optionally followed by an antiinflammatory agent. In some embodiments, the oxytocin, neuroplasticity agent, and/or antiinflammatory agent, are administered intranasally.

It is contemplated that the disclosed treatment allows a subject suffering from one or more of the aforementioned diseases or disorders to stimulate and regrow, or more quickly stimulate and regrow, neuronal connections in the brain with positive effects on mental and/or physical wellbeing. DETAILED DESCRIPTION

The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, 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.

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.

The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

The term “about” refers to a variation of +1%, ±3%, ±5%, or ±10% of the value specified. For example, “about 50” can in some embodiments includes a range of from 45 to 55. For integer ranges, the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “a cannabinoid” includes a plurality of such compounds.

As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, such as a clinical result. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. For use herein, the beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a given disease or disorder. Preferably, treatment of a subject using the methods described herein is accompanied by no or fewer side effects than are associated with currently available therapies for the disease or condition and/or disorder the quality of life of the subject, in particular, such as treatment resistant subjects, subjects who have severe side effects to common treatment medications, or those where a typical standard of care is ineffective or contraindicated. Typical standard of care can include medication, therapy, including physical or psychotherapy, or both.

As used herein, the term “effective amount” intends such amount of a compound or composition of the disclosure which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the 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 given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.

The term “neuroplasticity agent” is intended to refer to a compound or substance that increase dendritic spine density, growth, or enhance morphology. In certain instances, the agent may confer changes in synaptic plasticity or dendrite morphology by providing increased expression of pre-or postsynaptic plasticity-related proteins, as well as the density and/or function of axo-spinous synapses. Studies in both humans and animal models have demonstrated abnormal dendritic spine architecture in several psychiatric disorders, including depression and other stress-related illnesses. The negative impact of stress on the density and organization of dendritic spines is also thought to contribute to the behavioral deficits caused by stress exposure.

Specific neuroplasticity agents are shown below in Table 1. Such agents are commercially available or can be prepared and formulated according to published methods.

Table 1

Methods of Treatment

The neuropeptide oxytocin plays an evolutionarily conserved role in mammalian social behavior. Despite striking effects on animal social behavior after intracerebroventricular drug delivery, this delivery mode is impractical in humans. Intranasal oxytocin, which can be purchased from commercial sources, delivery provides a noninvasive alternative to increase central oxytocin activity, and has shown promise as a treatment for psychiatric illnesses. For example, research indicates that intranasal oxytocin administration improves theory of mind, memory for social cues, and increases gaze to the eye region. Intranasal oxytocin delivery is purported to increase central oxytocin concentrations via channels surrounding trigeminal and olfactory nerve fibers, which may facilitate increased activity at central oxytocin receptors. These findings, among others, have sparked interest in the use of intranasal oxytocin to treat psychiatric disorders characterized by social dysfunction; however, meta-analyses of oxytocin's effect in clinical populations have revealed mixed results to date.

Provided herein is a method for treating one or more disease or disorders selected from anhedonia, severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, irritable bowel syndrome, post-partum depression, peripartum depression, 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, and binge eating disorder, in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and additional agent as described herein, to a subject in need thereof.

In some embodiments of the methods disclosed herein, a subject (or patient) is administered an effective amount of one or more additional agents selected from an omega 3 fatty acid, a drug that curbs production of inflammatory chemicals, statin, steroid, antibiotic (minocycline), a drug used to treat sleep disorders (modafinil), and N-acetyl cysteine, a disease-modifying anti-rheumatic drug (DMARD), a salicylic acid derivate, a para-aminophenol derivative, an acetic acid derivative, a propionic or heteroaryl acetic acid derivative, anthranilic acid (fenemates), a sulfonanilide derivative, a diarylheterocycle (coxibs), an enolic acid derivative (oxicams), a NK3 receptor antagonist, an antibody, antibody fragment, or a biologic agent, colchicine, corticosteroid injections, a topical NSAID (e.g. diclofenac gel), an omega-3 fatty acid, curcumin, resveratrol, boswellia extract, ginger extract, and green tea extract.

In some embodiments, subjects in need of the methods described herein are those who suffer from bipolar 1 disorder or bipolar 2 disorder. In certain embodiments, the subject suffers from bipolar 1 disorder or bipolar 2 disorder and is unable to maintain in the positive zone for more than 24 or 48 hours without a manic episode. In some embodiments, the subject treatable by the methods disclosed herein suffers from bipolar 1 disorder or bipolar 2 disorder and is unable to go more than 24 hours, or more than 48 hours, without a manic episode. Subjects in need of the methods described herein can be identified by standard methods. Pain is determined by a subject reporting of the same, whereas mental illnesses can be a more subjective diagnosis. A large number of psychiatric tests, scales, and forms have been created over the years to help in diagnosing mental illness and assisting in treatment and follow-up. These scales have demonstrated high levels of accuracy and validity and the results can give important clues to possible mental disorders that may warrant treatment via the methods described herein.

In some embodiments, the subject is identified as described in Diagnostic Example 1.

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

The mood disorder scale (MDQ), developed by Dr Robert M.A. 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 impaired functioning. The Generalized Anxiety Disorder 7 item (GAD-7) was developed to diagnose generalized anxiety disorders 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 3 other common anxiety disorders: panic disorder (sensitivity 74%, specificity 81%), social anxiety disorder (sensitivity 72%, specificity 80%), and posttraumatic stress disorder (sensitivity 66%, specificity 81%).

The Clinical Global Impressions (CGI) scale is a 3-item observer-rated scale commonly used to measure symptom severity, global improvement, and therapeutic response. Each component of the CGI is rated separately; it does not yield a global score. Items 1 and 2 are rated on a 7-point scale; item 3 is rated from 0 to 4 (when rating item 3, therapeutic efficacy and treatment-related adverse events should be taken into account).

The Hamilton Depression Rating Scale has proven useful for determining the level of depression before, during, and after treatment. It is based on the clinician's interview with the patient and probes symptoms such as depressed mood, guilty feelings, suicide, sleep disturbances, anxiety levels and weight loss. The interview and scoring takes about 15 minutes. The rater enters a number for each symptom construct that ranges from 0 (not present) to 4 (extreme symptoms).

The Bipolar Clinical Scale or Bipolar Spectrum Diagnostic Scale (BSDS) was developed by Ronald Pies, MD and was later refined and tested by S. Nassir Ghaemi, MD, MPH and colleagues. The BSDS arose from Pies’s experience as a psychopharmacology consultant, where he was frequently called on to manage cases of “treatment-resistant depression.” In Pies’s experience, most of these cases eventually proved to be undiagnosed bipolar spectrum disorder. The question items of the BSDS were based on those questions that Pies found most helpful in detecting not only severe cases of bipolar disorder but also patients who fall into the “softer” end of the bipolar spectrum (e.g., patients with a history of major depressive episodes and 1 or 2 episodes of elevated mood and energy that last only 1 to 3 days, thus not meeting DSM-IV criteria for hypomania). The BSDS was validated in its original version and demonstrated a high sensitivity (0.75 in bipolar I and 0.79 in bipolar II and not otherwise specified individuals). Its specificity was high (0.85), which confers a significant value to this diagnostic tool in the detection of a wide range of presentations within the bipolar spectrum. Ghaemi and colleagues determined that a score of 13 is the optimal threshold for specificity and sensitivity in the detection of bipolar spectrum disorders. The BSDS has two sections. The first part includes a series of 19 sentences that describe the main symptoms of bipolar spectrum disorders. Each sentence is linked to a blank space that should be checked by patients who decide that the statement is an accurate description of their feelings or behaviors. Each checked statement is assigned 1 point. The second portion of the BSDS asks the patient to select the degree to which the 19-item narrative “fits” his or her own experience. The scale offers four possibilities: “This story fits me very well, or almost perfectly” (6 points); “This story fits me fairly well” (4 points); “This story fits me to some degree, but not in most respects” (2 points); and “This story doesn't really describe me at all” (0 points). 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, fears, insomnia, somatic complaints and behavior at the interview. Developed by M. Hamilton in 1959, the scale predates, of course, the current definition of generalized anxiety disorder (GAD). However, it covers many of the features of GAD and can be helpful also in assessing its severity. The major value of HAM-A is to document the results of pharmaco- or psychotherapy, rather than as a diagnostic or screening tool. It takes 15-20 minutes to complete the interview and scoring. Each item is simply given a 5-point score - 0 (not present) to 4 (severe).

The Brief Psychiatric Rating Scale (BPRS) is a tool clinicians or researchers use to measure psychiatric symptoms such as anxiety, depression, and psychoses. Persons having or suspected of having schizophrenia or other psychotic disorder manifest the disorder in multiple ways. The BPRS assesses the level of 18 symptom constructs such as hostility, suspiciousness, hallucination, and grandiosity. It is particularly useful in gauging the efficacy of treatment in patients who have moderate to severe psychoses. It is based on the clinician's interview with the patient and observations of the patient's behavior over the previous 2-3 days. The patient's family can also provide the behavior report. The rater enters a number for each symptom construct that ranges from 1 (not present) to 7 (extremely severe). The time necessary to complete the interview and scoring can be as little as 20-30 minutes.

Persons taking any kind of antipsychotic medication need to be monitored for movement disorders. The AIMS (Abnormal Involuntary Movement Scale) aids in the early detection of tardive dyskinesia as well as providing a method for on-going surveillance. Although the incidence of TD has been relatively low in recent years, changes in prescribing may result in increased occurrence. Clinicians will need to be alert to these possibilities and employ tools that will help them pick up developing problems as soon as possible. This simple checklist takes only 10 minutes to complete and uses a 5-point rating scale for recording scores for 7 body areas: face, lips, jaw, tongue, upper extremities, lower extremities, and trunk.

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

The Burns Anxiety Inventory (BAI) is an evaluation tool for measuring anxiety. The Burn Anxiety Inventory is a self -report anxiety assessment tool that evaluates anxious symptoms such as worry, nervousness or feelings of panic, or a racing heart. The higher the score, the greater the severity level of anxiety.

The Geriatric Depression Scale Short Form (GDS-S) is a 15-question scale developed as a basic screening measure for depression in older adults: a score of higher than 5 indicates that a more thorough clinical investigation is needed. Studies have shown that inflammation in major depressive disorder (MDD) is a factor that should be evaluated and understood and it is related to the increase of proinflammatory cytokines such as interleukin 1-beta (IL- 1 ), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-a), and interferongamma (IFN-y), 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).

Reductions in brain-derived neurotrophic factor (BDNF), a protein of the neurotrophic family of growth factors, has been reported in different neuropsychiatric diseases. The BDNF blood levels are decreased in major depressive disorder subjects and increase 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; Bjorkholm 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 subjected to chronic stress and anxiety, the number of synaptic connections in specific parts of the brain decrease. It is contemplated herein that administering a neuroplasticity agent can stimulate dendrite growth thereby restoring the lost synaptic connections, strengthen existing synaptic connections and even stimulate the growth of new neurons.

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

Intravenous ketamine, for example, promotes new brain growth by increasing the number of synaptic connections in the brain. Chronic stress continues to stimulate the hypothalamic pituitary axis (HP A) which continues the release of inflammatory cytokines. The inflammatory cytokines gain access to the brain and cause reduced production and reduced reuptake of dopamine, norepinephrine, serotonin and BDNF. The reduced BDNF prevents the normal growth, repair and maintenance of the various neuron’s synaptic connections. The dopamine neurons reduce the tonic release of dopamine leading to varying levels of anhedonia and depressed mood. With decreased production and reuptake of serotonin, the patients experience depressed mood. With decreased production and reuptake of norepinephrine, the patient experiences reduced focus and concentration. The most consequential effect of chronic stress is the reduction and reduced reuptake of dopamine which will be discussed further below.

By administering a neuroplasticity agent, the dendrites in the brain can regrow and lost connections can be restored. With IV ketamine alone, it has been determined that, under most circumstances, a series of infusions (e.g., six) may last anywhere from one month to several (e.g., 4-6) months. When the positive effects begin to wear off, a single booster infusion is often needed to extend the positive effects for another month or longer. It is contemplated by using the methods described herein, the positive effects can be extended or enhanced over ketamine alone. The method described will also provide quicker growth of the dendrites and their synaptic connections with other neurons.

In some embodiments, provided is a method for treating one or more disease or disorders selected from anhedonia, severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, post-partum depression, peripartum depression, 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, and binge eating disorder, in a subject in need thereof, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof.

In some embodiments, the additional agent is selected from an omega 3 fatty acid, a drug that curbs production of inflammatory chemicals, statin, steroid, antibiotic (minocycline), a drug used to treat sleep disorders (modafinil), and N-acetyl cysteine, a disease-modifying anti-rheumatic drug (DMARD). a salicylic acid derivate, a para-aminophenol derivative, an acetic acid derivative, a propionic or heteroaryl acetic acid derivative, anthranilic acid (fenemates), a sulfonanilide derivative, a diarylheterocycle (coxibs), an enolic acid derivative (oxicams), a NK3 receptor antagonist, an antibody, antibody fragment, or a biologic agent, colchicine, corticosteroid injections, a topical NS AID (e.g. diclofenac gel), an omega-3 fatty acid, curcumin, resveratrol, boswellia extract, ginger extract, and green tea extract.

In some embodiments, the additional agent is acetylsalicylic acid (aspirin), sodium salicylate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, mesalazine/mesalamine, parace tamol/acetaminophen, indomethacin, sulindac, diclofenac, etodolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, niflumic acid, meclofenamic acid, nimesulide, celecoxib, parecoxib, rofecoxib, valdecoxib, piroxicam, tenoxicam, or meloxicam.

In some embodiments, the additional agent is a disease-modifying anti-rheumatic drug (DMARD). In some embodiments, the disease-modifying anti-rheumatic drug (DMARD) is methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, or cyclosporine. In some embodiments, the additional agent is a NK3 receptor antagonist. In some embodiments, the NK3 receptor antagonist is osanetant.

In some embodiments, the additional agent is an antibody, antibody fragment, or a biologic agent. In some embodiments, the antibody, antibody fragment, or a biologic agent is ustekinumab, adalimumab, infliximab, etanercept, rituximab, abatacept, tocilizumab, or anakinra.

In some embodiments, the additional agent is selected from non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 fatty acids, drugs that curb production of inflammatory chemicals (cytokine inhibitors, e.g., infliximab and etanercept), statins, steroids, antibiotics (minocyclines), a drug used to treat sleep disorders (modafinil), and N-acetyl cysteine, known as NAC, and used to loosen the excess phlegm of cystic fibrosis and COPD and also taken as an antioxidant supplement.

In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytokine-inhibitors have shown antidepressant treatment effects compared to placebo, but also statins, poly-unsaturated fatty acids, pioglitazone, minocycline, modafinil, and corticosteroids may yield antidepressant treatment effects.

In certain embodiments, the additional agent is a nonsteroidal anti-inflammatory drug (NSAID). Exemplary, non-limiting NSAIDs include salicylic acid derivates (e.g., acetylsalicylic acid (aspirin), sodium salicylate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, mesalazine, mesalamine, and the like), para-aminophenol derivatives (e.g., paracetamol/acetaminophen), acetic acid derivatives (e.g., indomethacin, sulindac, diclofenac, etodolac, and the like), propionic or heteroaryl acetic acid derivatives (e.g., ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, and the like), anthranilic acid (fenemates) (e.g., mefenamic acid, niflumic acid, meclofenamic acid, and the like), sulfonanilide derivatives (e.g., nimesulide), diarylheterocycles (coxibs) (e.g., celecoxib, parecoxib, rofecoxib, valdecoxib, and the like), and enolic acid derivatives (oxicams) (e.g., piroxicam, tenoxicam, meloxicam, and the like).

It has been revealed that acetaminophen, also known as paracetamol, may lack anti-inflammatory actions, and is thus sometimes is not considered to be a NSAID. Its exact mechanism of action is not yet elucidated, but many hypotheses have been made regarding its central or peripheral actions. It has been shown to inhibit a third COX isoform, COX-3 in canine cerebral cortex, but a functional COX-3 has not been found in rodents or humans. Based on its similar pharmacological profile to selective COX-2 inhibitors, like lower gastrointestinal toxicity and no platelet inhibition, more recent studies have demonstrated selective actions on COX-2 in clinically relevant models. However, it is contemplated that acetaminophen can be used in the methods and compositions described herein. Other additional agents are also contemplated, such as, but not limited to, colchicine, corticosteroid injections, topical NSAIDs (e.g. diclofenac gel), omega-3 fatty acids, curcumin, resveratrol, boswellia extract, ginger extract, green tea extract, and the like.

In some embodiments, the method comprises administering the additional agent during the acute “stabilization” phase. The additional agent can be administered before, concurrently with, and/or after the neuroplasticity agent.

In some embodiments, the additional agent is administered orally. In some embodiments, the additional is administered intravenously.

In some embodiments, the additional agent 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.

In some embodiments, provided is a method for treating one or more disease or disorders selected from severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1 , CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof.

In some embodiments, provided is a method for treating one of severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome, in a subject, comprising administering an effective amount of oxytocin, an effective amount of one or more additional agents, an effective amount of ketamine, including but not limited to, racemic ketamine (mixture of enantiomers), esketamine, or (R)-ketamine, and optionally an effective amount of an anti-inflammatory agent to a subject in need thereof.

Also provided herein are methods for treating post-partum depression or peripartum depression, in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent to a subject in need thereof.

In some embodiments, the neuroplasticity agent is brexanolone or zuranolone (SAGE-217). Also provided herein are methods 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 an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent to a subject in need thereof.

In some embodiments, the subject exhibits anhedonia.

Also provided is a method for treating chronic fatigue syndrome in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent to a subject in need thereof.

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

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 intranasal.

It has been noted that questions remain about the ideal outcome measures used in clinical trials to evaluate a subjects response to many of these tests. Many outcome measures currently in use, including those described above, were designed to measure change in symptoms that occur over weeks to months rather than hours to days. For instance, changes in insomnia or appetite cannot reasonably be assessed over a period of hours. Yet, most care providers (e.g., physicians or therapists) use these scales, suggesting that more accurate ways to capture the clinical effects of these agents are needed. It is possible that identifying unidimensional constructs that can help parse the heterogeneity of depressive symptoms will ultimately create more refined rating scale scores to more successfully illuminate connections between specific symptoms and underlying pathophysiology (loline 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.

Major depressive disorder is typically characterized by a depressed mood with loss of interest and pleasure in almost all activities for at least a two-week period.

In some embodiments, the subject exhibits one or more symptoms of depression, such as sleep disturbances, change in energy levels, or difficulty concentrating, anhedonic symptoms (inability to feel pleasure), dysphoric symptoms (state of unease or dissatisfaction), dissociative symptoms, an externalization of anger, or aggressive symptoms. In some embodiments, provided herein are methods for treating anhedonia in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, optionally an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof. In some embodiments, provided herein are methods for treating anhedonia in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents, and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof.

Also provided herein are methods for treating anhedonia in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, and an effective amount of an anti-inflammatory agent, to a subject in need thereof.

Anhedonia is a condition characterized by a reduced ability to experience pleasure or enjoyment from activities that one previously found pleasurable. It is a common symptom of depression and other mental health disorders. Some common symptoms of anhedonia include loss of interest in activities (the subject may show a lack of interest in activities that they previously enjoyed, such as hobbies, socializing, or spending time with loved ones), decreased motivation (the subject may have difficulty feeling motivated to engage in activities, even if they are aware that they are important or would be beneficial), flat affect (the subject may show a lack of emotional expressiveness or the ability to experience a full range of emotions), difficulty experiencing pleasure (the subject may have difficulty experiencing pleasure from activities that are typically enjoyable, such as eating, socializing, or engaging in hobbies), social withdrawal (the subject may withdraw from social activities or avoid interactions with others due to a lack of interest or enjoyment).

An individual with anhedonia may appear emotionless or apathetic. Anhedonia can occur in different contexts and may have different causes, such as depression, schizophrenia, or substance abuse.

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

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

A rating scale for determining severity of mental disease or disorder termed a “Reward/Enjoyment Scale”, including, but not limited to, major depressive disorder, is described herein. The Reward/Enjoyment Scale described herein (See Example 4) can be used to determine a treatment method as well as when to continue treating a subject in the acute, or stabilization phase vs when to transition to “chronic” treatments, i.e., the “maintenance” phase. In some embodiments, the method comprises an acute “stabilization” phase and a “maintenance” phase.

Acute “Stabilization” Phase

The acute “stabilizing” phase typically comprises a series of treatments wherein at each treatment the subject is administered oxytocin and a neuroplasticity agent, optionally followed by an antiinflammatory agent, one or more times a week, such as 1, 2, or 3 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 severity of the initial illness and/or the improvement of the illness. In certain embodiments, the acute “stabilizing” phase lasts about 4-5 treatments, or 2-3 weeks. Severity and improvement can be determined by clinical methods known in the art such as, but not limited to, those described herein. The more negative (-1 to -10 on a reward/enjoyment scale) a patient is, the more treatments it will take to get the patient into the positive zone. The amount of the patient’s effort into applying positive coping skills (e.g., mindfulness, meditation, psychotherapy, proper diet, exercise and regulating sleep) will directly correlate with the overall antidepressant response.

The “negative” zone represents varying degrees of anhedonia as well as reward or relief from thinking, saying or doing negative things. A -1 is the least negative and a -10 is the most negative in the negative zone on the reward/enjoyment scale. When a patient loses synaptic connections in the reward pathways of the brain, the dopamine neurons seemingly go into an inactive state and the tonic release of dopamine decreases. When enough dopamine neurons go inactive, the low dopamine (hypodopaminergic) state will cause the patient to experience anhedonia, dysphoria, psychomotor slowing and a lack of motivation to seek out positive rewards. Those feelings will continue to worsen as the patient goes more negative (towards -10) in the negative zone.

Patients discover that they only get reward or relief from negative thoughts, statements or actions. They begin to seek out negative rewards to get relief from the dysphoria that they feel. The patients often develop a false narrative to support their negative thoughts, statements or actions. When their false narrative is challenged by others (typically loved ones), it can cause the patient to defend their false narrative and want to further isolate themselves from others. The negative zone has not yet been defined in the medical literature and has been a phenomena that has been observed.

As the patient loses more synaptic connections and they progress deeper into the negative zone, they seemingly get more reward and/or relief from their negative thoughts, statements and actions. Since the dopamine neurons are becoming less active as the patient continues to lose synaptic connections, it is postulated that the patients experience more relief through an up-regulation (or increased proliferation) of their mu opioid receptors. It is also possible that there is an up-regulation of their dopamine receptors (or increased proliferation) as the amount of dopamine released has been reduced. Thereby, as the patients go deeper into the negative zone, they get even more relief from things that cause more emotional and even physical pain. This theory would support why people deep in the negative zone experience immediate relief from non-suicidal self-injury (NSSI). The theory would also explain why people deeper in the negative zone get relief from suicidal thoughts. The thought of suicide causes them to feel like there will be an end to their pain and suffering, which makes them feel better.

It was hypothesized that the patient’s own oxytocin was being released during the ketamine infusion, and this was likely a significant reason as to how ketamine was helping to relieve anxiety given its known calming effect on the limbic system. It was then contemplated that other rapid neuroplasticity agents which also stimulate the release of oxytocin (i.e., Psilocybin, MDMA) might play a role in neurogenesis and provide a reduction in anxiety levels. It was then observed that administering oxytocin prior to the ketamine treatment resulted in a much more calm and euphoric ketamine experience. The extra calming effect was greatly appreciated by patients suffering from anxiety disorders. It was then observed that patients were recovering much more quickly from depression and anxiety than just ketamine alone. It is imperative that patients get as quickly to the positive zone as possible. It had been seen that ketamine treatments alone were a lot slower to relieve the effects of anxiety than they were with depression. With the addition of oxytocin treatment, it was observed that patients were experiencing a much quicker recovery from anxiety than was witnessed from ketamine infusions alone. Anxiety is a major contributor to chronic inflammation, which decreases BDNF and the continued loss of synaptic connections. Reducing anxiety through the addition of exogenous oxytocin has significantly reduced the inflammation in the brain and thereby is contemplated to enhance the neuroplasticity effects from the ketamine.

Oxytocin enhances the limbic system and what is deemed as “safe” or “unsafe.” This applies to people, places and things. There are varying levels of “safe” and “unsafe.” When the limbic system detects a threat and oxytocin is present, the feeling of “unsafe” will be enhanced motivating the person to avoid, fight or get away from that person, place or thing. When the limbic system determines a person, place or thing is “safe” in the presence of oxytocin, the person will be motivated to be involved with that person, place or thing. When a person feels connected to someone and that person is safe, physical touch will enhance the release of additional oxytocin causing a soothing and calming feeling. The opposite can be true as well. When a person deemed “unsafe” touches an individual, more oxytocin is released and that person will feel an enhanced urge to fight or run away from that “unsafe” individual. When determining whether a patient should receive oxytocin prior to the neuroplasticity agent, the patient’ s level of reactivity should first be assessed by a physician. Oxytocin administration should be avoided when dealing with a highly reactive patient (i.e., acutely suicidal, homicidal).

The anti-inflammatory agent is used after the neuroplasticity agent to decrease the amount of inflammation present thereby allowing neurogenesis to proceed uninhibited. The neurogenesis is enhanced by reducing the effect that inflammation has on reducing the release of BDNF. The antiinflammatory agent may cause an increased psychedelic effect when given with the ketamine. Thus, in some embodiments, the anti-inflammatory agent is administered after the psychedelic effects from the neuroplasticity agent have decreased.

In some embodiments, the acute “stabilization” phase comprises administering a first dose of oxytocin prior to administering the neuroplasticity agent. In some embodiments, the acute phase comprises intravenously administering a first dose of oxytocin prior to intravenously administering the neuroplasticity agent. In some embodiments, the acute phase comprises intranasally administering a first dose of oxytocin prior to intravenously administering the neuroplasticity agent. In some embodiments, the acute phase comprises intravenously administering a first dose of oxytocin prior to intranasally administering the neuroplasticity agent. In some embodiments, the acute phase comprises intranasally administering a first dose of oxytocin prior to intranasally administering the neuroplasticity agent.

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

In some embodiments, the dose of oxytocin administered at each treatment in the acute phase is from about 0.1 to about 100 International Units (IU). In some embodiments, the dose of oxytocin administered at each treatment in the acute phase 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). The oxytocin can be administered as a single administration (via IV or intranasal administration) or over multiple (i.e., two or more) administrations during each treatment.

In some embodiments, the neuroplasticity agent administered in the acute phase is ketamine. . In some embodiments, the neuroplasticity agent administered in the acute phase is esketamine. In some embodiments, the neuroplasticity agent administered in the acute phase is (R)-ketamine.

In some embodiments, the neuroplasticity agent administered in the acute phase is (2R,6R)- hydroxynorketamine (HNK).

In some embodiments, the neuroplasticity agent administered in the acute phase is psilocybin.

In some embodiments, the neuroplasticity agent administered in the acute phase is 3,4-Methyl enedioxymethamphetamine (MDMA). In some embodiments, the neuroplasticity agent administered in the acute phase is N,N- dimethyltryptamine (DMT or N,N-DMT).

In some embodiments, the neuroplasticity agent administered in the acute phase is lysergic acid diethylamide (LSD).

In some embodiments, the acute phase comprises administering dextromethorphan.

In some embodiments, the neuroplasticity agent administered in the acute phase is nuedexta (a combination of dextromethorphan and quinidine).

In some embodiments, the neuroplasticity agent administered in the acute phase is deudextromethorphan (AVP-786).

In some embodiments, the neuroplasticity agent administered in the acute phase is axsome (AXS-05).

In some embodiments, the neuroplasticity agent administered in the acute phase is dextromethadone (REL-1017).

In some embodiments, the neuroplasticity agent administered in the acute phase is zuranolone (SAGE-217).

In some embodiments, the neuroplasticity agent administered in the acute phase is brexanolone.

In some embodiments, the dose of ncuroplasticity agent administered at each treatment in the acute phase is from about 0.1 to about 300 mg. In some embodiments, the dose of ketamine administered at each treatment in the acute phase is 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, 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.

In some embodiments, the neuroplasticity agent is ketamine (e.g., racemic ketamine, esketamine, or (R)-ketamine) and is administered intranasally at an initial dose of 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, 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, optionally with a second intranasal dose administered 10-15 minutes later at a dose of 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, 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.

In some embodiments, the acute “stabilization” phase comprises a treatment about twice a week, or 2-3 times per week, wherein each treatment is separated by about two to four days, or by 3 days, or about 72 hours, from the previous infusion. During the acute “stabilization” phase, the oxytocin may or may not be administered at each treatment.

In some embodiments, the acute “stabilization” phase comprises administering 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.

In some embodiments, the acute “stabilization” phase comprises administering ketamine (c.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.

One meta-analysis of nine randomized, placebo-controlled studies found that (R,S)-ketamine’s antidepressant effects after a single administration typically begin 40 min post-infusion, peak approximately 24 h later, and lose superiority to placebo 10-12 days post-infusion. Other meta-analyses have corroborated 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.

In some embodiments, the method comprises further administering an anti-inflammatory agent during the acute “stabilization” phase. The anti-inflammatory agent can be administered before, concurrently with, and/or after the neuroplasticity agent.

In some embodiments, the method comprises further administering a nonsteroidal antiinflammatory drug (NSAID) during the acute “stabilization” phase. The nonsteroidal anti-inflammatory drug (NSAID) can be administered before, concurrently with, and/or after the neuroplasticity agent.

In some embodiments, the method comprises further administering acetaminophen during the acute “stabilization” phase. The acetaminophen can be administered before, concurrently with, and/or after the neuroplasticity agent.

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.

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.

In some embodiments, the method comprises further administering a nonsteroidal antiinflammatory drug (NSAID). In some embodiments, the method comprises further administering ketorolac (sold under the brand names Toradol®, and Biorolac® among others). In certain embodiments, the ketorolac is administered intravenously. In certain embodiments, the ketorolac is administered intramuscularly. In certain embodiments, the ketorolac is administered intranasally. In some embodiments, the 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.

In the acute phase, the patient may show an improved scoring on one or more tests, such as those described herein. In certain embodiments, the methods described herein result in a patient feeling significantly less depression and/or anxiety as assessed by the PHQ-9 and/or the Burns Anxiety Inventory score. With certain patients, although the Total Score may indicate a lessor effect, the patient often feels more resilient and is able to maintain some emotional consistency and is able to more effectively “bounce-back” after life stressor (e.g., a break-up, a move, a loss, job 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 after treatment exhibits a Burns Anxiety Inventory score of 21-30 (Moderate Anxiety) will likely feel more resilient even if the patient still has moderate anxiety. Thus, the acute phase may begin once the patient feels sufficient or enhanced resiliency to stressor(s), rather an amelioration of symptoms, even if the score does not reflect the same.

In certain embodiments, the patient’s PHQ-9 score 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% as determined by the PHQ-9. In certain embodiments, the patient’s PHQ-9 score 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% as determined by the PHQ-9, after treatment 4.

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 60%, 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 60%, or at least about 75%, or at least about 80% as determined by the Burns Anxiety Inventory, after treatment 4.

Accordingly, in some embodiments, the method comprises only the acute “stabilization” phase. However, in some embodiments, the method further comprises a “maintenance” phase. Once the patient is determined to be sufficiently improved, e.g., in the positive zone, based on their self-rated scores and physician assessment, the maintenance phase can begin.

Maintenance Phase

In some embodiments, the method comprises a maintenance phase comprising one or more additional treatments, where the oxytocin may or may not be administered at all or at each treatment. The treatment can comprise the same or different dose and/or route administration of oxytocin or neuroplasticity agent as was used in the acute phase. During the maintenance phase, each treatment dose of the maintenance phase decreases, remain unchanged, or increases from the previous treatment. In some embodiments, the maintenance phase comprises administering oxytocin at one or more treatments at substantially the same dose as was administered in the acute phase.

In some embodiments, the maintenance phase comprises administering oxytocin at one or more treatments at a lower dose than was administered in the acute phase. In certain embodiments, the maintenance phase comprises administering oxytocin at one or more treatments at a dose which is 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 45%, or 50% lower than the dose that was administered in the acute phase.

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

In some embodiments, the dose of oxytocin administered during the maintenance phase decreases as compared to the start of the maintenance phase.

Typically, the maintenance phase comprises one or more treatments comprising administering a neuroplasticity agent, with or without oxytocin at any given treatment.

In some embodiments, the maintenance phase comprises administering neuroplasticity agent at one or more treatments at substantially the same dose as was administered in the acute phase. In some embodiments, the maintenance phase comprises administering neuroplasticity agent at one or more treatments at a lower dose than was administered in the acute phase. In some embodiments, the maintenance phase comprises administering neuroplasticity agent at one or more treatments at a higher dose as was administered in the acute phase.

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

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

In some embodiments, the dose of neuroplasticity agent administered during the maintenance phase decreases as compared to the start of the maintenance phase. In some embodiments, the dose decreases by about 5%, or 10%, or 15%, or 20%, or 25%, or 30%, or 40%, or 45%, or 50% over the maintenance phase. In some embodiments of the maintenance phase, such as those where the time between treatments is extended (e.g., from every 2-4 weeks to every 2-6 months), the treatment dose may increase for either or both of the neuroplasticity agent and/or oxytocin. In some embodiments, each treatment dose of the maintenance phase increases 5 mg, 10 mg, or 15 mg based on the patient’ s response from the previous treatment.

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

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

In some embodiments, the method comprises further administering acetaminophen during the maintenance phase. The acetaminophen can be administered before, concurrently with, and/or after the neuroplasticity agent and/or oxytocin.

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

In some embodiments of the maintenance phase, an anti-inflammatory agent, nonsteroidal antiinflammatory 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.

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

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

In some embodiments of the maintenance phase, the 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.

In some embodiments, the maintenance phase comprises one treatment per week for 2-4 weeks, then one treatment every other week, or one treatment every 2-4 weeks for the first 6 months.

In some embodiments, the subject is isolated from human interaction. In some embodiments, the method further comprises the use of one or more adjunct therapies along with the methods described herein. Examples of adjunct therapies include e.g., psychotherapy, participation in social support groups, and/or additional therapies with one or more additional pharmaceutical agents.

Compositions

It should also be appreciated that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the formulation, route of administration, activity of the ncuroplasticity agent employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, and the judgment of the treating physician, and the severity of the particular disease being treated.

The oxytocin, anti-inflammatory, and neuroplasticity agents can be delivered separately or together by any suitable route, as pharmaceutical compositions which can comprise any number of excipients. Excipients that can be used include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic 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, administration of the oxytocin, antiinflammatory and neuroplasticity agent are each independently suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, intravitreal, or epidermal administration (e.g., by injection or infusion). The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intravitreal, and intrastemal injection and infusion. Alternatively, administration of one or more of oxytocin, anti-inflammatory agent, and neuroplasticity agent can be independently via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, e.g., intranasally, orally, vaginally, rectally, sublingually or topically.

For administration by inhalation or intranasal routes, the oxytocin, anti-inflammatory and neuroplasticity agent can each be independently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebulizer, usually with the use of a propellant, e.g., halogenated carbons derived from methane and Ethan, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons like butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator, may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.

Pharmaceutical compositions comprising oxytocin and neuroplasticity agent, optionally with an anti-inflammatory agent, can each independently be in the form of sterile aqueous solutions or dispersions. They can also be formulated in a microemulsion, liposome, or other ordered structure suitable to high drug concentration.

The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration and will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01% to about ninety-nine percent of active ingredient, or from about 0.1% to about 70%, or from about 1% to about 30% of active ingredient in combination with a pharmaceutically acceptable carrier.

Dosage regimens are adjusted to provide the optimum desired response (e.g., a 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. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

EXAMPLES

The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

DIAGNOSTIC EXAMPLE 1

In the following example, the amount of dopamine released in response to certain thoughts, words, foods or activities will be referred to as either high, medium or low. High dopamine foods would be fried, salty, sweet and desserts that are very desirable to the individual. They could also be “comfort” foods that also stimulate the release of oxytocin because the food is familiar to them (the way their mother made it). Medium and low dopamine foods would depend on the quality of the food and the person’ s individual tastes and desires.

High dopamine thoughts would be the thought of doing something exciting like travel, winning money, dating their dream person, becoming famous, and other similar stimulating thoughts. Moderate and low stimulating thoughts would depend on the individual’s desires, dreams, mood and expectations. Low dopamine thoughts would be considered simple positive thoughts like, “today will be a good day.”

High dopamine words would be considered very exciting or stimulating words that are considered very safe to the individual. Safe words would be words that are accepted by that person’s culture and society. They could be words that convey love or appreciation to another individual. They could be exciting words that are often used in advertising to capture a person’s attention. They could be humorous words that contribute to laughter.

Moderate dopamine words would be considered moderately stimulating words to each particular individual. They are considered moderately safe words to the individual. These words would be used more often by the individual and could include slang or respectful words.

Low dopamine words would be considered low stimulating words and would be considered safe to the individual. These words are the most common words used in the person’s language.

High dopamine activities would be very stimulating or risky activities where adrenaline is often also released. They would include sky diving, surfing big waves, extreme downhill mountain biking and rock climbing big mountains. They can also include risking large amounts of money when gambling, TikTok videos, intense video games, thriller movies, action movies, and suspenseful movies.

Moderate dopamine activities would depend on the individual and what they perceive to be considered moderate. Most forms of video entertainment and gaming entertainment would be considered moderate dopamine activities at the very least. Various forms of social media would be considered moderate to high dopamine activities depending on how active the person was with posting or just scrolling through other’s posts. Most outdoor games and sports would be considered moderate dopamine activities. Reading a stimulating book would be considered moderate to high dopamine depending on the subject matter. Going on a walk in more desirable nature such as the beach, forest or historically significant place would also be considered a moderate dopamine activity.

Low dopamine activities would be specific to each individual. Learning a new hobby or sport could be considered low dopamine. Reading material that the person is interested in (not moderately or high stimulating) would be considered “low dopamine reading.” Going on a walk in one’s neighborhood or area that is familiar and safe to them would be considered low dopamine. Doing a jigsaw puzzle, sudoku, crosswords, crafting, needling, wood working, gardening would all be considered low dopamine activities.

Negative Zone

General Principles

In the human brain, the dopaminergic systems play a central role in controlling movement, hormone release, emotional balance, reward, odor discrimination and vision. It is theorized that as a person’ s tonic or baseline level of dopamine decreases, based on decreased dopaminergic neuron activity from lost synaptic connections, they start to experience more emotional and physical pain. As a result of the increased physical and emotional pain, it is believed that more opioid receptors for endorphins arc produced to help provide more relief. The extra opioid receptors make the person more vulnerable to opioid addiction should they get exposed to exogenous opioids. With the extra opioid receptors, people experience relief from their baseline state of emotional/physical pain when they willingly hurt themselves, hurt others or allow themselves to be hurt by others. They do not get significant relief from being hurt by others against their will. They will become defensive and isolate themselves from those they think will hurt them.

If people take opioids prescribed from their doctor or illegally, they will experience a significant mood lift beyond the normal pain control. The deeper or more negative they are in the negative zone, the more intense the relief they will experience with the extra opioid receptors. They will likely become dependent on the opioids and find reasons to stay on them to help manage their mood. The person will develop tolerance (decreased opioid receptors) as they continue the opioids causing them to go up on the dose. They will notice that they no longer get relief from their negative coping skills since their opioid receptors have significantly decreased in number. These people become more hopeless and addicted to opioids as a result. They may even become more suicidal if they get significantly stressed. With the recent restrictions on opioids more people are turning to illegal opioids and fentanyl to treat their chronic pain and depressed mood. This has largely contributed to the current opioid epidemic and more opioid related overdoses.

People develop negative coping skills on a subconscious level and focus on negative thoughts, words and actions. People will meditate or ruminate on negative or hurtful experiences or dilemmas for hours at a time as they seek to get relief from their emotional and physical pain. In the short term the people experience relief from the release of their endogenous endorphins to help ease the suffering from the emotional pain they created. The long-term result is a rise in neuroinflammation and whole-body inflammation from the increased sense of threat and hopelessness that leads to increased chronic pain, hypervigi lance, anxiety and other inflammatory disorders. The inflammatory disorders include asthma, allergies, inflammatory bowel disease, ulcerative colitis, fibromyalgia, chronic fatigue, arthritis, cancer (i.e.. colon, breast, lung), cardiovascular disease, neurodegenerative disorders, gingivitis, eye disorders, Alzheimer’ s disease, metabolic syndrome and many more.

As people do their negative coping skills or take a substance to improve how they feel, they feel a tremendous amount of guilt and shame afterwards that also leads to endorphin release. As they feel more guilt and shame they continue to engage in their negative coping skills and addictions to substances which drives them deeper into the negative zone. Their feelings of low self worth worsen as they go deeper into the negative zone.

In the negative zone people become more reliant and dependent on positive oxytocin experiences with people, places, safe and meaningful objects, politics, religion and sports. They will cling to things that are familiar and seen as safe to them. They may become obsessive with certain philosophical viewpoints, hobbies, conspiracy theories and the unknown. These behaviors will become more intense as they go deeper or more negative in the negative zone.

When their baseline serotonin levels decrease as a result of decreased serotonergic neuron activity from lost synaptic connections, their overall threat level rises, and they become less trusting and more fearful of things, places, people and diseases. They seek out more opportunities to feel safe and manufacture positive oxytocin experiences which leads to anxiety disorders such as obsessive- compulsive disorder, eating disorders and schizoaffective disorders.

If the person has the opportunity for a lot of positive oxytocin experiences, they will feel more resilient to stress. They will find it soothing and safe to attend a church, club or organization where they can be around people with a similar culture, ideas or beliefs. They would need to have a safe place to live where there is at least one safe individual who provides a positive oxytocin experience for them. If there is one unsafe individual in the place of residence, the person will not be able to relax and feel safe leading to more anxiety. If there isn’t any safe individuals present in their home, a pet may provide a lower, but sustainable level of positive oxytocin. When people lose the one safe individual or pet they may have, they can become very unstable with their mood and anxiety levels and they are more likely to turn to their negative coping skills for relief.

If people feel stressed or unsafe, they are likely to experience a higher threat level and worsening anxiety. If people feel safe despite the stressors they are experiencing, they are more likely to experience depressed mood with less anxiety. When people feel anxiety, there is almost always underlying depressed mood. The positive symptoms from anxiety frequently mask the negative symptoms from depression.

When asked if they enjoy things, they may report that they enjoy things that are related to positive oxytocin experiences such as spending time with their loved ones, pets, going to church, political meetings, safe and meaningful places or objects. They may report that they enjoy negative movies or tv series (i.e. thriller, horror, true crime, war documentaries, etc.), negative books, harsh music and making hurtful comments to others.

The specific things people find enjoyable can make it hard to assess their level of anhedonia and where they arc in the negative zone. It is important to separate their negative interests, enjoyment watching others suffer and positive oxytocin experiences from enjoyment related more strictly to dopamine.

People first lose their ability to enjoy low dopamine thoughts, words, foods and activities as they enter the neutral zone. But those in the neutral zone report enjoyment still from medium and high dopamine thoughts, words foods and activities. As they go deeper in the negative zone they lose their enjoyment of medium and later high dopamine thoughts, words, foods and activities as their tonic or baseline level of dopamine continues to decrease. The increased loss of serotonin further aggravates their negative symptoms in the negative zone.

People in the negative zone often define themselves based on their occupation, hobbies, interests, sports, religion, philosophy, clubs and social status. When those people lose their occupation or get injured and can no longer perform, they lose their identity and sense of purpose. They can become very unstable based on where they are in the negative zone. Another common trait of people in the negative zone is that they have a hard time forgiving others or letting go of traumatic experiences as they frequently reflect on the hurt caused to them as a form of self-harm. If this behavior gets excessive, they may develop post-traumatic stress disorder. It has been observed that people in the deep negative zone are acting out the trauma (usually sexual in nature) that happened to them as a form of self-harm.

It is theorized that as you increase the number of inactive dopamine neurons, the risk increases for having a manic episode. The more inactive dopamine neurons one may have, the longer they can maintain their manic episode. Those in the negative zone with a rating from -1 to -5 may experience a hypomanic episode. A hypomanic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day.. While those who are -6 to -10 in the negative zone may experience a manic episode. A manic episode is characterized by an abnormal and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy, lasting at least one week and present most of the day. It has been observed that those with a history of Bipolar 1 or 2 disorder do not have manic or hypomanic episodes in the positive zone. This observation may be due to the decreased number of inactive dopamine neurons and higher baseline or tonic release of dopamine.

The following detailed descriptions of each level in the negative, neutral and positive zone will help the practitioner determine where the patient is as part of their recovery. A more simplified version of the different zones will be provided.

-1 People get the least amount of relief (approximately 10%) from their negative coping skills or self-harming thoughts, behaviors, words and actions. When they are not stressed, they may not feel like things are that bad for them. They do not experience reward for positive or low dopamine thoughts, words, foods or activities. They become more numb to their emotions and feelings for others. They become more self-centered and have a hard time feeling empathy for others.

Positive affirmations will not resonate with them. Their affect will be flat or negative. They will rate enjoyment of positive thoughts, words and activities at a 0 on scale of 0-10 (0 is no enjoyment and 10 is highest level imaginable). They will get tired easily. They have low energy levels and may frequently take naps. They may report chronic fatigue symptoms if they are sedentary.

Significant effort is needed to initiate most tasks. They get easily discouraged with difficult tasks with low and high reward. They will procrastinate most tasks.

More likely to engage in moderate to high dopamine thoughts, words, foods and activities. People will get minimal relief from drinking alcohol.

Difficulty experiencing any positive emotions except when related to a positive oxytocin experience. They will experience a lot of different negative emotions (0/10 on scale from 0-10). Less likely to exercise regularly. Difficulty with focus and attention as there is little that interests them. Their sleep schedule will vary and they will have difficulty sleeping or sleep too much.

When experiencing difficult or negative emotions they tend to isolate and avoid anything else they interpret as being difficult for them. They don’t feel resilient to stressors. They struggle to have hope for better times and better days ahead. When dealing with inflammation from being sick or physical injury, the person is easily overwhelmed.

They feel they have to “wear a mask” around people in the positive zone or in public as they know how they are supposed to act. They prefer to be around people who are negative or neutral as they feel like they can be themselves without having to wear a mask. They don’t have much interest in self- care. They put little effort into the care to their environment. Those with high anxiety may need a very clean and organized environment and cannot tolerate things being out of place.

May experience chronic pain with less significant long term physical ailments and more easily triggered by stress. Will be more concerned about their chronic pain and less likely to move as a result of their pain.

When stressed, people may put more effort into their negative coping skills to try and get relief from the emotional pain they are experiencing. They may try and hurt themselves or others emotionally or physically as they are trying to seek relief. For example, when a person uses suicidal thoughts as a negative coping skill gets more stressed, they may think more suicidal thoughts and possibly act on those suicidal thoughts as they have a more reactive mindset. It’s been observed that they can share their suicidal thoughts with loved ones in a subconscious effort to get empathy and cause emotional pain to their loved one. The suicidal person experiences pain briefly, but the release of endorphins will provide the suicidal person with relief from their emotional pain.

-2 People get approximately 20% relief from their pain with negative coping skills or selfharming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. When they are not stressed, they may feel like life is manageable. When they are stressed, they can become hopeless and feel like life is not worth living.

They do not experience reward for positive or low dopamine thoughts, words, foods or activities. They become more numb to their emotions and feelings for others. They experience emotional dysregulation. They become more self-centered and have a hard time feeling empathy for others. They experience more hopelessness as they don’t enjoy many things in life. The less opportunity they have for positive oxytocin experiences, the more hopeless they feel with depressed mood.

Positive affirmations will not resonate with them and they avoid saying them. Their affect will be flat or negative. They will rate enjoyment of positive thoughts, words and activities at a 0 on scale of 0- 10 (0 is no enjoyment and 10 is highest level imaginable). They will get tired easily. They have low energy levels and may frequently take naps. They can report chronic fatigue symptoms if they are sedentary.

More likely to engage in moderate to high dopamine thoughts, words, foods and activities. More likely to become dependent or addicted to high dopamine thoughts, words, foods, substances and activities. They look forward to drinking alcohol to get relief from their emotional pain. May engage in risky behaviors to experience more emotions and feelings.

Difficulty experiencing any positive emotions except when related to a positive oxytocin experience. They will experience a lot of different negative emotions (0/10 on scale from 0-10). Less likely to exercise at all. Difficulty with focus and attention as there is nothing positive that interests them. They find it easier to focus and place their attention on their negative coping skills. Their sleep schedule will vary and they will have difficulty sleeping or sleep too much. They experience more fatigue and tiredness in the morning and may become dependent on caffeine to help them feel more awake.

They feel they have to “wear a mask” around people in the positive zone or in public as they know how they are supposed to act. They prefer to be around people who are negative or neutral as they feel like they can be themselves without having to wear a mask. They find it is getting harder to “wear a mask” in public settings and prefer to be alone.

They don’t have much interest in self-care. They put little effort into the care to their environment. Those with high anxiety may need a very clean and organized environment and cannot tolerate things being out of place.

-3 People experience all of the same things that people at -2 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. They experience even more relief from drinking alcohol. They arc at a greater risk for opioid addiction as their body continues to make more opioid receptors to help with the greater sense of emotional and physical pain. People get approximately 30% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. When they are not stressed, they may feel like life is still worth living even though it is very difficult. When they are stressed, they may feel more hopeless and life is not worth living. They may begin to have suicidal thoughts when they are very stressed and feel unstable or unsupported.

They do not experience reward for positive or low dopamine thoughts, words, foods or activities. They become even more numb to their emotions and feelings for others. They experience more emotional dysregulation. They become more self-centered and have a hard time feeling empathy for others. They experience more hopelessness as they don’t enjoy many things in life. The less opportunity they have for positive oxytocin experiences, the more hopeless they feel with depressed mood. They may also feel less resilient if they don’t feel they have a purpose in their life.

When experiencing difficult or negative emotions they tend to isolate and avoid anything else they interpret as being difficult for them. They don’t feel resilient to stressors. They don’t have hope for better times and better days ahead. When dealing with inflammation from being sick or physical injury, the person feels overwhelmed.

Their efforts in self-care are becoming less important to them. They go long periods without brushing their teeth or taking showers.

They procrastinate most tasks until they have to do them. Their tasks may go incomplete well past the deadline. Their objective work or school performance decreases.

-4 People experience all of the same things that people at -3 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. They experience even more relief from drinking alcohol. They are at a greater risk for opioid addiction as their body continues to make more opioid receptors to help with the greater sense of emotional and physical pain.

People get approximately 40% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. When they are stressed, they may feel more hopeless and have more suicidal thoughts.

They do not experience reward for positive or low dopamine thoughts, words, foods or activities. They become even more numb to their emotions and feelings for others. They experience more emotional dysregulation. They become even more self-centered and lack empathy for others. They experience more hopelessness as they don’t enjoy many things in life. The less opportunity they have for positive oxytocin experiences, the more hopeless they feel with depressed mood. They may also feel less resilient if they don’t feel they have any purpose to their life.

-5 People experience all of the same things that people at -4 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions.

People have less self-worth and “hate the person they see in the mirror.” People may begin to alter their appearance in a way that is considered to be more negative. They may do more things that are considered socially unacceptable as a form of self-harm. People may disfigure their body with piercings or tattoos in more visible places that others may see as ugly, offensive or socially unacceptable. When they feel they are being misjudged by others for their appearance it will confirm to them that they don’t belong to their society.

They are at a greater risk for opioid addiction as their body continues to make more opioid receptors to help with the greater sense of emotional and physical pain. They may turn to more risky behaviors to obtain dopamine release like jumping from cliffs, skydiving, rock climbing, and surfing big waves. They experience even more relief from drinking alcohol. They become more dependent on psychoactive substances to “feel more alive.”

People with gambling disorder report they get relief from risking and losing large amounts of money. When they willingly gamble large amounts of money they get a high amount of dopamine for the anticipated potential big win. Even when they lose big amounts of money, they get significant relief from the endorphins when they experience the pain of losing the money.

People get approximately 50% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. It usually doesn’t take much stress for them to feel more hopeless and have more suicidal thoughts.

If people have been hurt or offended by another person, they are more likely to seek retaliation than be forgiving. The person may obsess over hurting the person or group of people emotionally or physically.

-6 People experience all of the same things that people at -5 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions.

They are at a greater risk for opioid addiction as their body continues to make more opioid receptors to help with the greater sense of emotional and physical pain. They may turn to more risky behaviors to obtain dopamine release. They experience even more relief from drinking alcohol. They become more dependent on psychoactive substances to “feel more alive” or numb the emotional pain they are experiencing.

People get approximately 60% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. They are more likely to have suicidal thoughts even when they are not stressed. They may really consider taking their own life or the way they would do it.

If people have been hurt or offended by another person, they are more likely to obsess over hurting the person or group of people emotionally or physically. They may get more active in selfdefense classes if they have anxiety about being hurt themselves. Or they may get involved in martial arts classes if they have thoughts of harming others. They may become more interested in weapons such as knives and guns and how to use them against others.

-7 People experience all of the same things that people at -6 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions. People will excessively pick at their skin, pluck eyebrows, pop pimples and cut themselves to get relief from the endorphins released in response to the initial pain.

People get approximately 70% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions as long as they are not taking any exogenous opioids. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. They are more likely to have suicidal thoughts even when they are not stressed. They may really consider taking their own life or the way they would do it.

-8 People experience all of the same things that people at -7 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions.

People get approximately 80% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. They are more likely to have suicidal thoughts daily. When stressed, they may actually attempt to take their own life. They are more of a threat to themselves or others.

-9 People experience all of the same things that people at -8 experience, but now with more negative emotions, feelings and pain as a result of the lower baseline release of dopamine. People rarely feel any emotions even from high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions. People get approximately 90% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions as long as they aren’t taking any exogenous opioids. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. They have suicidal thoughts daily. They are a frequently a threat to themselves or others.

-10 People experience all of the same things that people at -9 experience, but now with more negative emotions, feelings and pain as a result of the lowest baseline release of dopamine. People will become even more dependent on high dopamine thoughts, words, substances and activities. People will engage in more serious self-harm thoughts, words and actions. People get approximately 100% relief from their pain with negative coping skills or self-harming thoughts, behaviors, words and actions as long as they are not using any exogenous opioids. They experience more emotional and physical pain each day as a result of a lower baseline level of dopamine release. Even when they are not stressed, they feel like life is not worth living and it would be better if they were dead. They are more likely to have suicidal thoughts daily. When stressed, they may actually attempt to take their own life. They are a constant threat to themselves or others.

Neutral Zone

0 People do not get relief from their negative coping skills or self-harming thoughts, behaviors, words or actions. People report no enjoyment or reward for low dopamine thoughts, words, foods or activities. Positive affirmations will feel neutral. They may still try to be positive as that is a more socially acceptable behavior. Their affect will be neutral. They will rate enjoyment of positive thoughts, words and activities at a 0 on scale of 0-10 (0 is no enjoyment and 10 is highest level imaginable). They will get tired easily. They have low energy levels and may frequently take naps.

More likely to engage and enjoy moderate to high dopamine thoughts, words, foods and activities. Difficulty experiencing any positive emotions except when related to a positive oxytocin experience. They will experience a lot of different negative emotions (0/10 on scale from 0-10). Less likely to exercise regularly. Difficulty with focus and attention as there is little that interests them. Their sleep schedule will vary and they will have difficulty sleeping or sleep too much.

When experiencing difficult or negative emotions they tend to isolate and avoid anything else they interpret as being difficult for them. They don’t feel resilient to stressors. At times, they may have hope for better times and better days ahead. When dealing with inflammation from being sick or physical injury, the person is easily overwhelmed.

They prefer to be around people who are negative or neutral. They don’t have much interest in self-care. They put little effort into the care to their environment. Those with high anxiety may need a very clean and organized environment and cannot tolerate things being out of place.

Positive Zone

+1 Minimal enjoyment or reward for low dopamine thoughts, words, foods or activities. Will only feel reward when doing positive things. Positive affirmations will only feel good if they really resonate with the person. Will begin to smile in positive situations. Will rate enjoyment of positive thoughts, words and activities at a 1 on scale of 0-10 (0 is no enjoyment and 10 is highest level imaginable). Will get tired more easily. Low energy levels and enjoy taking naps.

They get no benefit from negative coping skills. Drinking alcohol no longer provides them with any relief and they report less enjoyment of it. When patients do or say something that is harmful to themselves or others, they get no benefit from it and only experience the pain.

Significant effort needed to initiate difficult tasks. Moderate effort needed to do more enjoyable tasks. Will dread getting started with positive activity but will feel reward and grateful when doing the positive activity. More easily discouraged with difficult tasks with low and high reward. Will procrastinate most tasks. Will initiate many tasks, but unlikely to finish them.

More likely to engage in moderate to high dopamine foods and activities. Will experience less positive and negative emotions (1/10 on scale from 0-10), but they will be appropriate for what they are thinking, saying or experiencing. Less likely to exercise regularly. Difficulty with focus and attention on things not interesting to them. Maintaining a regular sleep schedule is a low priority.

Will not experience enjoyment when feeling stressed. When experiencing difficult or negative emotions, it is harder to stay positive. They will feel less resilient to stressors. They are less likely to have hope for better times and better days ahead. When dealing with inflammation from being sick or physical injury, the person is more easily overwhelmed and will feel numb to their emotions.

They may find it hard to be around people who are negative. They may take more interest in self- care. They have low self-worth, but more than those in the negative or neutral zone. They may take some interest in having a more organized and cleaner environment.

+2 Minimal to moderate enjoyment or reward for low dopamine thoughts, words, foods or activities. Will feel more reward when thinking, saying and doing positive things. Will be less hesitant to engage in positive activities and will enjoy them when doing them. They will be optimistic in the less difficult circumstances. They will smile with positive situations and feel good about it. Positive affirmations will resonate with them more easily and can be more motivating depending on the affirmation. Will feel reward when doing positive things and for short time afterwards. Will rate enjoyment of positive thoughts, words and activities at a 2 (scale 0-10). Will get tired easily and more willing to take naps.

More effort needed to get started with difficult tasks or tasks with low reward. Easily discouraged when doing difficult tasks with low reward. They are less likely to get discouraged when doing difficult tasks with higher rewards. Easier to get motivated with more enjoyable tasks. More likely to finish the easier tasks once initiated. Will still struggle to finish difficult tasks or tasks with low reward. Will procrastinate the more moderate to difficult tasks.

Will find it hard to be around people who are negative. They will prefer to be around people who are more positive. Will engage in better self-care and will take some satisfaction in appearing well dressed and taken care of. They will likely work to organize and clean their environment.

May engage in moderate to high dopamine foods and activities. Will experience more positive and negative emotions (2/10 on scale from 0-10) and they will be appropriate for what they are thinking, saying or experiencing. Will not likely feel enjoyment when feeling stressed. When experiencing difficult or negative emotions, it is a little easier to stay positive and try to rebound from the negative emotions.

Will feel a little more resilient to stressors. They are more likely to have hope for better times and better days ahead. When dealing with inflammation from being sick or physical injury, the person is likely to feel overwhelmed with less emotions. They will feel more self- worth and no longer “hate the person in the mirror” as they may have done in the negative zone. May exercise when feeling motivated to do so and will likely enjoy it when they do so. Moderate difficulty with focus and attention on things not interesting to them. Sleep schedule will be difficult to maintain but may place a higher priority on getting regular sleep.

May experience chronic pain with significant long term physical ailments that will be easily worsened by stress. Will be concerned about their chronic pain, but more likely to move with the pain.

+3 Moderate enjoyment or reward for low dopamine thoughts, words, foods or activities. Will feel more significant positive reward when thinking, saying and doing positive things. Will be more motivated to engage in positive activities and will enjoy them when doing them. They will enjoy smiling and will do it more frequently. They try to be optimistic in most situations. Positive affirmations will resonate with them more easily and will be more motivating. Will feel reward when doing positive things and for a more significant time afterwards. Will rate enjoyment of positive thoughts, words and activities at a 3 (scale 0-10). Will get tired less easily and less likely to take naps.

Moderate effort needed to get started with difficult tasks or tasks with low reward. Less easily discouraged when doing difficult tasks with low reward. They are not likely to get discouraged when doing difficult tasks with higher rewards. More likely to finish the easier to moderate tasks once initiated. Will still struggle to finish difficult tasks or tasks with low reward. Will likely procrastinate the more difficult tasks.

May engage in moderate to high dopamine foods and activities. Will experience more positive and negative emotions (3/10 on scale from 0-10) and they will be appropriate for what they are thinking, saying or experiencing. When experiencing difficult or negative emotions, it is easier to stay positive and try to rebound from the negative emotions. They are more likely to feel resilient to their stressors. They are more likely to have hope for better times and better days ahead.

Will avoid being around people who are negative. Will prefer to be around others who are positive. Will place higher priority on self-care. They will have more self-worth and will stand up for themselves more. They will be more motivated to maintain a clean and organized environment.

May exercise when feeling motivated to do so and will enjoy it when they do it. Some difficulty with focus and attention on things not interesting to them. Sleep schedule can be difficult to maintain, but they may place a higher priority on getting regular sleep. When dealing with inflammation from being sick or physical injury, the person is less likely to feel overwhelmed and may feel more resilient.

May experience chronic pain with significant long term physical ailments that can be worsened by stress. Will be concerned about their chronic pain, but more likely to move with the pain and not let it limit their activities.

May begin to experience improved odor discrimination and vision.

+4 Moderate to high enjoyment or reward for low dopamine thoughts, words, foods or activities. Will feel significant positive reward when thinking, saying and doing positive things. Will be more motivated to engage in positive activities and will enjoy them when doing them. They enjoy smiling and laughing and will do it often. They are optimistic in most situations. Positive affirmations will resonate with them and will be more motivating. Will feel reward when doing positive things and for a significant time afterwards. Will rate enjoyment of positive thoughts, words and activities at a 4 (scale 0-10). Will report more energy and less interest in taking naps.

Less effort needed to get started with difficult tasks or tasks with low reward. Not likely to get discouraged when doing difficult tasks with low reward. They will stay positive and not get discouraged when doing difficult tasks with higher rewards. More likely to finish moderate tasks once initiated. May struggle to finish difficult tasks or tasks with low reward. Less likely to procrastinate the more difficult tasks.

Less likely to engage in moderate to high dopamine foods and activities. Will experience more positive and negative emotions (4/10 on scale from 0-10) and they will be appropriate for what they are thinking, saying or experiencing. When experiencing difficult or negative emotions, it is easier to stay positive and try to rebound from the negative emotions. They will hope for better times and better days ahead.

Will avoid being around people who are negative and will prefer to be around those who are positive. Will place a high priority on self-care. They will maintain a clean and organized environment.

More likely to exercise regularly and enjoy it. Little difficulty with focus and attention on things not interesting to them. A good sleep schedule will be a higher priority and will be easier to maintain. When dealing with inflammation from being sick or physical injury, the person is more likely to push through it or rest so as not to feel too overwhelmed. Will report improved odor discrimination and vision.

May experience chronic pain with significant long term physical ailments that can be worsened by stress. May be concerned about their chronic pain, but more likely to move with the pain and not let it limit their activities.

+5 High enjoyment or reward for low dopamine thoughts, words, foods or activities. Will feel significant positive reward when thinking, saying and doing positive things. They are optimistic with most difficult situations. Will be more motivated to engage in positive activities and will enjoy them when doing them. Positive affirmations will resonate with them and will be more motivating. They enjoy smiling and laughing and will try to find the humor in difficult situations. Will feel reward when doing positive things and for a significant time afterwards. Will rate enjoyment of positive thoughts, words and activities at a 5 (scale 0-10). Will report more energy and less interest in taking naps.

Less effort needed to get started with difficult tasks or tasks with low reward. Not likely to get discouraged when doing difficult tasks with low reward. They will stay positive and not get discouraged when doing difficult tasks with higher rewards. More likely to finish moderate tasks once initiated. May struggle to finish difficult tasks or tasks with low reward. Less likely to procrastinate the more difficult tasks. Less likely to engage in moderate to high dopamine foods and activities. Will experience more positive and negative emotions (5/10 on scale from 0-10) and they will be appropriate for what they are thinking, saying or experiencing. When experiencing difficult or negative emotions, it is easier to stay positive and try to rebound from the negative emotions. They hope to live a long life. They will hope for better times and better days ahead when dealing with difficult situations.

Will avoid being around people who are negative and will prefer to be around those who are positive. Will place a high priority on self-care and enjoy appearing well dressed and groomed. They will maintain a clean and organized environment. Will report improved odor discrimination and vision.

More likely to exercise regularly and enjoy it. Little difficulty with focus and attention on things not interesting to them. A good sleep schedule will be a high priority and will be easier to maintain. When dealing with inflammation from being sick or physical injury, the person is more likely to push through it when needed or rest so as not to feel too overwhelmed.

+6 All of the benefits of the person at a level +5. They will rate their level of enjoyment and emotions at a 6/10. Patients are more optimistic and motivated. They have a high level of stress resilience.

+7 All of the benefits of the person at a level +6. They will rate their level of enjoyment and emotions at a 7/10. Patients are more optimistic and motivated. They have a high level of stress resilience.

+8 All of the benefits of the person at a level +7. They will rate their level of enjoyment and emotions at a 8/10. Patients are more optimistic and motivated. They have a significantly high level of stress resilience.

+9 All of the benefits of the person at a level +8. They will rate their level of enjoyment and emotions at a 9/10. Patients are more optimistic and motivated. They have a significantly high level of stress resilience.

+10 All of the benefits of the person at a level +9. They will rate their level of enjoyment and emotions at a 10/10. They have a maximum level of enjoyment, emotions, optimism and motivation. They have the highest level of stress resilience.

Exemplary Method for Determining Treatment:

1. Call patient to determine whether or not they are a good candidate for ketamine treatment. Get a basic history and review of systems. Have patient complete a Patient Health Questionnaire (PHQ-9) for depression and the Burns Inventory questionnaire for their baseline rating. Have the patient provide a detailed medical history and have them sign the appropriate consent forms and patient privacy forms. Provide counseling at first appointment regarding inflammation, depression, anxiety and how the combined treatment reverses the symptoms of depression and anxiety. After an initial baseline set of vitals and physical exam, provide the first treatment of intranasal oxytocin. Place monitor devices on the patient to monitor their heart rate, rhythm and oxygen saturation. Start the first ketamine infusion at a very minimal rate and increase the rate every 8-10 minutes with the patient’s approval. Stop the infusion at 50 minutes. For intranasal ketamine, administer a low dose 5-15 mg every 10 - 15 minutes based on the patient’s comfort level with the experience. After 10-15 minutes, administer the anti-inflammatory agent through the IV, IM, oral or intranasal route depending on the agent used. At the next appointment (approx. 72 hours from their first treatment), have the patient complete the modified 3-day PHQ-9 and modified 3-day Burns Inventory questionnaire. Start with the administration of intranasal oxytocin at the very beginning of the appointment unless there was an adverse reaction with the first treatment that needs to be discussed further. Discuss how the patient responded to the first treatment and answer any questions they may have. Assess whether or not the patient is in the positive zone yet by determining if they are enjoying any low dopamine thoughts, words or activities. If not in the positive zone, assess where they are in the negative zone and provide counseling relative to where they are in the negative zone. Discuss increasing the dose by5-3O mg given the patient’s comfort level with the first infusion/nasal spray. Administer the second infusion by setting the infusion to be completed in 50 minutes. Repeat this process for as many treatments as needed to get the patient into the positive zone. It is imperative that the treatments continue two times a week (72 hours apart) until the patient is at least in the positive zone. It is important to note that patients get less relief from their negative coping skills as they get closer to the negative zone. When stressed, some patients may increase their negative coping skills to get more relief. This may include having increased suicidal thoughts or various forms of self-harming. It is important to encourage patients to seek out positive oxytocin experiences with other loved ones when/if they feel the need to turn to their negative coping skills and they don’t seem to be providing them with any relief. Once the patient is in the positive zone, they may begin to experience moments of enjoyment with low dopamine thoughts, words, foods and activities. They are not usually sustained in the low positive zone and are dependent on what the patient is thinking, saying or doing. It has been observed that people who are actively engaging in moderate to dopamine activities during treatment may not experience enjoyment from low dopamine activities even when they are in the low positive zone. The decreased or lack of enjoyment is a result of decreased dopamine receptors from overstimulation. The person needs to abstain from moderate to high dopamine activities during the treatment process to maximize their benefits. As the patient is receiving their treatments and more neurons are being reactivated, it may become necessary to reduce the doses of the person’ s antidepressant based on the mechanism of action. Antidepressants focused on preventing the reuptake of a certain neurotransmitter or enhancing the release of a certain neurotransmitter may need to be reduced based on the current dose. Once the person is high in the positive zone, a discussion with the person will determine at what frequency they will continue the treatments. If the person has been in the negative zone for many years, they may need more frequent treatments as they learn to adjust to the positive zone and attempt to maintain their benefits. Many patients continue with their negative coping skills, habits and thought patterns that served them well in the negative zone. They will continue to experience depressed mood and anxiety if they continue to think, say and do negative things. People with Bipolar 1 or 2 may be tempted to engage in high dopamine activities to try and initiate a manic or hypomanic episode. They learn that it is difficult to maintain the good feelings longer than 24 hours in the positive zone. They may become frustrated and feel depressed mood when they can’t sustain the good feelings like they could in the negative zone. People in the positive zone need to replace their negative coping skills and habits with new positive ones. Their negative habits, behaviors and thought patterns can still happen in the positive zone if/when the person feels stressed and their positive coping skills don’t seem to be working well enough to bring them the relief they need. Once the person is higher in the positive zone from multiple treatments, they will find that they are experiencing more highs and lows with their emotions that will be appropriate for what they are thinking, feeling and doing. As their baseline level of dopamine increases, their ability to experience a wider range of emotions increases where people at a +10 experience the greatest swings in their emotions.

25. When people are in the positive zone, they may have a difficult time adjusting to the new rules they must live by in order to maintain their benefits. They have to learn and practice new positive coping skills that they won’t be used to doing. The longer they have been in the negative zone the harder the transition may be.

26. Many patients continue with their negative coping skills, habits and thought patterns that served them well in the negative zone. They will continue to experience depressed mood and anxiety if they continue to think, say and do negative things.

27. They must learn a new emotional intelligence in the positive zone. They must replace their old negative habits with new positive ones that can be very difficult and overwhelming at first.

28. Some people struggle with their sense of identity depending on how long they have been in the negative zone.

29. Some people start to feel more isolated and alone as they start to yearn for more companionship in the positive zone.

30. Some people find it difficult to continue to associate with their former friends who are still in the negative zone. They report that their friends or loved ones are too negative and they no longer want to be around them.

31. People who were dependent on alcohol or other substances to lift their mood no longer get the same mood lifting properties from those substances.

32. People who were used to engaging in high dopamine activities in the negative zone have a harder time continuing their high dopamine activities in the positive zone. They find that they feel overstimulated and a need to stop their continued high dopamine activity. They become more content with low or moderate dopamine activities.

Treatment Example 1

Treatment for adult male or female subjects ages 18 to 65 years old having been diagnosed with one or more of major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, or irritable bowel syndrome. Timing:

Acute (stabilizing) phase is 2 times a week for 3-5 weeks depending on the severity of the initial illness. The more negative (-1 to -10 on a reward/enjoyment scale) a patient is, the more treatments it will take to get the patient into the positive zone. The amount of the patient’s effort into applying positive coping skills (e.g., mindfulness, meditation, psychotherapy, proper diet, exercise and regulating sleep) will directly correlate with the overall antidepressant response. Once the patient is clearly in the positive zone, based on their self-rated scores and physician assessment, the maintenance phase will begin.

Chronic (maintenance) phase begins after the acute (stabilization) phase and may initially be once a week for 2-4 weeks and then transition to every other week. Once the patient is maintaining their benefits, a treatment may be required once every 2-4 weeks for the first 6 months. The physician may alter the maintenance schedule to meet the patient’ s needs, but no more than one treatment per week. The physician may lengthen the treatment schedule based on the patient’s ability to maintain their positive coping skills and engage in psychotherapy regularly (weekly is preferrable). The physician may schedule a treatment off the normal schedule if the patient is anticipating a significant stressor or group of stressors.

Treatment regimens for the acute phase are as shown below in Tables la and lb.

Table la

Table lb

Dose:

Intranasal Oxytocin will be given primarily before the second medication regardless of whether the second medication is intravenous or inhalational. The oxytocin may be administered intravenously prior to or after the second medication. The dose of oxytocin will be: 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).

Intravenous (IV) Ketamine will be administered initially at a very low dose with the first treatment. 60 mg of ketamine will be diluted in a 60 mL syringe containing normal saline. The 60 ml syringe will be attached to a syringe pump with microtubing extending to the patient’s IV. The initial rate will be set at 10-20 mL/hr depending on the indication for treatment. All subjects with anxiety based disorders should be started at 10 mL/hr. Every 8-10 minutes, the physician may increase the dose a small amount based on the patient’s tolerance to the experience. A typical dose increase will be 5-10 mL/hr every 8 -10 minutes until 50 minutes.

The patient will be given at least 10-15 minutes or longer as needed to recover. Their post treatment vitals should return to within 25% of the patient’s pretreatment vitals. The post treatment vitals (heart rate, blood pressure, pulse oximetry, respiratory rate) should be within 25% of the pretreatment vitals before the patient monitors are removed. The only exception to remove the monitors sooner would be if the patient has to use the restroom before the vitals return to within 25% of the patient’s pretreatment values. The patient should be transported to the restroom via wheelchair and assisted as needed to avoid any potential fall. The patient should be reattached to the patient monitors and meet the proper discharge criteria before they are allowed to leave the clinic. The patient will need to be driven home after the treatment by a responsible adult. The patient will not be allowed to drive, participate in any hazardous activities or sign legal documents for 24 hours after the treatment.

The ketamine dose at every subsequent appointment will either decrease, remain unchanged or be increased from the previous treatment dose. A typical increase would be 5 mg, 10 mg or 15 mg based on the patient’s response from the previous treatment. Once the patient has achieved their optimal benefits, the dose of ketamine should remain the same or be slightly decreased based on the patient’ s comfort with the treatment dose.

Intranasal Ketamine: Initial dose will be either 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to 300 mg.

Second intranasal ketamine dose administered 10-15 minutes later based on patient’s tolerance (physician determined). It will be either 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to 300 mg.

The first intranasal dose of the ketamine treatment will be at a very low introductory dose to determine a patient’s sensitivity to the medication. 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.

After the initial treatment, only 2 doses of intranasal Ketamine will be given separated by 10 -15 minutes as determined by the supervising physician. The oxytocin dose will remain constant throughout the treatment process. The doses will go up with each treatment based on the patient’s overall response and tolerance of the treatment experience.

Once in the maintenance phase, the patient may come in to the treatment clinic for a weekly oxytocin intranasal treatment.

Doses of other medications listed above combined with Oxytocin will be determined by future research studies.

Treatment Example 2

Treatment for adult female subjects ages 18 to 65 years old having been diagnosed with one or more of post-partum depression or peripartum depression.

Timing:

Chronic (maintenance) phase begins after the acute phase and may initially be once a week for 2- 4 weeks and then transition to every other week. Once the patient is maintaining their benefits, a treatment may be required once every 2-4 weeks for the first 6 months. The physician may alter the maintenance schedule to meet the patient’s needs, but no more than one treatment per week. The physician may lengthen the treatment schedule based on the patient’s ability to maintain their positive coping skills and engage in psychotherapy regularly (weekly is preferrable). The physician may schedule a treatment off the normal schedule if the patient is anticipating a significant stressor or group of stressors.

Treatment regimens for the acute phase are as shown below in Tables 1c and Id.

Table 1c

Table Id

Dose:

The patient will be given at 10-15 minutes or longer as needed to recover. Their post treatment vitals should return to within 25% of the patient’s pretreatment vitals. The post treatment vitals (heart rate, blood pressure, pulse oximetry, respiratory rate) should be within 25% of the pretreatment vitals before the patient monitors are removed. The only exception to remove the monitors sooner would be if the patient has to use the restroom before the vitals return to within 25% of the patient’s pretreatment values. The patient should be transported to the restroom via wheelchair and assisted as needed to avoid any potential fall. The patient should be reattached to the patient monitors and meet the proper discharge criteria before they are allowed to leave the clinic. The patient will need to be driven home after the treatment by a responsible adult. The patient will not be allowed to drive, participate in any hazardous activities or sign legal documents for 24 hours after the treatment.

Second intranasal ketamine dose administered 10-15 minutes later based on patient’s tolerance (physician determined). It will be cither 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, up to 300 mg.

Treatment Example 3

Treatment for male or female subjects having been diagnosed with one or more of 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.

Treatment: see Examples 1 and 2.

Route: see Examples 1 and 2.

Timing: see Examples 1 and 2.

For pre-adult subjects (under 18 years, e.g., 16-18 years old) or geriatric (greater than 65 years, e.g., 66-75 years old)

Dose: The initial dose for these disorders will be much smaller. There will be a much slower progression of the dose based on the patient’ s comfort level.

For pre-adult subjects, the treatment will be at lower initial doses of Neuroplasticity Medication than major depressive disorder (MDD).

For geriatric subjects, the treatment will be at lower doses of neuroplasticity agent. Treatment Example 4

The following Example shows treatment results for several patients. Table 2 shows patient information and diagnosis at the start of treatment.

Table 2

Results below were determined using the Patient Health Questionnaire (PHQ-9) and Burn Anxiety Inventory. In the following, the dose for the Burns Anxiety Inventory was the same dose as presented in the PHQ-9 data tables. In the PHQ-9 data in the tables, severity is reported as: EXT or ED (Extremely Difficult), VD (Very Difficult), SD (Somewhat difficult), and ND (Not Difficult). The PHQ- 9 questionnaire was modified only to reflect the shortened time period between treatments in order to assess improvement during those time periods.

Patient 1: Patient has had four different suicide attempts and four involuntary hospitalizations. Patient tried over 15 antidepressants without relief. Patient presented with severe suicidality, depression, and anxiety. Current medications: Mirtazapine 15 mg once a day; propranolol 10 mg as needed; oral contraceptive. The patient entered the positive zone after treatment 3. The patient had never experienced relief so fast. The patient experienced some difficult stressors during the maintenance phase and recovered well. The patient feels very stable.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 2: Patient had been on sertraline 200 mg once a day for 4 years. The patient was able to wean off of it during a stress-free period approx. 1 year before present treatment. With stress, patient’s OCD returned and was worse than previously experienced. The patient restarted sertraline after treatment 4. The patient entered into the positive zone after the treatment 6. Treatments 10-12 were intranasal ketamine. Patient did not go above 100 mg of sertraline and was more stable after last treatment.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 3: Patient had been an active alcoholic since 18 years of age. Patient had been on several antidepressants before without success. Meds: Seroquel 100 mg at night; Klonopin 1 mg at night; Latuda 50 mg once daily. The patient entered the positive zone after treatment 4. The patient then started oxytocin treatment. The patient attributes the addition of the oxytocin for helping to stay sober. The patient continued to stay sober for 18 months. The patient weaned off medications and is only taking 50- 100 mg of Seroquel at night.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 4: The patient couldn’t tolerate any antidepressants (tried Zoloft without success, and had been taking 20 mg of Lexapro for 1 year at the beginning of treatment). The patient entered the positive zone after treatment 5. All treatments were with intranasal ketamine and intramuscular Toradol. It was observed that higher doses were necessary since some of the ketamine dripped down the back of the throat or out the nose. Once stabilized, the patient was doing great emotionally, socially and ended up earning straight A’s by the end of the school year. The patient was able to give a public talk about how ketamine saved his life and how he no longer feels suicidal.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 5: The patient was experiencing severe depression and mild psychoses. Current medication regimen was not helping. Meds: Latuda 120 mg; Seroquel 25mg at night. The patient entered the positive zone after treatment 5. The patient weaned off her Latuda and Seroquel after treatments and has been maintaining a job and romantic relationship.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 6: Patient was just taking supplements and did not want to take any oral anti-depressant medications. The patient entered the positive zone after treatment 2. Patient hasn’t needed any since last treatment. PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 10: This patient had PTSD starting at the age of 17, and struggled off and on with depression and anxiety until experiencing a new traumatic event approx. 1 year prior to treatment. Meds: Lexapro 20 mg once daily; Xanax 0.5 mg as needed. The patients anxiety responded much quicker with oxytocin than what was seen with ketamine treatment alone.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 11: Patient had tried two anti-depressants without any relief. The patient’s current medication regimen was also not helping. Current Meds: Adderall (extended release) 30 mg once daily; Adderall (immediate release) 10 mg up to 3 times a day as needed for concentration and focus; Lexapro 20 mg once daily; trazadonc 50 mg at night; Ncxium as needed and Allcgra as needed. Patient responded well and was in the positive zone after treatment 4. The patient had some significant stressors as she first got into the positive zone. The patient hasn’t needed any treatments since her last treatment. PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 14: Patient did not want to take any oral anti-depressants as they haven’ t helped in the past. Patient got into the positive zone after treatment 3. The patient did great after his last treatment and hasn’t needed anymore.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 15: Patient had chronic pain, depression, and anxiety. Patient on high dose opioids and wanted to wean down on the doses, but the depression and anxiety were too much when weaning. The patient felt his oral anti-depressant medications hadn’t helped in the past. Meds: Fentanyl patch 75 mcg every 2 days; Oxycodone 30 mg tablets taken 3-5 times per day as needed. The patient was in the positive zone after treatment 4.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 16: Patient had chronic pain from a devastating car accident which caused a traumatic brain injury and an L5 burst fracture. The patient had struggled with depression since 12 years old. The patient didn’t have any success with oral anti-depressants and didn’t want to take them. Meds: Spironolactone for acne. The patient was in the positive zone after treatment 2. The patient had difficulty adjusting to the positive zone but is doing much better with pain, depression and anxiety.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 18: The patient got out of the mental health ward the same day as the first treatment. The patient had been doing self-harm by cutting. This patient was deep in the negative zone and didn’t want to be on anti-depressants. Meds: none. The patient entered into the positive zone after treatment 4. The patient started Buspar 10 mg twice daily and Lexapro 10 mg once daily after treatment 2 as wasn’t sure if they could continue with the ketamine treatments. The patient was very happy with his results and he felt more resilient despite his significant stressors.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Patient 19: This patient had been struggling with depression and anxiety since teenage years.

The patient had tried anti-depressants over the years with not much relief. Current Meds: Celexa 60 mg once daily; Armor thyroid 90 mg once daily. The patient entered the positive zone after treatment 3. The patient has continued to do well, and planning to wean off Celexa.

PHQ-9 DEPRESSION DATA

BURNS ANXIETY INVENTORY DATA

Tables 3 and 4 show patient information and percent improvement of symptoms achieved using the methods described herein after treatments 3, 4, 5, and 6. Although it may be that a patient is able to move from the acute “stabilization” phase to the maintenance phase in 4-5 treatments (or 2-3 weeks), it may vary based on the particular patient.

Table 3: PHQ-9

*based on Total Score

ND = No Data

Table 4: Burn Anxiety Inventory

*based on Total Score

ND = No Data

It should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations arc considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

The disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

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 were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

WHAT IS CLAIMED IS:

1. A method for treating one or more disease or disorders selected from anhedonia, severe anxiety, major depressive disorder (MDD) single or recurrent, persistent depressive disorder (cyclothymia), treatment resistant depression (TRD), disruptive mood regulation disorder, bipolar 1 disorder, bipolar 2 disorder, premenstrual dysphoric disorder, schizoaffective disorder, adjustment disorder, complex regional pain syndrome (CRPS) type 1, CRPS type 2, chronic neuropathic pain, chronic pain syndromes, chronic low back pain, fibromyalgia, migraine headaches, chronic neuropathic pain, acute neuropathic pain, irritable bowel syndrome, post-partum depression, peripartum depression, 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, and binge eating disorder, in a subject in need thereof, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, an effective amount of one or more additional agents selected from an omega 3 fatty acid, a drug that curbs production of inflammatory chemicals, statin, steroid, antibiotic (minocycline), a drug used to treat sleep disorders (modafinil), and N-acetyl cysteine, a disease-modifying anti-rheumatic drug (DMARD), a salicylic acid derivate, a para-aminophenol derivative, an acetic acid derivative, a propionic or heteroaryl acetic acid derivative, anthranilic acid (fenemates), a sulfonanilide derivative, a diarylheterocycle (coxibs), an enolic acid derivative (oxicams), a NK3 receptor antagonist, an antibody, antibody fragment, or a biologic agent, colchicine, corticosteroid injections, a topical NSAID (e.g. diclofenac gel), an omega-3 fatty acid, curcumin, resveratrol, boswellia extract, ginger extract, and green tea extract, and optionally an effective amount of an additional anti-inflammatory agent, to a subject in need thereof.

2. The method of claim 1 , wherein the additional agent is acetylsalicylic acid (aspirin), sodium salicylate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, mesalazine/mesalamine, paracetamol/acetaminophen, indomethacin, sulindac, diclofenac, etodolac, ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin, mefenamic acid, niflumic acid, meclofenamic acid, nimesulide, celecoxib, parecoxib, rofecoxib, valdecoxib, piroxicam, tenoxicam, or meloxicam.

3. The method of claim 1, wherein the additional agent is a steroid.

4. The method of claim 3, wherein the steroid is a glucocorticoid.

5. The method of claim 4, wherein the glucocorticoid is prednisone, prednisolone, dexamethasone, betamethasone, or hydrocortisone.

6. The method of claim 1, wherein the disease-modifying anti -rheumatic drug (DMARD) is methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, or cyclosporine.

7. The method of claim 1, wherein the antibody, antibody fragment, or a biologic agent is ustekinumab, adalimumab, infliximab, etanercept, rituximab, abatacept, tocilizumab, or anakinra.

8. The method of any one of claims 1-7, wherein the method further comprises administering a cytokine-inhibitor, poly-unsaturated fatty acid, pioglitazone, minocycline, modafinil, or corticosteroid.

9. The method of any one of claims 1-8, 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, nuedexta (a combination of dextromethorphan and quinidine), deudextromethorphan (AVP-786), axsome (AXS-05), dextromethadone (REL-1017), or zuranolone (SAGE-217).

10. The method of any one of claims 1-9, wherein the disease or disorder is post-partum depression or peripartum depression.

11. The method of claim 10, wherein the neuroplasticity agent is brexanolone or zuranolone (SAGE- 217).

12. The method of claim 1, wherein the disease or disorder is 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.

1 . The method of claim 12, wherein the subject exhibits anhedonia.

14. The method of claim 12 or 13, wherein the subject is from 16-18 years or from 66-75 years.

15. A method for treating anhedonia in a subject, comprising administering an effective amount of oxytocin, an effective amount of a neuroplasticity agent, optionally in combination with an effective amount of one or more additional agents, and optionally an effective amount of an anti-inflammatory agent, to a subject in need thereof.

16. The method of any preceding claim, wherein the method comprises an acute phase and a maintenance phase.

17. The method any preceding claim, wherein the method comprises an acute phase and the acute phase comprises administering a first dose of oxytocin prior to administering the neuroplasticity agent.

18. The method of any preceding claim, wherein the method comprises an acute phase and the acute phase comprises administering a first dose of the neuroplasticity agent prior to administering oxytocin.

19. The method of any preceding claim, wherein the oxytocin is administered intravenously.

20. The method of any preceding claim, wherein the oxytocin is administered intranasally.

21. The method of any preceding claim, wherein the neuroplasticity agent is administered intravenously.

22. The method of any preceding claim, wherein the neuroplasticity agent is administered intranasally.

23. The method of any preceding claim, wherein the dose of oxytocin is 0.1 to 100 International Units (IU).

24. The method of any one claims 1-22, wherein the dose of oxytocin is 0.1 to 75 International Units

(IU).

25. The method of any preceding claim, the method comprises an acute phase and the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine.

26. The method of any preceding claim, the method comprises an acute phase and the acute phase comprises administering racemic ketamine, esketamine, or (R)-kctaminc intravenously at a total dose of about 60 mg, optionally over 50 minutes.

27. The method of any one claims 1-25, the method comprises an acute phase and the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine intravenously at a total dose of about 40 mg, optionally over 50 minutes.

28. The method of any one claims 1-25, the method comprises an acute phase and the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine intranasally at an initial dose of 0.1 to 300 mg, optionally with a second intranasal ketamine dose administered 10-15 minutes later at a dose of 0.1 to 300 mg.

29. The method of any one claims 1-25, the method comprises an acute phase and the acute phase comprises administering racemic ketamine, esketamine, or (R)-ketamine intranasally at an initial dose of 0.1 to 200 mg, optionally with a second intranasal ketamine dose administered 10-15 minutes later at a dose of 0.1 to 200 mg.

30. The method of any preceding claim, the method comprises an acute phase and the acute phase is 2 treatments per week for 3-5 weeks.

31. The method of any preceding claim, the method comprises a maintenance phase and the maintenance phase comprises one treatment per week for 2-4 weeks, then one treatment every other week, or one treatment every 2-4 weeks for the first 6 months.

32. The method of any preceding claim, the method comprises a maintenance phase and each treatment dose of the maintenance phase decreases, remain unchanged, or increases from the previous treatment.

33. The method of any preceding claim, the method comprises a maintenance phase and each treatment dose of the maintenance phase increases 5 mg, 10 mg, or 15 mg based on the subject’s response from the previous treatment.

34. The method of any preceding claim, wherein the method further comprises administering an additional anti-inflammatory agent.

35. The method of any preceding claim, wherein the method further comprises administering a nonsteroidal anti-inflammatory drug (NS AID).

36. The method of any preceding claim, wherein the method further comprises administering ketorolac.