Dextromethadone as a disease-modifying treatment for neuropsychiatric disorders and diseases

Abstract

Methods and compositions for modifying the course and severity of a neuropsychiatric disorder, comprising administering to a subject suffering from the neuropsychiatric disorder a composition comprising a substance selected from dextromethadone, dextromethadone metabolites, d-methadol, d-alpha-cetylmethadol, d-alpha-normethadol, l-alpha-normethadol, and pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of the filing dates of U.S. Patent Application No. 63 / 031,785 filed on 29 May 2020, U.S. Patent Application No. 63 / 010,391 filed on 15 April 2020, U.S. Patent Application No. 62 / 993,188 filed on 23 March 2020, U.S. Patent Application No. 62 / 963,874 filed on 21 January 2020, and U.S. Patent Application No. 62 / 956,839 filed on 3 January 2020, all of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to the treatment of various disorders and diseases, and to compounds and / or compositions for such treatment. [Background technology]

[0003] This section is intended to introduce to the reader various aspects of the field that may be related to the various aspects of the invention described and / or claimed below. This discussion is intended to help provide the reader with background information to facilitate a better understanding of the various aspects of the invention. Therefore, it should be understood that these descriptions should be read in this regard and not as endorsements of the prior art.

[0004] Many neuropsychiatric disorders are serious clinical conditions that negatively impact various aspects of an individual's life. For example, major depressive disorder (MDD) is a serious clinical condition that affects mood, behavior, cognition, motivation, energy, socialization and work capacity, as well as basic functions such as appetite, sexual activity and sleep. It is generally characterized by a depressed mood lasting at least two weeks, present in most situations. This is often accompanied by low self-esteem, decreased interest in normally enjoyable activities, including eating and sexual activity, reduced cognitive function, low energy, and pain and / or distress without apparent cause. MDD can negatively impact an individual's family and social life, professional life and / or education, as well as sleep, eating, sexual habits and overall health, and can lead to suicide.

[0005] MDD is thought to be caused by a combination of genetic and environmental factors. Risk factors include a family history of the condition, major life changes, health problems, certain medical conditions, and certain drug and substance abuse. A significant risk is thought to be related to genetics. Diagnosis of MDD is based on an individual's reported experience and examination by a trained healthcare provider. Examination may be performed to rule out health conditions that may cause similar symptoms. MDD is more severe and longer-lasting than depression (depressed mood) alone, which is a feeling of sadness or sadness that can be self-contained and temporary, generally does not affect cognitive function and energy levels, and does not substantially impair the ability to work or socialize.

[0006] The most widely used criteria for diagnosing depressive disorders and conditions are found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association, which is typically used in the United States and non-Western countries, and in the International Statistical Classification of Diseases and Related Health Problems (ICD-10) of the World Health Organization, which is typically used in Western countries.

[0007] MDD is classified as a mood disorder in the DSM-5. Diagnosis is determined by the presence of a single or recurrent major depressive episode. Further modifying phrases are used to classify both the episode itself and the course of the disorder. The ICD-10 system lists similar criteria for diagnosing depressive episodes (mild, moderate, or severe).

[0008] More specifically, to be diagnosed with MDD according to the DSM-5, a person must have five or more of the following symptoms, and experience them at least once a day for a period of more than two weeks: (1) feeling sad or irritable for most of the day, almost every day; (2) having less interest in most activities that were previously enjoyed; (3) sudden weight gain or loss, or changes in appetite; (4) difficulty falling asleep or wanting to sleep more than usual; (5) feeling restless; (6) unusual fatigue or loss of energy; (7) often feeling worthless or guilty about things that would not normally cause the person to feel that way; (8) difficulty concentrating, thinking or making judgments; and (9) thoughts of self-injury or suicide.

[0009] One novel feature of MDD and other neuropsychiatric disorders is the dysfunction of the molecular function of certain brain cells (e.g., neurons and astrocytes) that results in the dysfunction of neural circuits (i.e., multiple neurons interconnected by synapses, e.g., cells that are part of the endorphin system). In light of this application, this neural circuit dysfunction is particularly characterized by, or may be caused by, dysfunction of ion channels [e.g., ion channels essential for N-methyl-D-aspartate receptors (NMDARs)].

[0010] Patients with MDD are typically treated with standard antidepressants and / or counseling, and the first step taken by their primary care physician is often the prescription of antidepressants. Such medications include selective serotonin reuptake inhibitors (SSRIs) [including well-known drugs such as fluoxetine (Prozac) and citalopram (Celexa)], serotonin and norepinephrine reuptake inhibitors (SNRIs), and bupropion. Serotonin is a brain chemical thought to be important for mood regulation. Patients with MDD appear to have low levels of serotonin. Therefore, increasing the amount of available serotonin is widely considered beneficial in the treatment of these patients.

[0011] The precise mechanisms of action of SSRIs and SNRIs are unknown, but the hypothesized mechanism involves the inhibition of inward transporters, accompanied by an increase in selected neurotransmitters (serotonin and / or norepinephrine) at the synaptic junction. The acute and chronic efficacy of these drugs is highly unpredictable. Similar unpredictability in response is common to atypical antidepressants that act on different receptors and / or pathways. In MDD, the effect size of these treatments tends to be low (around 0.3), and in the case of SSRIs (the current standard treatment for MDD), the therapeutic effect, if present (more than 50% of patients do not respond to first-line antidepressants), is usually delayed by 4-8 weeks and generally requires sustained treatment for several months. In summary, attempts to directly modulate neurotransmitter receptors and pathways in MDD, as well as in chronic disorders such as chronic pain disorders, anxiety disorders, and other neuropsychiatric disorders (including schizophrenia), have been unsuccessful, current treatments have been largely unsuccessful, and are based on symptomatic approaches (drugs that produce an increase in serotonin, a chemical thought to control mood).

[0012] For example, some mental symptoms may be temporarily improved by modulating a neurotransmitter pathway selected for a specific symptom(s) (e.g., modulation of the serotonin pathway by SSRI drugs for depression), but this modulation may also interfere with the function of other neurons in other circuits or areas of the brain (or even other tissues, e.g., extra-CNS tissue) that function at least partially on the same neurotransmitter pathway but could not have been dysfunctional. In addition, acute pharmacologically induced changes in neurotransmitter concentrations in the synaptic cleft may trigger compensatory biofeedback mechanisms with unpredictable long-term consequences. Thus, these currently used drugs, especially when used chronically, can lead to poor and unpredictable long-term outcomes due to molecular feedback mechanisms. Due to the non-selectivity in these mechanisms of action, some neurotransmitter pathway modulators (e.g., SSRIs) may also have effects on extra-neuronal pathways, leading to further side effects, such as sexual dysfunction and metabolic side effects, such as weight gain, impaired glucose tolerance, diabetes, and lipid metabolism dysfunction.

[0013] Furthermore, because there are numerous different endogenous neurotransmitter / receptor systems, manipulating one neurotransmitter system (or several neurotransmitter systems) may modulate the function of a dysfunctional circuit in a way that does not (or is unlikely to) act on the primary cause of the dysfunction in that circuit (e.g., hyperactivity of NMDARs), while improving the symptoms of the selected target. Thus, such drugs are unlikely to restore physiological cellular and circuit function. As a result, dysfunctional cells that induced and maintained the impairment will remain dysfunctional despite (and often for these reasons) pharmacologically induced changes in the surrounding levels of neurotransmitters. Fluoxetine and other drugs classified as SSRIs for MDD are examples of such neurotransmitter pathway modulators for the serotonin / 5-HT receptor system. In clinical trials, they typically showed weak effect sizes, as well as delayed, unpredictable, and often non-sustaining efficacy.

[0014] Furthermore, when discontinuing SSRIs, patients may experience withdrawal symptoms similar to those that occur with most drugs affecting neurotransmitters and these pathways. Abrupt discontinuation of symptomatic medication can even lead to symptom exacerbation (worsening of symptoms compared to baseline before treatment). In some cases, exacerbation may occur even when the symptomatic medication is continued rather than discontinued, after a certain period of time (for example, with dopamine agonists).

[0015] Despite the well-known shortcomings of current pharmacotherapy, clinicians continue to use these drugs because there are virtually no effective alternatives (if any) to manage insufficient responses to antidepressant therapy. Furthermore, to date, our understanding of the molecular mechanisms underlying MDD and related neuropsychiatric disorders is limited. Therefore, if first-line antidepressants fail to alleviate the symptoms of MDD, clinicians may maximize the dose of the initial standard antidepressant, switch to a different antidepressant, resort to electroconvulsive therapy, or augment treatment with uninsured drugs, even considering all the shortcomings associated with these treatments. While some patients experience symptom improvement with subsequent or augmented treatments, the likelihood of remission decreases with additional treatment steps, and those who receive more treatment steps before becoming asymptomatic are more likely to relapse. The greatest patient benefit is realized when the first or second treatment step is successful, but such success is often not achievable with current treatment methods.

[0016] In addition, the slow onset of action and side effects of currently available treatments contribute to poor patient adherence. To date, the U.S. Food and Drug Administration (FDA) has approved only three drugs as adjuncts to antidepressants for the treatment of MDD. All three are second-generation atypical antipsychotics (aripiprazole, extended-release quetiapine, and brexpiprazole), which carry an increased risk of neuroleptic malignant syndrome, tardive dyskinesia, and metabolic side effects including diabetes, dyslipidemia, and weight gain. Furthermore, the delayed onset of action of standard antidepressants is linked to the risk of suicide.

[0017] A further problem with current methods and compositions for treating MDD (and other disorders) is that certain individuals may be resistant to treatment. Treatment-resistant depression (TRD) is a term used in psychiatry to describe a condition affecting individuals who have MDD (or other similar disorders) and do not adequately respond to a course of appropriate antidepressants within a given timeframe. There are various standard definitions of TRD. For regulatory purposes (FDA), TRD is currently defined as failure to respond to at least two appropriate attempts with standard antidepressants in a current major depressive episode. Inadequate response was traditionally defined as no clinical response at all (e.g., no improvement in depressive symptoms). However, many clinicians consider a response inadequate if an individual does not achieve complete remission of symptoms. Individuals with TRD who do not adequately respond to antidepressant treatment may be referred to as pseudoresistant. Several factors that can cause inadequate treatment include premature discontinuation of treatment, insufficient dosage of medication, patient non-adherence to medication, misdiagnosis, and co-occurring neuropsychiatric disorders. Cases of TRD are sometimes classified based on the medication to which the patient is resistant (e.g., SSRI resistance). In TRD, the clinical benefits and improvements in quality of life achieved by further treatment, such as psychotherapy or the addition of lithium or atypical antipsychotics, are only slightly supported as of 2020.

[0018] Therefore, currently, treatments for disorders such as MDD and TRD (and other disorders similar to MDD, such as persistent depressive disorder, postpartum depressive disorder, and social anxiety disorder) are not optimal. In recent years, treatments (other than those mentioned above) have been proposed to address single symptoms affecting mood (e.g., single symptoms of depression).

[0019] For example, the inventors have previously disclosed that dextromethadone can be used to treat pain and addiction (see U.S. Patent No. 6,008,258) and can be used to treat selected psychological and / or psychiatric symptoms (see U.S. Patent No. 9,468,611), in that selected enantiomers of molecules currently included in the opioid class and their derivatives modulate NMDARs at doses or concentrations that do not have clinically meaningful opioid receptor effects, and these selected enantiomers may be therapeutic for pain and a single psychiatric symptom.

[0020] However, MDD is defined as a disorder that is more complex and severe than a single mental symptom (e.g., a single symptom of depression), and is a pathological entity. As noted above, there is a consensus among experts that a single mental symptom does not define a neuropsychiatric disorder, and that treatment of a single symptom does not translate to an impact on the clinical course of a neuropsychiatric disorder. Therefore, treatment for a single symptom of depression (e.g., as described in U.S. Patent No. 9,468,611) is considered irreducible to the treatment of MDD and has therefore not been used to treat MDD. Furthermore, mood improvements that do not improve the disorder will not affect motivation, cognitive, social and work capacity, or sleep.

[0021] From this perspective, DSM-5 defines neuropsychiatric disorders as "syndromes characterized by clinically significant impairments in an individual's cognition, affective regulation, or behavior, reflecting a dysfunction in underlying psychological, biological, or developmental processes of mental functioning." The final version of ICD-11 (the successor to ICD-10) contains a very similar definition. There is a consensus among experts that a single psychiatric symptom does not define a neuropsychiatric disorder as defined by DSM-5 and ICD-11. A psychiatric symptom may be, for example, a standalone characteristic of an individual rather than a substantial part of a disease or disorder. Furthermore, a psychiatric symptom may be attributable to another primary disorder, such as fatigue in a patient with cancer or anemia, anxiety in a patient with pheochromocytoma, or depressed mood in a patient with hypothyroidism. In addition, treatment of a single symptom is not necessarily expected to affect the course of a neuropsychiatric disorder. Therefore, currently, treatments for a single mental symptom (e.g., treatment for the sole symptom of depression) have not been considered to be conducive to conversion to a neuropsychiatric disorder (e.g., MDD), because such treatments can alleviate the symptom (e.g., the symptom of depression), but are not considered to have a therapeutic effect on the course of a defined neuropsychiatric disorder. Currently, there are no treatments for MDD that have been shown to have a therapeutic effect on the course of MDD.

[0022] As mentioned above, MDD is thought to be caused by a combination of genetic and environmental factors. The genetic + environmental (G+E) paradigm is becoming increasingly complex for neuropsychiatric disorders. To date, more than 100 independent genetic variants have been associated with an increased risk of developing MDD [Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M et al. (March 2019), "Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions," Nature Neuroscience, vol. 22(3): pp. 343-352]. Some of these variants may include genetic abnormalities in ion channels, including NMDARs. MDD is associated with (1) neuronal loss and atrophy in selected brain regions, including the mesial prefrontal cortex (mPFC) and hippocampus [Kempton MJ, Salvador Z, Munafo MR, Geddes JR, Simmons A, Frangou S, Williams SC (2011), "Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder," Archives of General Psychiatry, Vol. 68 (No. 7): pp. 675-690], and (2) changes in neural circuits [Korgaonkar MS, Goldstein-Piekarski AN, Fornito A, Williams LM, "Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder," Mol Psychiatry, November 6, 2019]. Furthermore, MDD is associated with increased cardiovascular risk, cancer, and obesity (Howard et al., 2019). (Cited above) These associated and / or related disorders, laboratory indicators of systemic inflammation, and images suggestive of structural brain changes (neuroatrophy and apoptosis) represent part of a disorder that far exceeds the range of individual symptoms and is unlikely to substantially improve with purely symptomatic treatment. Available treatments, including SSRIs, SNRIs, bupropion, and atypical antipsychotics, have not been shown to affect the course of the disease. SSRIs, SNRIs, bupropion, and atypical antipsychotics show similar effects when administered early or late in the course of the disease, which is characteristic of symptomatic treatment (disease-modifying treatments, on the other hand, which have the potential to favorably alter the course of the disease by modifying its pathological mechanisms, are more effective when administered earlier in the course of the disease).

[0023] Therefore, MDD, TRD, and other neuropsychiatric disorders are not defined solely by the presence of symptoms such as depression, anxiety, fatigue, and mood instability. While symptoms of depression, anxiety, fatigue, and mood instability may be essential for the diagnosis of MDD and TRD, depressed mood alone is not sufficient for the diagnosis of MDD. For this reason, drugs that symptomatically improve depressed mood and have no other effects will not significantly affect the course of MDD, TRD, or other neuropsychiatric disorders. Effective disease-modifying treatments for neuropsychiatric disorders, including MDD and other diseases and disorders, require drugs that have effects beyond the scope of symptomatic treatment of one or more psychiatric symptoms. Such disease-modifying treatments would be highly desirable, but currently, such treatments are unknown. Even esketamine, a drug approved in recent years, has been limited to TRD due to cognitive and other side effects, and its disease-modifying effect has not been demonstrated. [Prior art documents] [Patent Documents]

[0024] [Patent Document 1] U.S. Patent No. 6,008,258 [Patent Document 2] U.S. Patent No. 9,468,611 [Non-patent literature]

[0025] [Non-Patent Document 1] Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, et al. (March 2019), "Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions," Nature Neuroscience, Vol. 22 (No. 3): pp. 343-352. [Non-Patent Document 2] Kempton MJ, Salvador Z, Munafo MR, Geddes JR, Simmons A, Frangou S, Williams SC (2011), "Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder", Archives of General Psychiatry, Vol. 68(7): pp. 675-690. [Non-Patent Document 3] Korgaonkar MS, Goldstein-Piekarski AN, Fornito A, Williams LM, Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder, Mol Psychiatry, November 6, 2019 [Non-Patent Document 4] Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, et al. Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol. 2019;39:226-37 [Non-Patent Document 5] Fogaca MV, Fukumoto K, Franklin T, et al., N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019; Vol. 44 (No. 13): pp. 2230-2238. [Non-Patent Document 6] Milenkovic VM, Stanton EH, Nothdurfter C, Rupprecht R, Wetzel CH, The Role of Chemokines in the Pathophysiology of Major Depressive Disorder, Int J Mol Sci. 2019; vol. 20(9): p. 2283 [Non-Patent Document 7] De Martin S, Vitolo O, Bernstein G, Alimonti A, Traversa S, Inturrisi CE, Manfredi PL, The NMDAR Antagonist Dextromethadone Increases Plasma BDNF Levels in Healthy Volunteers Undergoing a 14-Day In-Patient Phase 1 Study, ACNP 57th Annual Meeting: Poster Session II. ACNP 57th Annual Meeting: Poster Session II. Neuropsychopharmacol. Volume 43, pages 228-382 (2018) [Non-Patent Document 8] Guillemin GJ, Quinolinic acid: neurotoxicity, FEBS J. 2012; vol. 279 (issue 8): p. 1355 [Non-Patent Document 9] Maes M et al., Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci. 2002;71:1837-1848 [Non-Patent Document 10] Capuron L et al., Interferon-alpha-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment, Biol. Psychiatry. 2003, 54:906-914. [Non-Patent Document 11] Raison CLら, CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression, Mol. Psychiatry. 2010, 15 volumes: 393~403 pages [Non-licensed Document 12] Du J, Li XH, Li YJ. Glutamate in peripheral organs: Biology and pharmacology, Eur J Pharmacol. 2016; Volume 784: Pages 42~48 [Non-licensed Document 13] Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis, Neurology. 1992; Volume 42 (No. 1): 43-50 [Non-licensed Document 14] Ramirez LA, Perez-Padilla EA, Garcia-Oscos F, Salgado H, Atzori M, Pineda JC. A new theory of depression based on the serotonin / kynurenine relationship and the hypothalamic-pituitary-adrenal axis, Biomedica. 2018; Volume 38 (No. 3): Pages 437~450. Published on September 1, 2018 [Non-licensed Document 15] Berretta N, Jones RS. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 1996; Volume 75: 339~344 [Non-licensed Document 16] Bannai H, Niwa F, Sherwood MW, Shrivastava AN, Arizono M, Miyamoto A, Sugiura K, Levi S, Triller A, Mikoshiba K. Bidirectional control of synaptic GABAAR clustering by glutamate and calcium. Cell reports. 2015 Dec 29; Vol. 13 (No. 12): pp. 2768~80 [Non-licensed Document 17] Bouvier G, Bidoret C, Casado M, Paoletti P. Presynaptic NMDA receptors: Roles and rules. Neuroscience. 2015; Volume 311: Pages 322~340 [Non-licensed Document 18] Leach K, Sexton PM and Christopoulos A, Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology, Trends Pharmacol. Sci. Volume 28: Pages 382~389, 2007 [Non-licensed Document 19] Kenakin TP, Overview of receptor interaction of agonists and antagonists, Curr. Protoc. Pharmacol. Chapter 4: Unit 4.1, 2008 [Non-licensed Document 20] Kenakin TP, Biased signaling and allosteric machines: new vistas and challenges for drug discovery, Br. J. Pharmacol. Volume 165: Pages 1659~1669, 2012 [Non-licensed Document 21] Paoletti P, Bellone C, and Zhou Q, NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity, and disease, Nat. Rev. Neurosci, Vol. 14: pp. 383-400, 2013. [Non-Patent Document 22] Kotermanski SE, Johnson JW. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci. 2009; Vol. 29 (No. 9): pp. 2774-2779. [Non-Patent Document 23] Sava A, Formaggio E, Carignani C, Andreetta F, Bettini E, Griffante C. NMDA-induced ERK signaling is mediated by NR2B subunit in rat cortical neurons and switches from positive to negative depending on stage of development. Neuropharmacology. 2012; 62(2): 925-932 [Non-Patent Document 24] Kuner T, Schoeffer R. Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels. J Neurosci. 1996; Vol. 16 (No. 11): pp. 3549-3558. [Non-Patent Document 25] Mealing GA, Lanthorn TH, Small DL, et al. Structural modifications to an N-methyl-D-aspartate receptor antagonist result in large differences in trapping block. J Pharmacol Exp Ther. 2001; 297(3): 906-914 [Non-Patent Document 26] Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatry. January 1999; Vol. 14 (No. 1): pp. 3-47. [Non-Patent Document 27] Zott B, Simon MM, Hong W, et al., A vicious cycle of β amyloid-dependent neuronal hyperactivation. Science. 2019; Vol. 365 (No. 6453): pp. 559-565. [Non-Patent Document 28] Pontius, AA, Overwhelming Remembrance of Things Past: Proust Portrays Limbic Kindling by External Stimulus-Literary Genius Can Presage Neurobiological Patterns of Puzzling Behavior. Psychological Reports, Vol. 73 (Issue 2), 1993, pp. 615-621 [Non-Patent Document 29] Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther. 1987; Volume 41 (No. 4): Pages 392~401

Non-licensed Document 30

Non-licensed Document 31

Non-licensed Document 32

Non-licensed Document 33

Non-Patent Document 34

Non-Patent Document 35

Non-Patent Document 36

Non-licensed Document 46

Non-licensed Document 47

Non-licensed Document 48

Non-licensed Document 49

Non-licensed literature 50

Non-licensed Document 51

Non-licensed Document 52

Non-licensed Document 53

Non-licensed Document 54

Non-licensed Document 55

Non-licensed Document 56

Non-licensed Document 61

Non-licensed Document 62

Non-licensed Document 63

Non-licensed Document 64

Non-licensed Document 65

Non-licensed Document 70

Non-licensed Document 71

Non-licensed Document 72

Non-licensed Document 73

Non-licensed Document 103

Non-licensed Document 104

Non-licensed literature 105

Non-licensed Document 106

Non-licensed Document 107

Non-licensed Document 108

[0026] A particular representative aspect of the present invention is described below. It should be understood that these aspects are presented solely to provide the reader with a brief overview of the specific forms the invention may take, and that these aspects are not intended to limit the scope of the invention. In fact, the invention can encompass a variety of aspects that are not expressly described below.

[0027] As described above, current treatments for MDD and other neuropsychiatric disorders are inadequate. The effectiveness of current drug regimens is highly unpredictable, and attempts at direct modulation of neurotransmitter receptors and pathways in MDD, as well as other chronic disorders, including chronic pain disorders, anxiety disorders, and other neuropsychiatric disorders such as schizophrenia, have not been promising. The challenges identified are: (1) current drugs used to target neural circuit dysfunction may induce feedback molecular actions that cause or exacerbate neuropsychiatric symptoms and disorders; (2) these drugs may also interfere with non-dysfunctional neural circuits within the same neurotransmitter pathway; (3) the nonselectivity of the action of current drugs may result in effects on extra-nerve tissues, causing further side effects; (4) current drugs may alter the function of dysfunctional circuits in a way that improves symptoms, but they do not act on the primary cause of the dysfunction; (5) patients may experience withdrawal symptoms upon discontinuation of currently used drugs; and (6) patients may actually experience worsening of symptoms upon discontinuation of currently used drugs.

[0028] Furthermore, as mentioned above, while treatments exist for individual symptoms (e.g., the sole symptoms of depression), such treatments (e.g., compounds and / or compositions for symptomatic treatment) are not considered useful for treating disorders, such as MDD. For example, certain drugs that have a positive effect on the sole symptoms of depression have been shown to have favorable safety, tolerability, and pharmacokinetic profiles (see Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J et al., Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol. 2019; vol. 39: pp. 226-227), there is no teaching or suggestion of the efficacy of such drugs for MDD or any neuropsychiatric disorder, nor is there any teaching or suggestion of their efficacy for MDD without cognitive side effects.

[0029] Further studies have shown that drugs like dextromethadone induce rapid antidepressant effects in animal models of depression-like behavior through mTORC1-mediated synaptic plasticity in the mPFC, similar to ketamine (see, for example, Fogaca MV, Fukumoto K, Franklin T, et al., N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019; Vol. 44 (No. 13): pp. 2230-2238). However, these findings are limited to attempts to explain experimentally induced improvements in depression-like behavior in mouse models. However, these mouse models of depression-like behavior have never been considered convertible to neuropsychiatric disorders like MDD, as they were used to determine the potential for behavioral improvements that would only result in drugs useful for depression as a standalone symptom (which, as mentioned above, is separate from the clinical disorder of MDD, and treatment is not considered convertible between the two), and which could potentially translate to antidepressant effects in humans.

[0030] However, aspects of the present invention reduce and / or eliminate the challenges of MDD and other such disorders using the treatment. Generally, comprehensive aspects of the present invention provide disease-modifying treatments for MDD and other disorders. A “disease-modifying” treatment, or a treatment having the potential to be “disease-modifying,” as used herein, includes a drug treatment that has the potential to favorably alter the course of the disease by modifying its pathological mechanisms. Disease-modifying treatments are therefore potentially curative. In contrast, symptomatic treatments are generally only temporary relief; they alleviate symptoms but do not directly address the molecular causes of the disease.

[0031] In this specification, both the terms “disease” and “disorder” may be used in discussions of novel disease-modifying treatments developed by the inventors. Generally, “disease” has a defined (or better defined) pathophysiology, while “disorder” lacks or is absent a pathophysiological explanation. MDD (and other disorders discussed herein) are defined by those skilled in the art as “disorders” due to the lack of a clear pathophysiological explanation. However, our efforts (disclosed herein) have for the first time revealed the pathophysiology of MDD (generally, an excessive influx of Ca2+ through NMDARs (e.g., persistently active NMDARs containing GluN2C and GluN2D subunits) in neurons that are part of a particular circuit (e.g., the endorphin circuit), and that this excessive influx directly impairs the neural plasticity (e.g., the production of synaptic proteins, e.g., GluN1 subunit and other NMDAR subunits) necessary for forming neural connectivity (e.g., “healthy” emotional memories that can replace pathological emotional memories)). Through the embodiments described herein, the inventors have clarified this pathophysiology, and MDD (and other disorders sharing similar pathophysiology) can now be considered as diseases rather than disorders. Therefore, both terms, “disease” and “disorder,” can be used interchangeably herein when discussing these disorders.

[0032] Therefore, one aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the step of administering a composition to a subject suffering from a neuropsychiatric disorder, wherein the composition contains a substance for treating the disorder (in a manner that exhibits a disease-modifying effect). In this aspect, the substance may be selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The neuropsychiatric disorder to be treated may be selected from (but not limited to) major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment depressive disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder, and overactive bladder disorder.

[0033] Another aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the steps of (1) diagnosing an individual with a neuropsychiatric disorder; (2) developing a course of treatment for the individual's neuropsychiatric disorder; and (3) administering a substance to the individual as at least part of the course of treatment for the individual's neuropsychiatric disorder. In this aspect, the substance can be selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The neuropsychiatric disorders treated may include (but are not limited to) major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement-related depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder, and overactive bladder disorder.

[0034] One embodiment of this aspect of the present invention is a method for treating MDD, comprising the steps of (1) diagnosing an individual with MDD, (2) developing a course of treatment for the individual's MDD, and (3) administering dextromethadone to the individual as at least part of the course of treatment for the individual's MDD.

[0035] Another aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the step of inducing the synthesis and membrane expression of an NMDAR subunit, an AMPAR subunit, or other synaptic protein contributing to neuroplasticity and organizing NMDAR channels in a subject. In this aspect, the subject is suffering from a neuropsychiatric disorder (examples of such neuropsychiatric disorders include major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder and overactive bladder disorder). In this embodiment of the present invention, induction of the synthesis of NMDAR subunits, AMPAR subunits, or other synaptic proteins contributing to neuronal plasticity is carried out by administering to a subject a substance selected from d-methadone, d-methadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof.

[0036] Another aspect of the present invention relates to a method for treating a disease or disorder characterized by ion channel dysfunction, comprising: (1) diagnosing an individual with a disease or disorder characterized by ion channel dysfunction; (2) developing a course of treatment for the individual's disease or disorder, wherein the course of treatment for the disease or disorder involves the restoration of ion channel dysfunction; and (3) administering a substance to the individual as at least part of a course of treatment for the restoration of ion channel dysfunction. The substance used can be selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof.

[0037] Another aspect of the present invention relates to a method for diagnosing a disorder as a disease caused, exacerbated, or maintained by pathologically hyperactive NMDAR channels. The method of this aspect comprises administering a composition to a subject diagnosed with at least one disorder of unknown pathophysiology selected from neurological disorders, neuropsychiatric disorders, ophthalmic disorders, otological disorders, metabolic disorders, osteoporosis, genitourinary disorders, renal dysfunction, infertility, premature ovarian failure, hepatic disorders, immunological disorders, oncological disorders, and cardiovascular disorders. The composition comprises a substance selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. Next, the efficacy of the composition in at least one disorder is determined by measuring a disorder-specific endpoint before and after administration of the composition, and if the subject shows improvement in a specific endpoint, the subject is diagnosed with a disorder caused, exacerbated, or maintained by a pathologically hyperactive NMDAR channel. Since the endpoint may be specific to a particular disorder, measuring the endpoint following administration of the composition makes it possible to determine the specific disorder to be diagnosed.

[0038] Based on the above determination, the disorder is caused by excessive Ca through NMDARs in certain brain cells. 2+ It can be diagnosed as being caused by the influx of [unclear]. The disorders may be selected from neurological disorders, neuropsychiatric disorders, ophthalmic disorders, otological disorders, metabolic disorders, genitourinary disorders including osteoporosis and overactive bladder, renal dysfunction, infertility, premature ovarian failure, hepatic disorders, immunological disorders, oncological disorders, cardiovascular disorders including arrhythmias, heart failure and angina pectoris, inflammatory disorders, and other diseases and disorders that are pathologically induced, maintained, or exacerbated by hyperactive NMDARs.

[0039] In support of these and other aspects of the present invention, the inventors hereby disclose for the first time that dextromethadone has a rapid, robust, sustained, and statistically significant efficacy with a large effect size for MDD (and thus potentially for other neuropsychiatric disorders and TRD) at an effective dose for MDD without cognitive side effects. The discussion and data demonstrating this are shown in the following examples (particularly Example 3), and only the data in the examples of this application enable the conclusion that dextromethadone may have a disease-modifying effect on neuropsychiatric disorders, such as MDD. The inventors also determined that dextromethadone induces this sustained therapeutic response without side effects and without evidence of withdrawal or rebound, which indicates a specific disease-modifying mechanism of action that was not previously recognized.

[0040] In light of our novel discovery and disclosure that dextromethadone has rapid, robust, sustained, and statistically significant efficacy with a large effect size for patients diagnosed with MDD and / or TRD: As described in more detail below, we disclose a double-blind, placebo-controlled, prospective, randomized clinical trial showing that dextromethadone can induce remission of the disease in more than 30% of patients who had not responded to previous antidepressant treatment, compared to a 5% remission rate in patients randomized to placebo (remission of the disease as defined as a MADRS score of ≤10; the MADRS rating scale not only measures depressed mood but also provides assessment criteria for motivation, cognitive ability for concentration, sleep, appetite, social ability and suicide risk). Furthermore, this remission occurred within the first week of treatment, improvement was seen as early as day 2, and statistical significance was achieved by day 4. Notably, remission lasted for at least one week after discontinuation of treatment, and potentially longer in some patients. In Example 3, when measured accurately using a special scale (ad hoc scale), there were no signs or symptoms of withdrawal or rebound.

[0041] As a general rule (as described above), the effects of symptomatic medications for chronic conditions rapidly diminish or abruptly disappear after discontinuation of the drug (especially after abrupt discontinuation), and abrupt discontinuation of symptomatic medication may even result in the disappearance of withdrawal symptoms and signs, or even an exacerbation of symptoms (i.e., worsening of symptoms compared to baseline before treatment). In contrast, we hereby find that the improvement with dextromethadone persists at the completion of the treatment cycle, which is the first to demonstrate the disease-modifying effect of dextromethadone. The fact that dextromethadone-induced remission persists after discontinuation of treatment in patients with MDD indicates that the action of dextromethadone is not purely symptomatic; that is, dextromethadone does not simply produce an improvement in the patient's mood, an effect that can disappear upon discontinuation of the drug (e.g., as occurs with opioid or alcohol use, or even with the use of all currently approved standard antidepressant treatments). Therefore, the persistence of this disease remission suggests that dextromethadone is not merely a symptomatic treatment, but rather has a previously unrecognized disease-modulating mechanism (e.g., a primary effect on the modulation of neuroplasticity that persists beyond discontinuation of treatment).

[0042] This discovery by the inventors creates an embodiment of the present invention that applies to the use of dextromethadone for therapeutic disease-modifying treatment (as opposed to symptomatic treatment) for MDD and other neuropsychiatric disorders. As described above, treatment of a single symptom is not necessarily expected to influence the course of neuropsychiatric disorders. The genetic + environmental (G+E) paradigm is becoming increasingly complex for neuropsychiatric disorders. To date, more than 100 independent genetic variants have been associated with an increased risk of developing MDD (Howard DM et al., 2019). Some of these variants may include genetic abnormalities in ion channels, including NMDARs. Furthermore, MDD and TRD have been shown to be related to inflammatory states [Milenkovic VM, Stanton EH, Nothdurfter C, Rupprecht R, Wetzel CH, The Role of Chemokines in the Pathophysiology of Major Depressive Disorder, Int J Mol Sci. 2019; Vol. 20 (No. 9): p. 2283; Ho et al., 2017]. By modulating inflammation, dextromethadone can influence the course of the disorder (i.e., exhibiting a disease / disorder modifying effect revealed here for the first time by the inventors).

[0043] MDD is associated with neuronal loss and atrophy in selected brain regions, including the median prefrontal cortex (mPFC) and hippocampus (Kempton et al., 2011), and is related to changes in neural circuits (Korgaonkar et al., 2019). Furthermore, MDD is associated with increased cardiovascular risk, cancer, and obesity (Howard et al., 2019). These associated and / or related diseases, laboratory indicators of systemic inflammation, and images suggestive of structural brain changes (neural atrophy and apoptosis) cited above are unlikely to improve with purely symptomatic treatment. As strongly demonstrated by the data presented in the following examples (particularly in the data shown and discussed in Example 3), all of the above, including the associated diseases, immunological abnormalities, and structural CNS defects (both at levels of reversible neural circuit failure or irreversible neuronal apoptosis), can instead be improved or cured with disease-modifying treatments such as dextromethadone.

[0044] Furthermore, using numerous different endogenous neurotransmitter / receptor systems, manipulation of one neurotransmitter system (or even several) can modulate the function of a dysfunctional circuit, and this modulation can improve targeted symptoms, as is hypothesized for some drugs currently used clinically. However, drugs are unlikely to act on the primary cause of the dysfunction in that circuit (e.g., hyperactivity of NMDARs), and therefore are unlikely to restore physiological cellular and circuit function. In other words, dysfunctional cells that have been induced and maintained will remain dysfunctional despite changes in surrounding neurotransmitter levels (this is due to a biofeedback mechanism triggered by increased neurotransmitter levels, and therefore these symptomatic treatments, while initially seemingly beneficial, may ultimately worsen the disease or disorder they were trying to improve). As mentioned above, fluoxetine and other drugs classified as SSRIs for MDD are examples of such neurotransmitter pathway modulators for the serotonin / 5-HT receptor system. In clinical trials, these typically showed weak effect sizes, delayed and often incomplete and / or non-sustained efficacy (furthermore, upon discontinuation of SSRIs, patients may experience withdrawal symptoms similar to those that occur with most drugs that directly affect neurotransmitter concentrations and the pathways modulated by these neurotransmitters). Therefore, as described, these current treatments do not demonstrate disease-modifying effects. However, since no more effective treatments have been discovered or disclosed to date, those skilled in the art continue to use such drugs.

[0045] However, based on the new data disclosed herein, the inventors hereby disclose the potential therapeutic effects of dextromethadone as both an adjunct or monotherapy. In this regard, the inventors disclose that the effects of dextromethadone were very robust in patients with MDD and concomitant antidepressant treatment, which demonstrates the potentially therapeutic effects of dextromethadone not only for CNS abnormalities associated with MDD but also for CNS abnormalities potentially associated with MDD treatment. In other words, excessive Ca in selected neurons with pathologically hyperactive NMDARs 2+ The downregulation exerted by dextromethadone in response to inflow may occur in disorders or diseases where NMDAR hyperactivity is primary or secondary to various triggers, including antidepressant treatment, regardless of the presence or absence of concomitant neuropharmacological treatment.

[0046] In light of the results of our research as shown in the following examples, we disclose that dextromethadone can be used as a disease-modifying treatment for MDD in patients receiving antidepressant treatment (and having an inadequate response to such treatment), and also in relation to excess Ca 2+ The inventors disclose that the selective modulating effect of dextromethadone on influx may be useful for patients who have not yet received treatment that may potentially alter CNS neurotransmitter pathways (dextromethadone as the first disease-modifying agent for neuropsychiatric disorders, i.e., dextromethadone monotherapy). Furthermore, the inventors disclose that dextromethadone and behavioral psychotherapy can be successfully combined in the treatment of MDD and related disorders, for example, in certain patients after the downmodulation of excessive NMDAR activity (i.e., excessive Ca 2+ It is disclosed that psychotherapy is only acceptable after downmodulation of pathologically open NMDAR channels with inflow.

[0047] The inventors' demonstration of the full potential of dextromethadone therapy as an NMDAR ion channel modulator represents a paradigm shift in the molecular understanding of numerous neuropsychiatric disorders and conditions, including MDD, and thus expands the clinical and research facilities for treatment, prevention, and diagnosis to disease-modifying agents that address molecular pathophysiology, beyond the symptomatic psychotropic drugs currently available, for the treatment of various disorders and diseases. Excess Ca in cells (neurons or other cells) that are part of selected CNS circuits (or extra-CNS tissues) 2+ Downregulation of influx would allow cells to recover function and autoregulate the amount of neurotransmitter synthesis (and other synaptic and extrasynaptic proteins) and their membrane expression (including synaptic scaffolds and frameworks) and / or release (NGF, including BDNF, for example).

[0048] Therefore, when neurotransmitters or agonist / antagonist drugs (e.g., dopamine, GABA, drug agonists at opioid receptors) for selected receptors are directly modulated by the drug, this fine-tuning is practically impossible. Drugs that directly target receptors can be very effective for the acute treatment of many symptoms (e.g., opioids for acute pain, benzodiazepines for panic attacks, and dopamine blockers for psychotic events), and their short-term side effects are well understood and accepted, but these same drugs are less effective, their long-term effects are less understood and less predictable, and therefore their use can not only fail to cure the disease but can also be harmful if the treatment is chronic. Chronic treatment with opioids for chronic pain, or with benzodiazepines for chronic disorders with pronounced anxiety (e.g., GAD, PTSD, OCD), or with dopamine blockers for the chronic management of psychotic states, generally results in severe and sometimes irreversible side effects, including exacerbation of the primary disorder. The new data on dextromethadone disclosed herein by the inventors, as well as the newly revealed mechanism of action of dextromethadone, will enable better targeted treatment of disorders such as MDD, MDD-related disorders, other neuropsychiatric disorders, and even extra-CNS disorders.

[0049] These and other advantages of this application will become apparent to those skilled in the art with reference to the following drawings and detailed description.

[0050] The accompanying drawings incorporated herein and forming part thereof illustrate embodiments of the present invention and, together with the general description of the invention set forth above and the detailed description of embodiments set forth below, are useful in illustrating the principles of the present invention. [Brief explanation of the drawing]

[0051] [Figure 1]This graph shows the L-glutamate CRC for cell lines GluN2A, GluN2B, GluN2C, and GluN2C in the presence of 10 μM glycine. Data are reported as mean ± SEM, n=5. [Figure 2A] This graph shows the effect of 100nm L-glutamic acid on GluN2A. [Figure 2B] This graph shows the effect of 100nm L-glutamic acid on GluN2B. [Figure 2C] This graph shows the effect of 100nm L-glutamic acid on GluN2C. [Figure 2D] This graph shows the effect of 100nm L-glutamic acid on GluN2D. [Figure 2E] This graph shows the effect of 100nm L-glutamate on GluN2C (in cells with low expression levels). [Figure 3A] This graph shows the effect of dextromethadone on the L-glutamate concentration response curve (CRC) in receptor types GluN1-GluN2A. [Figure 3B] This graph shows the effect of dextromethadone on L-glutamate CRC in receptor types GluN1-GluN2B. [Figure 3C] This graph shows the effect of dextromethadone on L-glutamate CRC in receptor types GluN1-GluN2C. [Figure 3D] This graph shows the effect of dextromethadone on L-glutamate CRC in receptor types GluN1-GluN2D. [Figure 4A] This graph shows the effect of memantine on L-glutamate CRC in receptor types GluN1-GluN2A. [Figure 4B] This graph shows the effect of memantine on L-glutamate CRC in receptor types GluN1-GluN2B. [Figure 4C]Graph showing the effect of memantine on L-glutamate CRC in the receptor type GluN1-GluN2C. [Figure 4D] Graph showing the effect of memantine on L-glutamate CRC in the receptor type GluN1-GluN2D. [Figure 5A] Graph showing the effect of (±)-ketamine on L-glutamate CRC in the receptor type GluN1-GluN2A. [Figure 5B] Graph showing the effect of (±)-ketamine on L-glutamate CRC in the receptor type GluN1-GluN2B. [Figure 5C] Graph showing the effect of (±)-ketamine on L-glutamate CRC in the receptor type GluN1-GluN2C. [Figure 5D] Graph showing the effect of (±)-ketamine on L-glutamate CRC in the receptor type GluN1-GluN2D. [Figure 6A] Graph showing the effect of (±)-MK801 on L-glutamate CRC in the receptor type GluN1-GluN2A. [Figure 6B] Graph showing the effect of (±)-MK801 on L-glutamate CRC in the receptor type GluN1-GluN2B. [Figure 6C] Graph showing the effect of (±)-MK801 on L-glutamate CRC in the receptor type GluN1-GluN2C. [Figure 6D] Graph showing the effect of (±)-MK801 on L-glutamate CRC in the receptor type GluN1-GluN2D. [Figure 7A] Graph showing the effect of dextromethorphan on L-glutamate CRC in the receptor type GluN1-GluN2A. [Figure 7B] Graph showing the effect of dextromethorphan on L-glutamate CRC in the receptor type GluN1-GluN2B. [Figure 7C] This graph shows the effect of dextromethorphan on L-glutamate CRC in receptor types GluN1-GluN2C. [Figure 7D] This graph shows the effect of dextromethorphan on L-glutamate CRC in receptor types GluN1-GluN2D. [Figure 8A] This graph shows the percentage effect of dextromethadone on 4.6 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8B] This graph shows the percentage effect of dextromethadone on 14 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8C] This graph shows the percentage effect of dextromethadone on 41 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8D] This graph shows the percentage effect of dextromethadone on 123 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8E] This graph shows the percentage effect of dextromethadone on 370 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8F] This graph shows the percentage effect of dextromethadone on 1.1 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8G] This graph shows the percentage effect of dextromethadone on 3.3 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8H]This graph shows the percentage effect of dextromethadone on 10 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8I] This graph shows the percentage effect of dextromethadone on 100 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 8J] This graph shows the percentage effect of dextromethadone on 1 mM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9A] This graph shows the percentage effect of (±)-ketamine on 4.6 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9B] This graph shows the percentage effect of (±)-ketamine on 14nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9C] This graph shows the percentage effect of (±)-ketamine on 41 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9D] This graph shows the percentage effect of (±)-ketamine on 123 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9E] This graph shows the percentage effect of (±)-ketamine on 370 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9F] This graph shows the percentage effect of (±)-ketamine on 1.1 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 9G]Graph showing the % effect of (±)-ketamine on 3.3 μM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 9H] Graph showing the % effect of (±)-ketamine on 10 μM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 9I] Graph showing the % effect of (±)-ketamine on 100 μM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 9J] Graph showing the % effect of (±)-ketamine on 1 mM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10A] Graph showing the % effect of memantine on 14 nM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10B] Graph showing the % effect of memantine on 41 nM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10C] Graph showing the % effect of memantine on 123 nM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10D] Graph showing the % effect of memantine on 370 nM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10E] Graph showing the % effect of memantine on 1.1 μM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10F] Graph showing the % effect of memantine on 3.3 μM L-glutamate at receptor subtypes GluN2A, GluN2B, GluN2C and GluN2D. [Figure 10G] This graph shows the percentage effect of memantine on 10 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 10H] This graph shows the percentage effect of memantine on 100 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 10I] This graph shows the percentage effect of memantine on 1 mM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11A] This graph shows the percentage effect of dextromethorphan on 4.6 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11B] This graph shows the percentage effect of dextromethorphan on 14 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11C] This graph shows the percentage effect of dextromethorphan on 41 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11D] This graph shows the percentage effect of dextromethorphan on 123 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11E] This graph shows the percentage effect of dextromethorphan on 370 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11F] This graph shows the percentage effect of dextromethorphan on 1.1 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11G]This graph shows the percentage effect of dextromethorphan on 3.3 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11H] This graph shows the percentage effect of dextromethorphan on 10 μM L-glutamic acid in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11I] This graph shows the percentage effect of dextromethorphan on 100 μM L-glutamic acid in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 11J] This graph shows the percentage effect of dextromethorphan on 1 mM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12A] This graph shows the percentage effect of (±)-MK801 on 4.6 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12B] This graph shows the percentage effect of (±)-MK801 on 14nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12C] This graph shows the percentage effect of (±)-MK801 on 41 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12D] This graph shows the percentage effect of (±)-MK801 on 123 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12E] This graph shows the percentage effect of (±)-MK801 on 370 nM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12F]This graph shows the percentage effect of (±)-MK801 on 1.1 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12G] This graph shows the percentage effect of (±)-MK801 on 3.3 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12H] This graph shows the percentage effect of (±)-MK801 on 10 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12I] This graph shows the percentage effect of (±)-MK801 on 100 μM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 12J] This graph shows the percentage effect of (±)-MK801 on 1 mM L-glutamate in receptor subtypes GluN2A, GluN2B, GluN2C, and GluN2D. [Figure 13A] This image shows the expression of the NMDAR1 subunit in ARPE-19 cells. [Figure 13B] This image shows the expression of the NMDAR2A subunit in ARPE-19 cells. [Figure 13C] This image shows the expression of the NMDAR2B subunit in ARPE-19 cells. [Figure 14] This graph shows the cell viability of ARPE-19 cells after treatment with the NMDAR agonist L-glutamate alone (10 mM L-Glu) or in combination with dextromethadone. ***P<0.001 compared to vehicle-treated control cells (one-way ANOVA, followed by Tukey post-hoc test). [Figure 15A] This graph shows the protein expression of the NMDAR1 subunit (control = untreated cells, acute = 24-hour treatment, chronic = 6-day treatment). Data are expressed as mean ± SEM. [Figure 15B]This graph shows the protein expression of the NMDAR2A subunit (control = untreated cells, acute = 24-hour treatment, chronic = 6-day treatment). The data is expressed as mean ± SEM. [Figure 15C] This graph shows the protein expression of the NMDAR2B subunit (control = untreated cells, acute = 24-hour treatment, chronic = 6-day treatment). The data is expressed as mean ± SEM. [Figure 16] This graph shows hypothetical values ​​for the NR1 subunit at various glutamate concentrations. [Figure 17] This is a schematic diagram showing patient screening and administration schedule in a Phase 2 study of two doses of dextromethadone in patients with MDD. [Figure 18] Table of adverse events that occurred during treatment - This represents the overall safety population. [Figure 19A] Figure 19B, along with this figure, shows a table of adverse events that occurred under treatment, categorized by system organ class, basic term, and safety population. [Figure 19B] This figure, along with Figure 19A, shows a table of adverse events that occurred under treatment, categorized by organ system, basic terminology, and safety population. [Figure 20] This table lists particularly noteworthy adverse events (AESIs) categorized by organ system, basic terminology, and safety group. [Figure 21] This is a table of clinician administered dissociative states scale scores. [Figure 22] This graph shows the plasma concentrations of dextromethadone at different dose levels (25 mg and 50 mg) on ​​day 1. [Figure 23] This graph shows the trough plasma concentration levels of dextromethadone at different dose levels (25 mg and 50 mg). [Figure 24]This graph shows the MADRS scores in the treatment group of the Phase 2 study, which demonstrated a statistically significant difference compared to placebo from day 4 to day 14. [Figure 25] This graph shows the percentage of patients with MADRS scores less than 10, indicating remission. [Figure 26] This graph shows the percentage of respondents who experienced a MADRS reduction of >50% from baseline. [Figure 27A] This graph shows the effect of 10 μM gentamicin on 0.04 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2A. [Figure 27B] This graph shows the effect of 10 μM gentamicin on 0.04 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDARs containing GluN1 and GluN2B. [Figure 27C] This graph shows the effect of 10 μM gentamicin on 0.04 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2C. [Figure 27D] This graph shows the effect of 10 μM gentamicin on 0.04 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2D. [Figure 28A] This graph shows the effect of 10 μM gentamicin on 0.2 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDARs containing GluN1 and GluN2A. [Figure 28B] This graph shows the effect of 10 μM gentamicin on 0.2 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDARs containing GluN1 and GluN2B. [Figure 28C] This graph shows the effect of 10 μM gentamicin on 0.2 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2C. [Figure 28D]This graph shows the effect of 10 μM gentamicin on 0.2 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2D. [Figure 29A] This graph shows the effect of 10 μM gentamicin on 10 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDARs containing GluN1 and GluN2A. [Figure 29B] This graph shows the effect of 10 μM gentamicin on 10 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDARs containing GluN1 and GluN2B. [Figure 29C] This graph shows the effect of 10 μM gentamicin on 10 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2C. [Figure 29D] This graph shows the effect of 10 μM gentamicin on 10 μM L-glutamic acid in cell lines expressing dihetomer recombinant human NMDAR containing GluN1 and GluN2D. [Figure 30] This graph shows the quinolinic acid CRC plots for each of the four NMDA receptor subtypes (GluN2A, GluN2B, GluN2C, and GluN2D). [Figure 31] This graph shows gentamicin CRC plots for each of the four NMDA receptor subtypes (GluN2A, GluN2B, GluN2C, and GluN2D). [Figure 32A] This graph shows the effects of 100 μM to 1,000 μM quinolinic acid and quinolinic acid with 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 32B] This graph shows the effects of 100 μM to 1,000 μM quinolinic acid and quinolinic acid with 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 32C]This graph shows the effects of 100 μM to 1,000 μM quinolinic acid and quinolinic acid with 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 32D] This graph shows the effects of 100 μM to 1,000 μM quinolinic acid and quinolinic acid with 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 33A] This graph shows the effects of 40 nM L-glutamic acid and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 33B] This graph shows the effects of 40 nM L-glutamic acid and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 33C] This graph shows the effects of 40 nM L-glutamic acid and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 33D] This graph shows the effects of 40 nM L-glutamic acid and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 34A] This graph shows the effects of 40 nM L-glutamic acid and L-glutamine with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 34B] This graph shows the effects of 40 nM L-glutamic acid and L-glutamine with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 34C]This graph shows the effects of 40 nM L-glutamic acid and L-glutamine with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 34D] This graph shows the effects of 40 nM L-glutamic acid and L-glutamine with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 35A] This graph shows the effects of 200 nM L-glutamic acid, and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 35B] This graph shows the effects of 200 nM L-glutamic acid, and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 35C] This graph shows the effects of 200 nM L-glutamic acid, and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 35D] This graph shows the effects of 200 nM L-glutamic acid, and L-glutamic acid with 100 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 36A] This graph shows the effects of 200 nM L-glutamic acid and L-glutamic acid with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 36B] This graph shows the effects of 200 nM L-glutamic acid and L-glutamic acid with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 36C] This graph shows the effects of 200 nM L-glutamic acid and L-glutamic acid with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 36D] This graph shows the effects of 200 nM L-glutamic acid and L-glutamic acid with 1,000 μM quinolinic acid and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 37A] This graph shows the effects of 1,000 μM quinolinic acid and quinolinic acid with 10 g / ml gentamicin and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2A. [Figure 37B] This graph shows the effects of 1,000 μM quinolinic acid and quinolinic acid with 10 g / ml gentamicin and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2B. [Figure 37C] This graph shows the effects of 1,000 μM quinolinic acid and quinolinic acid with 10 g / ml gentamicin and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2C. [Figure 37D] This graph shows the effects of 1,000 μM quinolinic acid and quinolinic acid with 10 g / ml gentamicin and / or 10 μM dextromethadone added, in the presence of 10 μM glycine using GluN2D. [Figure 38A] Figures 38A-D are scattered dot plots of MDARS CFB in patients treated with placebo or 25 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38B]Figures 38A-D are scattered dot plots of MDARS CFB in patients treated with placebo or 25 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38C] Figures 38A-D are scattered dot plots of MDARS CFB in patients treated with placebo or 25 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38D] Figures 38A-D are scattered dot plots of MDARS CFB in patients treated with placebo or 25 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38E] Figures 38E-H are scattered dot plots of MDARS CFB in patients treated with placebo or 50 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38F] Figures 38E-H are scattered dot plots of MDARS CFB in patients treated with placebo or 50 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38G] Figures 38E-H are scattered dot plots of MDARS CFB in patients treated with placebo or 50 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 38H] Figures 38E-H are scattered dot plots of MDARS CFB in patients treated with placebo or 50 mg of dextromethadone (REL-1017) on days 7 and 14 (horizontal bars indicate the median). [Figure 39] This chart shows the protocol diagram for applying test items. [Figure 40] This graph shows the effect of test items on L-glutamate / glycine-induced currents in hGluN1 / hGluN2C NMDAR. [Figure 41] This figure shows sample currents recorded in hGluN1 / hGluN2C-CHO cells, representing representative current traces recorded from two different cell types treated with 10 / 10 μM L-glutamic acid / glycine in the absence or presence of 10 μM dextromethadone (left) or 1 μM (±)-ketamine (right). [Figure 42] This figure includes graphs showing sample traces of onset and offset kinetics experiments for test parameters in cells treated with 10 μM dextromethadone (left) or 1 μM (±)-ketamine (right). [Figure 43] The traces represent the % current recorded with 10 μM dextromethadone (center line; gray shading), 10 μM (±)-ketamine (bottom line; black shading), and 1 μM (±)-ketamine (top line; light gray shading), while the inner black line is a graph showing a summary of the onset dynamics experiment of the test item, which is a relative fit. [Figure 44] This graph shows a comparison of tauons from the 10 μM dextromethadone (left column) and 1 μM (±)-ketamine (right column) experiments in Example 6 Part I. [Figure 45] The traces represent the % current recorded with 10 μM dextromethadone (gray shading), 1 μM (±)-ketamine (black shading), and 10 μM (±)-ketamine (light gray shading), while the black lines inside represent a graph summarizing the offset dynamics experiment of the test items, which is relative fitting. [Figure 46] This graph shows a comparison of the tauoff values ​​for experiments using 10 μM dextromethadone (left column) and 1 μM (±)-ketamine (right column). [Figure 47]This graph demonstrates that intracellular dextromethadone did not modify the current induced by 10 / 10 μM L-glutamate / glycine. [Figure 48] This graph demonstrates that intracellular dextromethadone did not increase the electrical current blockage caused by extracellular dextromethadone. [Figure 49] This chart shows the protocol diagram for applying test items. [Figure 50] This chart shows the effect of test item sample tracing in trapping assays. [Figure 51A] This graph shows the blockade caused by 10 μM dextromethadone (left column in 51A-C) or 1 μM (±)-ketamine (right column in 51A-C) (Figure 51A). Values ​​are reported as mean ± sem (n=13 for dextromethadone and n=11 for (±)-ketamine). An unpaired t-test was performed. [Figure 51B] This graph (Figure 51B) shows the residual block (residual block) caused by 10 μM dextromethadone (left column in 51A-C) or 1 μM (±)-ketamine (right column in 51A-C). Values ​​are reported as mean ± sem (n=13 for dextromethadone and n=11 for (±)-ketamine). An unpaired t-test was performed. [Figure 51C] This graph (Figure 51C) shows the block trapped by 10 μM dextromethadone (left column in 51A-C) or 1 μM (±)-ketamine (right column in 51A-C). Values ​​are reported as mean ± sem (n=13 for dextromethadone and n=11 for (±)-ketamine). An unpaired t-test was performed. [Figure 52A] This graph shows the gene expression of the inflammation-related cytokine [IL-6 (Figure 52A)] as measured by qRT-PCR in rat livers fed a standard diet, a Western-style diet, and a Western-style diet + d-methadone. **p<0.01, ***p<0.001, and ****p<0.0001, one-way ANOVA followed by Tukey's post-hoc test. [Figure 52B] This graph shows the gene expression of the inflammation-related cytokine [IL-10 (Figure 52B)] as measured by qRT-PCR in rat livers fed a standard diet, a Western-style diet, and a Western-style diet + d-methadone. **p<0.01, ***p<0.001, and ****p<0.0001, one-way ANOVA followed by Tukey's post-hoc test. [Figure 52C] This graph shows the gene expression of the inflammation-related cytokine [CCL2 (Figure 52C)] as measured by qRT-PCR in rat livers fed a standard diet, a Western-style diet, and a Western-style diet + d-methadone. **p<0.01, ***p<0.001, and ****p<0.0001, one-way ANOVA followed by Tukey's post-hoc test. [Figure 53A-C] These are photographs resulting from histological analysis of liver tissue by hematoxylin-eosin staining of paraffin-embedded liver sections, demonstrating that rats fed a standard diet exhibited normal liver structure (Figure 53A), while lipid accumulation causing typical swelling of hepatic steatosis was observed in rats fed a Western diet (Figure 53B, arrow). However, a reduction in steatosis can be observed in rats treated with d-methadone (Figure 53C). Photographs are 10× magnification. [Figure 54A-B] This graph shows the expression levels of two genes [GPAT4 (Figure 54A) and SREPB2 (Figure 54B)] involved in lipid metabolism, demonstrating that the expression of both genes significantly increased with the administration of a Western-style diet, and that d-methadone treatment was able to cause a significant decrease in their expression. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001, one-way ANOVA followed by Tukey's post-hoc test. [Modes for carrying out the invention]

[0052] One or more specific embodiments of the present invention are described below. Not all features of the actual embodiments are described herein in order to provide a concise understanding of these embodiments. It should be recognized that in the development of any such actual embodiment, as in an engineering or design project, numerous embodiment-specific decisions must be made, such as compliance with the developer's specific goals, e.g., system-related and business-related constraints, which may vary from embodiment to embodiment. Furthermore, it should be recognized that while such development efforts may be complex and time-consuming, they will nevertheless be routine design, manufacturing, and production work for those skilled in the art who benefit from this disclosure.

[0053] As used herein, the terms dextromethadone; esmethadone; REL-1017; S-methadone; d-methadone; and (+)-methadone define the same chemical molecule and are interchangeable.

[0054] When used herein, “disease-modifying” treatments, or treatments with “disease-modifying” potential, include drug treatments that have the potential to favorably alter the course of the disease by modifying the pathological molecular mechanisms. Disease-modifying treatments are therefore potentially curative. In contrast, symptomatic treatments generally provide only temporary relief; they alleviate symptoms but do not address the molecular causes of the disease.

[0055] In the case of dextromethadone and MDD, in at least a subset of patients, MDD is caused by excess Ca mediated by NMDARs in certain CNS cells, such as neurons or astrocytes, which are part of the endorphin pathway. 2+ The inventors hypothesize that this is caused by influx. 2+Influx activates intracellular downstream signals that disrupt the production of various synaptic proteins. The unavailability of these synaptic proteins interferes with the formation of neural connections (e.g., those necessary for the formation of emotional memories) in humans with MDD, causing the depressive phenotype. This excessive Ca 2+ Invasion preferentially occurs through NMDAR channels containing NR2c and NR2D subunits (persistent and pathologically hyperexcitable NMDARs containing GluN2C and GluN2D subunits) during the resting membrane potential.

[0056] Dextromethorphan, as disclosed by the inventors, has a positive charge similar to that of Mg in its voltage-dependent NMDAR channel blockade, inserts itself into the pore of the NMDAR (similarly to Mg 2+ ), and downregulates excessive Ca 2+ influx. A decrease in previous excessive Ca 2+ influx to physiological amounts activates downstream signaling that results in the production of an appropriate amount of synaptic proteins for constructing new "healthy" emotional memories in selected brain circuits. Thus, MDD is restored through a healing molecular mechanism, which is not by simply directly acting on opioid receptors or even serotonin receptors, as previously hypothesized for most drugs with effects on the individual symptoms of depression, to relieve symptoms. 2+

[0057] Therefore, dextromethorphan reduces excessive Ca 2+The disorders caused by this are potentially curative and therefore disease-modifying. In the case of MDD, the inventors disclose the involvement of the endorphin circuit and that the opioid affinity of dextromethadone can transport the molecule toward opioid receptors (dual receptors, heteroreceptors) that are structurally associated with NMDARs and expressed by neurons that are part of the endorphin circuit. The binding to these opioid receptors disclosed by the inventors does not produce the typical opioid effect as has been thought to date by those skilled in the art. This absence of the typical opioid effect at previously unknown effective doses of MDD relates to the structural association of these opioid receptors with NMDARs, as detailed in the following examples.

[0058] As used herein, “memory” includes cognitive memory, affective memory, social memory, and motor memory. The terms “memory,” “learning,” “(LTP)+(LTD),” “neuroplasticity” (“spine expansion” + “spine formation” + “synaptic strengthening” + “neurite growth” + “synaptic pruning”) and “connectome” may be used interchangeably herein. Personality and self-awareness are forms of memory. MDD and related disorders can be considered signs of pathological affective memory.

[0059] As used herein, “synaptic framework” may include all elements present in the synapse of a neuron, including all receptors, including excitatory and inhibitory receptors, including ion channel type and metabomodulatory receptors; synaptic vesicles in the presynaptic neuron; all elements of the postsynaptic thickening; and synaptic cleft molecules, including adhesion proteins.

[0060] As used herein, “NMDAR framework” may include all elements of the glutamateregic system, including the relative and absolute densities and locations of NMDAR subtypes. This includes the framework of synaptic “hotspots” (regions on the membrane of glutamate-receiving cells with a diameter of 100-200 nanomoles, closest to the glutamate-releasing region of glutamate-releasing cells). NMDAR subtypes may include triheteromers (e.g., NR1-2A-2B) containing the NR1-2A-D diheteromer and NR1-NR2A-D, and triheteromers NR1-2A-D-3AB (e.g., NR1-2D-3A or NR1-NR3A-NR2C) and diheteromers NR1-NR3A-B. NMDAR membrane locations may include synaptic (presynaptic and postsynaptic), perisynaptic, extrasynaptic, and non-neuronal membranes on, for example, astrocytes or extra-CNS cell populations. The location can refer to a specific region in the brain and / or within a specific neural circuit, including a microcircuit and / or a specific receptor system (e.g., the endorphin system). In some embodiments, the NMDAR framework is intended to include other glutamate receptors (e.g., AMPAR and kainate receptors and metabotropic NMDARs).

[0061] As used herein, “positive allosteric modulator (PAM)” and “negative allosteric modulator (NAM)” refer to endogenous and exogenous ions and molecules (including endogenous and exogenous toxins, peptides, steroids (including hormones)), as well as drugs and physical and chemical stimuli, that are capable of influencing the opening of ion channels, particularly including the opening and closing of NMDARs. Gentamicin is included among the allosteric modulators of NMDARs. PAMs and NAMs can be non-competitive when they bind in close proximity to the agonist site, but not to the agonist site. They can also be non-competitive when they bind to sites distant from the agonist site, as in the case of dextromethadone and other channel pore blockers described herein.

[0062] As used herein, “agonist substance” refers to endogenous and exogenous molecules capable of influencing the opening of ion channels, including the opening and closing of NMDARs, by binding to the agonist site (including the NMDA site) of an NMDAR. Such molecules include toxins and drugs, as well as endogenous substances such as quinolinic acid.

[0063] As used herein, “epigenetic code” refers to precisely regulated Ca via NMDAR. 2+ This refers to the coding for epigenetic instructions (partially mediated via the Cam-CaMKII, CREB, and m-ToR pathways) that regulate selected translation, synthesis, protein assembly and differentiation, migration and neural plasticity of cells, represented by differential patterns of influx, and subsequently including constant reshaping of the neuronal connectome and regulation of the NMDAR framework itself (regulation of regulators in a real-time, constant self-learning paradigm). This coding is precise and constantly changing via NMDAR (subsequent stimulation determines the differential pattern of Ca2+ influx). 2+ This epigenetic code, consisting of the amount of influx, is common to all species that have NMDAR and the NMDAR framework. 2+ These differential patterns of inflow modulate the NMDAR framework, and are then modulated by it. Code (i.e., Ca 2+ The differential influx patterns are common within species having the same NMDAR subunits GluN1, GluN2A-D, and GluN3A-B, as well as related isoforms and potential subtypes. The GluN3A-B subunit does not enable glutamate binding, Ca 2+ By forming NMDAR subtypes that are impermeable or relatively impermeable to LTP, they can function as inhibitors to LTP. In the case of part of the synaptic framework, these subtypes are Ca 2+ It functions as a downregulator of influx. Cellular (neuronal and non-neuronal) activity is thus influenced by net Ca across different ion channels, particularly NMDAR channels. 2+It is regulated by the inflow.

[0064] NMDAR-mediated Ca 2+ Invasion activates downstream signaling pathways, such as (1) Cam-CaMKII-GIT1-βPIX-RAC1-PAK1 (actin remodeling pathway), (2) RAS-MEK-ERK1-2-CREB (cyclic AMP-responsive element-binding protein (CREB)-mediated transcription gene expression pathway), (3) PI3K-AKT-REHB-mTOR [rapamycin's mechanical target (mTOR)-dependent mRNA translation of plasticity-related proteins (PRPs)], and (4) the PRP pathway. Activation of one or more of these pathways mediates synaptic modulation, including synaptic maintenance and spine expansion and memory consolidation, among other downstream effects.

[0065] As described above, while treatment of a single psychiatric symptom (e.g., a single psychiatric symptom of depression) has been previously described, to date there are no effective disease-modifying treatments for neuropsychiatric disorders (e.g., MDD and related disorders). Disease-modifying treatments require drugs(s) that go beyond the scope of symptomatic treatment of one or more psychiatric symptoms. The inventors hereby address the problems described in the background art. In this regard, the inventors disclose that dextromethadone unexpectedly induces a rapid, robust, and sustained potentially curative therapeutic effect in patients with MDD. Furthermore, these effects are achieved at doses that do not cause cognitive side effects. This indicates a specific disease-modifying mechanism of action that was previously unrecognized, rather than a symptomatic treatment of psychiatric symptoms.

[0066] Therefore, aspects of the present invention reduce and / or eliminate the challenges of MDD and other such disorders using the treatment. Generally, comprehensive aspects of the present invention provide disease-modifying treatments for MDD and other disorders. A “disease-modifying” treatment, or a treatment having the potential to be “disease-modifying,” as used herein, includes a drug treatment that has the potential to favorably alter the course of the disease by modifying its pathological mechanisms. Disease-modifying treatments are therefore potentially curative. In contrast, symptomatic treatments are generally only temporary relief; they alleviate symptoms but do not address the molecular causes of the disease.

[0067] Therefore, one aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the step of administering a composition to a subject suffering from a neuropsychiatric disorder, wherein the composition comprises a substance selected from d-methadone, d-methadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The neuropsychiatric disorder may be selected from (but not limited to) major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder, and overactive bladder disorder.

[0068] Another aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the steps of (1) diagnosing an individual with a neuropsychiatric disorder; (2) developing a course of treatment for the individual's neuropsychiatric disorder; and (3) administering a substance to the individual as at least part of the course of treatment for the individual's neuropsychiatric disorder. In this aspect, the substance can be selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The neuropsychiatric disorders treated may include (but are not limited to) major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement-related depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder, and overactive bladder disorder.

[0069] One embodiment of this aspect of the present invention is a method for treating MDD, comprising the steps of (1) diagnosing an individual with MDD, (2) developing a course of treatment for the individual's MDD, and (3) administering dextromethadone to the individual as at least part of the course of treatment for the individual's MDD.

[0070] Another aspect of the present invention relates to a method for treating a neuropsychiatric disorder, comprising the step of inducing the synthesis of an NMDAR subunit, an AMPAR subunit, or other synaptic proteins contributing to neuroplasticity and the organization and expression of NMDAR channels in a subject. In this aspect, the subject is suffering from a neuropsychiatric disorder (examples of such neuropsychiatric disorders include major depressive disorder, persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, substance use disorder and overactive bladder disorder). In this embodiment of the present invention, induction of the synthesis of NMDAR subunits, AMPAR subunits, or other synaptic proteins contributing to neuronal plasticity is carried out by administering to a subject a substance selected from d-methadone, d-methadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof.

[0071] Another aspect of the present invention relates to a method for treating a disease or disorder characterized by ion channel dysfunction, comprising: (1) diagnosing an individual with a disease or disorder characterized by ion channel dysfunction; (2) developing a course of treatment for the individual's disease or disorder, wherein the course of treatment for the disease or disorder involves the restoration of ion channel dysfunction; and (3) administering a substance to the individual as at least part of a course of treatment for the restoration of ion channel dysfunction. The substance used can be selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. In certain embodiments, ion channels are essential to one or more NMDARs. In certain embodiments, ion channels are essential to NMDARs containing a Grun2C subunit. In certain embodiments, ion channels are essential to NMDARs containing a Grun2D subunit. In certain embodiments, ion channels are essential for an NMDAR containing a Glun2B subunit. In certain embodiments, ion channels are essential for an NMDAR containing a Glun2A subunit. In certain embodiments, ion channels are essential for an NMDAR containing a Glun3A subunit.

[0072] Another aspect of the present invention relates to a method for diagnosing a disorder as a disorder caused, exacerbated, or maintained by a pathologically hyperactive NMDAR channel. The method of this aspect comprises administering a composition to a subject diagnosed with at least one disorder of unknown pathophysiology selected from neurological disorders, neuropsychiatric disorders, ophthalmic disorders, otological disorders, metabolic disorders, osteoporosis, genitourinary disorders, renal dysfunction, infertility, premature ovarian failure, hepatic disorders, immunological disorders, oncological disorders, and cardiovascular disorders. The composition comprises a substance selected from dextromethadone, dextromethadone metabolites, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. Next, the efficacy of the composition in at least one disorder is determined by measuring a disorder-specific endpoint before and after administration of the composition, and if the subject shows improvement in a specific endpoint, the subject is diagnosed with a disorder caused, exacerbated, or maintained by a pathologically hyperactive NMDAR channel. Since the endpoint may be specific to a particular disorder, measuring the endpoint following administration of the composition makes it possible to determine the specific disorder to be diagnosed.

[0073] In certain embodiments based on the aspects of the present invention listed above, the substance is the sole activator in the composition for the treatment of the neuropsychiatric disorder.

[0074] In certain embodiments based on the aspects of the present invention listed above, the substance is isolated from its enantiomer or newly synthesized.

[0075] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out under conditions effective for the substance to bind to the NMDA receptor of the subject, thereby providing relief to the subject by modifying the course and severity of the neuropsychiatric disorder. In certain embodiments, relief is selected from the following: cure of the neuropsychiatric disorder, prevention of the neuropsychiatric disorder, reduction of the severity of the neuropsychiatric disorder, and reduction of the duration of the neuropsychiatric disorder.

[0076] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out as monotherapy.

[0077] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is performed as part of an auxiliary treatment for the second substance.

[0078] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out under conditions effective for action on ion channels, neurotransmitter systems, neurotransmitter pathways, or receptors selected from ion channel glutamate receptors, 5-HT2A receptors, 5-HT2C receptors, opioid receptors, AChR, SERT, NET, sigma-1 receptors, K channels, Na channels, and Ca channels. In certain embodiments, the receptor is an opioid receptor selected from MOR, KOR, and DOR. In other embodiments, the step of administering the composition is carried out under conditions effective for action on ion channel glutamate receptors, where the ion channel glutamate receptor is an NMDAR. In other embodiments, the action on ion channel glutamate receptors includes voltage-gated channel blockade of NMDARs expressed by the cell membrane. In other embodiments, the action on ion channel glutamate receptors includes voltage-gated channel blockade of NMDARs expressed by the cell membrane, which has a preferential effect on NMDARs containing NR2C and NR2D subunits. In other embodiments, the action on ion channel-type glutamate receptors includes the induction of the synthesis of NMDAR subunits or other synaptic proteins that contribute to neuronal plasticity, and contributes to the membrane expression of said synaptic proteins.

[0079] In certain embodiments based on the aspects of the present invention listed above, the subject is a vertebrate. In certain embodiments, the vertebrate is a human.

[0080] In certain embodiments based on the aspects of the present invention listed above, the substance is dextromethadone. In certain embodiments, dextromethadone is in the form of a pharmaceutically acceptable salt. In certain embodiments, dextromethadone is delivered in a total daily dose of 0.1 mg to 5,000 mg.

[0081] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition modifies the course and severity of the neuropsychiatric disorder in the subject, and the relief begins within a period selected from two weeks or less after the first administration of the substance, seven days or less after the first administration of the substance, four days or less after the first administration of the substance, and two days or less after the first administration of the substance.

[0082] In certain embodiments based on the aspects of the present invention listed above, the therapeutic effect of dextromethadone resulting from the administration of the composition reaches an effect size greater than or equal to 0.3 in a Phase 2 clinical trial, or greater than or equal to 0.5 in a Phase 2 clinical trial, or greater than or equal to 0.7 in a Phase 2 clinical trial. In certain embodiments, the therapeutic effect lasts for at least one week after discontinuation of the treatment. In certain embodiments, the duration of the therapeutic effect after discontinuation of the treatment is equal to or greater than the duration of the treatment.

[0083] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is performed in addition to, or in combination with, the administration of one or more antidepressants to a subject.

[0084] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is performed in addition to, or in combination with, the administration of one or more of magnesium, zinc, or lithium to a subject.

[0085] In certain embodiments based on the aspects of the present invention listed above, the subject has an obesity index equal to or less than 35.

[0086] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is used to improve cognitive function, improve social function, improve sleep, improve sexual function, improve the ability to work, or improve motivation for social activities.

[0087] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is performed orally, intraoral, sublingual, rectally, vaginally, nasally, via aerosol, percutaneously, parenterally, intravenously, subcutaneously, epidurally, intrathecally, intraauricularly, intraocularly, or locally.

[0088] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out in doses of 0.01 to 1000 mg per day.

[0089] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out at a dose of 25 mg per day. In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out at a dose of 50 mg per day.

[0090] In certain embodiments based on the aspects of the present invention listed above, the administration of the composition includes a step of administering a loading dose of the composition, followed by an administration of a daily dose of the composition.

[0091] In certain embodiments based on the aspects of the present invention listed above, the loading dose of the composition includes an amount of substance greater than the amount of substance present in each daily dose of the composition.

[0092] In certain embodiments based on the aspects of the present invention listed above, steady-state or higher plasma levels are reached on the first day after administration of the composition. In certain embodiments, steady-state or higher plasma levels are reached within four hours of administration of the composition.

[0093] In a particular embodiment based on the aspects of the present invention listed above, after the step of administering the composition, the total plasma level of the substance in the subject is in the range of 5 ng / ml to 3000 ng / ml.

[0094] In certain embodiments based on the aspects of the present invention listed above, the unbound level of the substance in the target is 0.5 nM to 1,500 nM after administration of the composition.

[0095] In certain embodiments based on the aspects of the present invention listed above, following the administration of the composition, the unbound level of the substance in the target is in the range of 0.1 nM to 1,500 nM.

[0096] In certain embodiments based on the aspects of the present invention listed above, the step of administering the composition is carried out as an intermittent treatment schedule selected from every other day, once every three days, once a week, every other week, every two weeks, every two weeks, every three months, once a week every year, and once a month every year.

[0097] In certain embodiments based on the aspects of the present invention listed above, the administration of the composition is performed alternately with a placebo during a selected intermittent treatment schedule.

[0098] In certain embodiments based on the aspects of the present invention listed above, the method includes one or more of magnesium, zinc, or lithium instead of or in addition to a placebo.

[0099] In certain embodiments, one aspect of the present invention may further relate to digital applications for monitoring the course of a disability, including digital monitoring of symptoms and signs, as well as outcomes of functional and disability impairment.

[0100] In addition, the inventors also disclose for the first time in this application that dextromethadone reduced NAFLD and potentially NASH and modulated inflammatory markers in “Western diet” rats (as shown in Example 11 below). The inventors also disclose for the first time in this application that dextromethadone has the potential to modulate biomarkers associated with MDD and TRD in patients (as shown in Example 7 below).

[0101] In light of our findings (disclosed herein) that dextromethadone has rapid, robust, sustained, and statistically significant efficacy with a large effect size for patients diagnosed with MDD and / or TRD: As described in more detail below, we disclose a double-blind, placebo-controlled, prospective, randomized clinical trial showing that dextromethadone can induce disease remission (defined as a MADRS score of 10 or less) in more than 30% of patients within the first week of treatment, compared to a 5% remission rate in patients randomized to placebo. Notably, remission lasted for at least one week after discontinuation of treatment, and for longer in some patients. The MADRS rating scale not only measures depressed mood but also provides assessment criteria for motivation, cognitive ability for concentration, sleep, appetite, social ability, and suicide risk.

[0102] As a general rule (as described above), the effect of a symptomatic drug for a chronic condition after discontinuation of a drug (especially after abrupt discontinuation, as in the clinical trials disclosed by the inventors) tends to rapidly diminish or abruptly disappear, and abrupt discontinuation of a symptomatic drug may even result in an exacerbation of symptoms (i.e., worsening of symptoms compared to baseline before treatment) as well as withdrawal symptoms. In contrast, the inventors hereby find that improvements resulting from disease-modifying treatments (e.g., those disclosed herein) tend to persist upon completion of the treatment cycle. The fact that dextromethadone-induced remission persists after discontinuation of treatment in patients with MDD indicates that the action of dextromethadone is not purely symptomatic (i.e., dextromethadone does not simply produce an improvement in the patient's mood, an effect that may disappear upon discontinuation of a drug, such as that which occurs with the use of opioids or alcohol for MDD). Therefore, the persistence of this disease remission suggests that dextromethadone is not merely a symptomatic treatment (as previously thought), but rather involves a previously unrecognized disease-modulating mechanism (e.g., modulation of neuroplasticity that persists beyond discontinuation of treatment).

[0103] Furthermore, the inventors disclose novel molecular mechanisms that explain these disease-modifying effects of dextromethadone. These mechanisms are described in more detail in Examples 1 to 11 below.

[0104] The inventors have described differential blockade of NMDAR subtypes containing two distinct subunits, 2A and 2B. Here, the inventors have determined that (1) differential blockade of NMDARs extends to all tested NMDAR subtypes (subtypes A, B, C, and D), particularly subtypes C and D, and (2) the blockade is glutamate-dependent, active even at very low glutamate concentrations (the glutamate concentration in the synaptic region is influenced by several variable factors, including the intensity and timing of stimulation and glutamate clearance). Even very low glutamate concentrations can produce downstream consequences, especially when present in the extracellular space for extended periods (tonic ambient glutamate). The inventors' efforts in this regard are detailed in Example 1 below.

[0105] Example 1 also discloses that among all known test compounds with NMDAR blocking activity (the test components included other FDA-approved NMDAR channel blockers and experimental agents, e.g., MK-801), dextromethadone exhibits the lowest potency and the fewest subtype preferences, characteristics that the inventors believe can explain its efficacy without side effects. Furthermore, the inventors noted the preference for GluN2C in clinical use for all test compounds, with the exception of MK-801 (a higher affinity NMDAR blocker that is not clinically used due to its severe cognitive side effects). This GluN2C preference, common to selected NMDAR non-competitive channel blockers and not previously disclosed for dextromethadone, is described in differential pattern Ca 2+ This is provided to help understand the downstream effects of infusion and the potential therapeutic effects of this new class of drugs on pathological conditions.

[0106] Example 2 (hereinafter) demonstrates that dextromethadone induces GluN1 mRNA in ARPE-19 retinal pigment cells and also discloses that dextromethadone induces the synthesis and expression of selected protein subunits that form NMDARs (including GluN1, which is necessary for the membrane expression of NMDARs). Furthermore, we hereby demonstrate that dextromethadone also affects the transcription of GluN2C and 2D mRNAs, as well as the synthesis of related protein subunits 2C and 2D.

[0107] The inventors' efforts, detailed in Example 2, also demonstrate that dextromethadone differentially modulates the synthesis of NMDAR subunits (for example, modulating the synthesis of the GluN2A subunit but not the GluN2B subunit). This selectivity shown in the test cell line (ARPE-19) in Example 2 demonstrates the modulating effect of dextromethadone (and thus the differential pattern of Ca modulated by dextromethadone). 2+ In addition to exhibiting a regulatory effect on influx, it also shows a selective effect of subunits on the synthesis of proteins that form NMDARs. These findings by the inventors reveal novel aspects of the basis of physiological and pathological memory formation, including its association with MDD (and other similar pathophysiologically based disorders).

[0108] From this perspective, NMDARs are recognized as important and essential for memory formation in vertebrates, and four different subtypes (GluN2A-D) have existed across all vertebrate species for over 500 million years. This is due to the expansion of coding ability brought about by the differentiation of NMDAR subtypes (differential Ca that forms the epigenetic code). 2+ This highlights the evolutionary importance of fine-tuning the influx pattern. The NMDAR blocking effect of dextromethadone in ARPE-19 cells, and the resulting modulation of protein transcription and synthesis, are demonstrated. 2+The downregulation of influx is (1) selective for NMDAR proteins and (2) selective for NMDAR subtypes, e.g., GluN1 and GluN2A subunits versus GluN2B subunits, and therefore selective for the assembly and expression of NMDAR subtypes in this cell line (as outlined in Example 2). These mechanisms lead to the introduction of the synthesis of novel, selected NMDAR subunits (and thus the assembly and expression of novel, selected NMDAR subtypes), and demonstrate potential for synaptic modulation / enhancement effects on dextromethadone (e.g., modulation of postsynaptic NMDARs).

[0109] These newly recognized mechanisms (disclosed by the inventors) are separate from and add to the effects on BDNF production in human subjects (BDNF can reverse presynaptic strengthening and neurite growth effects) disclosed by the inventors [De Martin S, Vitolo O, Bernstein G, Alimonti A, Traversa S, Inturrisi CE, Manfredi PL, The NMDAR Antagonist Dextromethadone Increases Plasma BDNF Levels in Healthy Volunteers Undergoing a 14-Day In-Patient Phase 1 Study, ACNP 57th Annual Meeting: Poster Session II. Neuropsychopharmacol. Vol. 43, pp. 228-382 (2018)]. This study may demonstrate enhancement of plasma levels of BDNF from dextromethadone in healthy volunteers, but the subjects did not have a diagnosis of MDD, and therefore there was no instruction or suggestion of treating MDD with dextromethadone. In fact, BDNF enhancement with dextromethadone has not been consistently demonstrated in patients with MDD, and therefore the instruction of studies like De Martin has never been applied to MDD (as described above in the background technology, treatment with dextromethadone has been limited to the treatment of a single symptom, and this treatment has never been considered convertible to neuropsychiatric disorders, such as MDD). However, the disclosure of Example 2 (postsynaptic NMDAR modulation by dextromethadone, revealed by induction of the synthesis of selected NMDAR subunits) provides a complementary mechanism for dextromethadone-induced neuroplasticity from BDNF and provides a new level of understanding of the mechanisms of neuronal transcription, production, and release of BDNF.

[0110] In Example 3, the inventors also disclose surprising results from a Phase 2a trial of dextromethadone in patients with MDD. The molecular mechanisms of synaptic strengthening disclosed by the inventors (and described throughout the Examples) potentially explain the surprising disease-modifying effects of dextromethadone in patients with MDD and support the novel disclosures of this application regarding the use of dextromethadone as a disease-modifying treatment for related disorders, including MDD and TRD, as well as for a number of neuropsychiatric and other disorders.

[0111] The disclosure herein of the molecular effects and mechanism of action of dextromethadone, which were previously unknown, further demonstrates its potential efficacy for a number of neuropsychiatric, metabolic, and cardiovascular diseases and disorders. Hereafter, we present that (in a certain subset of patients) the disease and disorder is caused by excessive Ca through pathologically hyperactive NMDARs. 2+ It may be disclosed that the influx is induced or maintained. Prior to the efforts of the present invention disclosed herein, it was believed by those skilled in the art that the primary mode of action of dextromethadone is the blockade of hyperactive NMDAR channels at the PCP site of the intramembrane domain of NMDARs, and that receptor occupancy by dextromethadone is therapeutic only for the symptomatic treatment of a single psychological symptom (e.g., pain, addiction, depression, and anxiety). However, the efforts and discoveries of the inventors outlined in Examples 1-11 demonstrate that dextromethadone can be therapeutic (as a disease modifier) ​​for a number of diseases and disorders, including MDD and related disorders, sleep disorders, anxiety disorders, and cognitive disorders, far exceeding receptor occupancy (due to sustained neuroplastic effects) and therefore not merely a symptomatic agent as previously thought.

[0112] As disclosed herein, dextromethadone exerts its disease-modulating therapeutic effect by modulating the production and membrane expression of novel and functional NMDARs, thereby potentially reequilibriumating the functionality of certain cells (e.g., synaptic strength generation, and thus memory formation) and reactivating their roles in circuits and tissues (e.g., connectivity). The GluN1 subunit is essential for receptor expression. Therefore, dextromethadone can not only modulate pathologically hyperactive NMDARs, but can also induce the synthesis and expression of novel functional NMDARs that enable proper function of certain neurons that are part of a particular circuit (i.e., presynaptic strengthening of synapses, and memory formation including the formation and modulation of emotional memories). Dextromethadone, and potentially other NMDAR blockers, exert their effects by blocking the pore channels of NMDARs, thereby increasing Ca 2+ In addition to altering the pattern of invasion (an action that potentially explains the symptomatic effect), it also alters NMDAR expression on the cell membrane (a novel mechanism of action disclosed by the inventors that explains the robust, rapid, and sustained effect of its unexpected disease modification, particularly as demonstrated by the results of the clinical trial exemplified in Example 3 below).

[0113] As described above, the inventors demonstrate (in Example 2) that dextromethadone not only induces GluN1 mRNA but also modulates the production of GluN1 protein subunits and other GluN2A protein subunits. The inventors also found that these effects were more evident in cells exposed to low concentrations of dextromethadone for one week (corresponding to the clinical protocol of Example 3, in which patients were treated with relatively low drug doses for one week). While not bound by any theory, the inventors found that NMDARs expressed on the membrane of ARPE-19 cells exposed to excessive stimulation (by high concentrations of glutamate or, for example, excessive light) pathologically opened (e.g., excessively), and excessive Ca 2+We believe that the influx includes the deactivation of gene activity related to the production of synaptic proteins, including the production of NMDAR subunits, and causes deactivation of cellular activity, including differential modulation of NMDAR1 and NMDAR2A-D (see Figure 16 and Example 2).

[0114] Excessive stimulation and / or Ca 2+ When cells damaged by influx are exposed to dextromethadone, excess Ca 2+ Invasion is downregulated, and synaptic protein production resumes. In ARPE-19 cells, the NMDAR1 subunit (necessary for NMDAR membrane expression) and, for example, the GluN2A subunit are induced (but not the GluN2B subunit). When exposed to a certain amount of stimulation, such as light, this selectivity is probably not accidental and is potentially related to the functionality / specialization of the ARPE-19 cell line. When applying stimulation to different cell lines that have different functionalities and different NMDAR membrane expression frameworks and are part of different circuits or different tissues, or even in the same cell line when differential stimulation (different glutamate concentrations or different intensity or quality of light exposure, different experimental settings) is applied, the selective modulation of this NMDAR subunit will be different when stimulation is applied.

[0115] In addition to the above, the inventors (in Example 5) have shown that dextromethadone, which is shown herein by the inventors as a positive allosteric modulator (PAM) of NMDARs, can be used in gentamicin-exposed cells to control Ca 2+ Downregulation of inflow is also demonstrated herein. Gentamicin is toxic to the hair cells of the ear, which are cells that convert sound into electrochemical signaling. Therefore, Example 5 shows that excess Ca 2+ Excitotoxicity due to influx can be caused not only by excessive presynaptic glutamate release (e.g., during prolonged psychological stress), but also by excessive Ca 2+This paper describes the potential disease-modifying effects of dextromethadone even at very low glutamate concentrations (even physiological concentrations) when influx is caused by toxic PAM.

[0116] Toxic PAMs are one of several different chemicals and can act through two main mechanisms: (1) increasing the maximum response to glutamate (aPAM), and / or (2) shifting the ED50 of glutamate to the left (bPAM). In Example 5, gentamicin appears to act as an aPAM via mechanism (1) for GluN2B, and as a bPAM via mechanism (2) for GluN2A, GluN2C, and GluN2D. The mechanism of bPAM for NMDAR subtypes containing GluNC and GluND subunits is relevant to this disclosure due to the disclosed mechanism of action of dextromethadone. As suggested by Example 1 (preference for GluN1-GluN2C and activity for the GluN2D subtype), and Examples 2, 5, and 6, dextromethadone is a persistent Ca 2+ Ca through permeable GluN1-GluN2C and GluN1-GluN2D subtypes (and subtypes containing the GluN3 subunit) 2+ It is possible to selectively block inflows.

[0117] Dextromethadone has a mechanism of action that allows it to selectively target NMDARs containing persistently and pathologically hyperactive GluN1-GluN2C (and GluN1-GluN2D subtype and possibly subtypes containing the GluN3 subunit) regardless of the cause (any of the numerous molecules that act at the agonist site or as PAM, including excess glutamate or exogenous or endogenous chemicals including antibodies). 2+ (Due to interruption of current), the present inventors have identified a pathological and persistent excess of Ca 2+Permeable NMDARs are determined to be potentially prophylactic, therapeutic, and / or diagnostic for a number of diseases induced or maintained by them. In the case of MDD, NMDAR agonists (e.g., quinolinic acid) also increase extracellular glutamate by a different mechanism [Guillemin GJ, Quinolinic acid: neurotoxicity, FEBS J. 2012; vol. 279 (no. 8): p. 1355], thus further enhancing NMDAR activity. Dextromethadone antagonizes the additive neurotoxic effect of quinolinic acid, as seen in Example 5. Therefore, the results of Examples 1 and 2, the results for the NMDAR PAM gentamicin and agonist quinolinic acid in Example 5, the Phase 2 results in MDD patients showing rapid, robust, and sustained efficacy detailed in Example 3, and the results and disclosures detailed in Examples 6 to 11 strongly demonstrate the disease-modifying effects of dextromethadone for patients with MDD and other diseases characterized by NMDAR hyperactivation.Therefore, disorders associated with MDD, such as PPD (Maes M et al., Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci. 2002; Vol. 71: pp. 1837-1848) and inflammatory states [Capuron L et al., Interferon-alpha-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment, Biol. Psychiatry. 2003, Vol. 54: pp. 906-914; Raison CL et al., CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression, Mol. Psychiatry. 2010, Vol. 15: pp. 393-403; Du J, Li XH, Li YJ. Glutamate in peripheral organs: Biology and pharmacology, Eur] [J Pharmacol. 2016; Vol. 784: pp. 42-48] Dextromethadone may also be a candidate for treatment.

[0118] Patients with CNS disorders, including encephalopathy associated with increased quinolinic acid levels in serum and / or CSF, as exemplified by patients with Lyme disease [Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis, Neurology. 1992; Vol. 42 (No. 1): pp. 43-50], may also be improved by dextromethadone. In addition, immunological responses to infections and depression that cause changes in the hypothalamic-pituitary-adrenal axis (as demonstrated by the BP-lowering effect of dextromethadone in our Phase 1 MAD trial) are all related to excessive Ca via NMDARs hyperstimulated by dextromethadone and, for example, quinolinic acid. 2+ This downward regulation of inflow has a positive effect [Ramirez LA, Perez-Padilla EA, Garcia-Oscos F, Salgado H, Atzori M, Pineda JC. A new theory of depression based on the serotonin / kynurenine relationship and the hypothalamic-pituitary-adrenal axis, Biomedica. 2018; Vol. 38 (No. 3): pp. 437-450. Published September 1, 2018]. Modulation of the hypothalamic-pituitary-adrenal axis was also demonstrated by the BP-lowering effect of dextromethadone in our Phase 1 MAD trial.

[0119] During normal (physiological) brain activity, stimulation and depolarization of presynaptic neurons are accompanied by the opening of AMPAR (Na + Inflow, postsynaptic depolarization, and NMDAR voltage-dependent Mg 2+ (with the release of blockage), opening of NMDAR and Ca 2+ This leads to the release of glutamate in the synaptic cleft by the axon, accompanied by an influx of Ca. 2+Influx, in physiological amounts, promotes neuroplasticity through the activation of CaMKII at the postsynaptic level [introduction of synaptic protein synthesis and synaptic strengthening via BDNF synthesis and release in the extracellular space, accompanied by nutrient (spine generation and growth) and tropic (direction of growth) effects on synaptic strengthening and neuritis in postsynaptic cells, and at both postsynaptic and presynaptic levels]. Direct activation of NMDARs in presynaptic cells can also contribute to neuroplasticity at the presynaptic level, for example, by modulating glutamate stores (Berretta N, Jones RS. Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex. Neuroscience 1996; Vol. 75: pp. 339-344).

[0120] The experimental results of the present inventors shown in Examples 1 to 11 indicate that Ca mediated by NMDAR 2+ When the influx is excessive, it suggests that cells cease producing synaptic proteins and neurotrophic factors (the first step in excitotoxicity, which can potentially progress to apoptosis). Dextromethadone is a marker of excess Ca 2+ By downregulating influx, it restores the neural plasticity mechanism (production of neurotrophic factors including synaptic proteins and BDNF). This potentially prevents the progression of cellular dysfunction and apoptosis, and thus MDD [and MDD-related disorders, and potentially excess Ca via NMDARs in selected cells that are part of selected cell populations, tissues, and circuits in the CNS and extra-CNS tissues]. 2+ Influx of the virus can induce, maintain, or exacerbate a number of diseases (Du et al., 2016), leading to disease-modifying treatments.

[0121] Ca for LTP mechanism 2+ The downstream effect is accompanied by an inverted U-shaped curve: Ca 2+ The inflow is a certain amount of Ca 2+Up to the inflow, LTP has the advantage, and then Ca 2+ When the influx becomes excessive, cells become dysfunctional (excitotoxic), and LTP is inhibited. 2+ If the influx continues, the cells will suffer permanent damage. If a neuron with an overstimulated NMDAR (where LTP is disrupted due to excitotoxicity) is part of one or more functional circuits or tissues, specific damage and disease may occur in the damaged circuit or tissue.

[0122] Therefore, the molecular effects of dextromethadone presented in the examples provide a potential mechanism for the results observed in Example 3 with respect to MDD: namely, the unexpectedly potent positive (very statistically significant p-value with a large effect size), rapid (unexpectedly, the first signal of efficacy began on day 2 with the 25 mg dose, and was statistically significant on day 4 with both the 25 mg and 50 mg doses), and sustained / long-lasting / continuous (statistically significant clinically meaningful therapeutic effect and large effect size lasting at least one week after abrupt discontinuation of the one-week treatment course) efficacy results observed in the Phase 2 trial detailed in Example 3. These neuroplastic effects, including NMDAR-mediated LTP, can also explain the better unexpected signal (as seen in Example 3) observed in patients randomized to the 25 mg dose (with a corresponding lower dextromethadone plasma concentration of around 300 nM) compared to patients receiving the 50 mg dose (with a corresponding higher dextromethadone plasma concentration of around 600 nM). The therapeutic effect of dextromethadone potentially follows an inverted U-shaped curve similar to that described for other NMDAR opening channel blockers, such as ketamine. Ultimately, the safety window for dextromethadone may be broad (Example 3), but the therapeutic concentration range can be individualized, at least for MDD, to a daily dose between 5 and 100 mg and / or 12.5 and 75 mg, and plasma concentrations between 50 and 900 ng / ml and / or free levels between 5 and 90 (see Example 3). This aspect, when BMI is considered in a sub-analysis of Phase 2a trial results, is detailed below.

[0123] These robust efficacy results (including sustained efficacy after discontinuation of the drug) make it clear here for the first time that dextromethadone does not simply improve symptoms in isolation. Rather, dextromethadone is for patients with MDD, MDD-related disorders, and potentially other neuropsychiatric and metabolic disorders, and NMDAR hyperactivation in selected cells (hypothalamic-pituitary axis disorders, e.g., hypertension, and potentially cardiovascular and metabolic disorders, and other disorders described by Du et al., 2016, incorporated herein by reference) and excess Ca 2+ This shows a strong signal of producing disease / disability modifying effects for patients with other disorders potentially related to influx.

[0124] These unexpectedly potent positive and sustained effects are unprecedented in studies of MDD using drugs that do not cause psychotropic side effects. Furthermore, as detailed below, the extreme tolerability and safety of dextromethadone (having a placebo-like adverse event profile at a highly effective 25 mg oral daily dose) indicates that the activity of dextromethadone on pathologically hyperactive channels (hyperactive NMDARs) is highly selective (involving selective sparing of physiologically functioning channels). Therefore, the efficacy of dextromethadone may potentially extend to a number of diseases and disorders induced or maintained by cell / circuit dysfunction resulting from hyperactive NMDARs (e.g., NMDAR hyperstimulation by glutamate or other agonists or PAMs).

[0125] Therefore, while dextromethadone is useful for treating individual symptoms, such as pain and depression (disclosed by the inventors in U.S. Patent Nos. 6,008,258 and 9,468,611), the inventors hereby argue that it can produce disease-modifying effects, and thus can control excess Ca in selected cells that are part of a selected subpopulation, tissue, and / or circuit. 2+We were the first to determine that it is also useful as a disease-modifying treatment for a number of diseases and disorders that are induced, maintained, or exacerbated by the cessation of physiological neuroplasticity and / or other physiological cellular functions caused by influx (which had not been previously recognized).

[0126] When hyperactive NMDARs are expressed at selected sites on the membrane of selected cells that are part of specific structural and functional circuits, NMDARs can trigger the release of excess Ca in selected cells, cell lines, populations, tissues, and circuits. 2+ This allows for influx and causes cellular dysfunction (also known as excitotoxicity). In the nervous system (NS), dysfunction of CNS cells (neurons, astrocytes, oligodendrocytes, and other glial cells including microglia) causes changes in brain connectivity in selected circuits, depending on spatiotemporal factors (developmental age and location within the NS) and NS cell subtype. Patients may present this circuit dysfunction as a syndrome, disorder, or disease, such as one of several neuropsychiatric disorders.

[0127] Such syndromes, disorders, or diseases include MDD (as enumerated in DMS5 and ICD11) or Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment [including mild cognitive impairment (MCI) associated with aging and chronic disease and its treatment]; Parkinson's disease; and disorders associated with parkinsonism, including, but not limited to, Parkinsonian dementia; and disorders associated with the accumulation of beta-amyloid protein (including, but not limited to, frontotemporal dementia). and its variants, frontal lobe variants, primary progressive aphasia (including semantic dementia and progressive non-fluent aphasia), cerebral vascular disorders or tau protein and its metabolites (including, but not limited to, these), corticobasal degeneration, supranuclear palsy; epilepsy; NS trauma; NS infection; NS inflammation [including inflammation from autoimmune disorders (e.g., NMDAR encephalitis) and cytopathology from toxins (including microbial toxins, heavy metals, pesticides, etc.)]; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological and oculoacral coordination disorders; neurodegenerative diseases of the retina such as glaucoma, diabetic retinopathy and age-related macular degeneration; amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder ("ADHD") and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; Prader-Willi syndrome; cerebral palsy; eating disorders [including anorexia nervosa ("AN"), bulimia nervosa ("BN") and binge eating disorder ("BED")], reward system disorders including trichotillomania; self-injurious dermatitis; nail biting; substance and alcohol abuse and dependence; migraine; fibromyalgia; and one or more peripheral neuropathy of any etiology.

[0128] The inventors consider a subset of patients diagnosed with neuropsychiatric disorders listed in DMS5 and ICD11 to be suffering from disorders induced and / or maintained by hyperactive NMDARs, just as the MDD patient described in Example 3. Drugs such as dextromethadone, having the molecular action disclosed in Examples 1-7 and the clinical efficacy (efficacy and safety) presented in Example 3, are potentially safe and effective for selected patients diagnosed with neuropsychiatric disorders listed in DMS5 and ICD11, including NMDAR encephalitis and other immunological disorders affecting NMDARs, as well as the diseases and disorders described by Du et al., 2016 (diseases and disorders described by Du et al., incorporated herein by reference).

[0129] Therefore, dextromethadone can be used not only as a preventive and / or therapeutic agent, but also as a safe and effective diagnostic tool for selecting patients diagnosed with neuropsychiatric disorders listed in DMS5 and ICD11 who are likely to have impairments induced and / or maintained by hyperactive NMDARs. Accordingly, the inventors also disclose dextromethadone not only as a preventive or therapeutic agent, but also as a diagnostic tool for diagnosing NMDAR dysfunction in a number of diseases and disorders, including neurological, neuropsychiatric, ophthalmic (including visual impairment), otological (including hearing impairment, balance disorders, dizziness, and tinnitus), metabolic (including impaired glucose tolerance and diabetes, hepatic disorders including NAFLD and NASH, osteoporosis), immunological, oncological, and cardiovascular (including CAD, CHF, and HTN), as well as other diseases and disorders, such as those listed above and those described by Du et al., 2016. Administration of dextromethadone via any of the routes disclosed herein may be useful in the diagnosis of diseases and disorders induced or maintained by hyperactive NMDARs in vertebrates, mammals, and humans.

[0130] Based on the novel experimental data disclosed herein, the inventors have also found that dextromethadone selectively targets certain pathologically hyperactive NMDARs (e.g., a subset of persistently hyperactive NMDARs, e.g., subtypes NR1-GluN2C and / or NR1-GluN2D, and / or subtypes containing 3A and / or 3B subunits) and delivers excess Ca only to hyperactive NMDAR channels that functionally and structurally impair cells. 2+ We disclose that the inflow can be downregulated. As shown by the FLIPR experiment in Example 1, the effect of dextromethadone in NMDARs differs depending on the intensity of presynaptic stimulation (the blocking effect of dextromethadone increases with increasing glutamate stimulation) and depending on the NMDAR subtype. This experiment was conducted using Mg 2+ It does not contain Mg, therefore this is because AMPAR depolarization induced by presynaptic glutamate release is released from NMDAR into the synaptic cleft. 2+ This is similar to a situation where Mg has already been released in vivo. 2+ The presence of may make dextromethadone less relevant (i.e., dextromethadone is inactivated Mg 2+ It is unlikely to have a blocking effect on channels that have already been blocked, because these are already blocked and inactive, for example, Mg 2+ While blocked by Ca 2+ This is because the subtypes GluN2A and B are impermeable to Ca. However, these different effects of dextromethadone on receptor subtypes A-D are important for elucidating its selective effects on persistently and pathologically hyperactive channels, such as NR1-NR2C (and NR1-NR2D subtype or 3A-B subunit-containing subtype). Ca through opening channels induced by dextromethadone 2+Downregulation of influx induces the production of synaptic proteins, including NR1, NR2A-D, and NR3A-B subunits, in humans (Example 2), and modulates neuroplastic activity, including the production of other synaptic proteins and neurotrophic factors. Neurotrophic factors are known to act on both postsynaptic and presynaptic neuroplasticity.

[0131] The inventors hereby disclose that dextromethadone, a non-competitive opening channel blocker, acts directly and selectively to regulate Ca+ influx in pathologically hyperactive channels, thereby reactivating physiological neuroplasticity in presynaptic and postsynaptic cells. Blocking pathologically hyperactive channels results in positive downstream consequences, including activation of genes for the synthesis of key factors for neuroplasticity, such as synaptic proteins (Example 2) containing GLUN1 and 2A subunits and neurotrophic factors including BDNF, and excess Ca 2+ It regulates the influx. This activation of neuronal plasticity activity for neuronal synthesis causes abnormal excess Ca to stop the production of neuronal plasticity peptides in cells. 2+ This demonstrates a modification of the invasion, thereby leading to the resumption of physiological neuroplasticity.

[0132] Supporting the mechanism of action disclosed by the inventors, this reactivation of cellular function (selectively for cells damaged by excessive Ca+ influx), and thus reactivation of damaged CNS circuits, is clinically manifested by the inventors' surprising findings regarding a rapidly initiating, robust, and sustained effect (after discontinuation of treatment) in patients with MDD. This finding (see Example 3) is linked to increased NMDAR activity (and excessive Ca+ in selected neurons). 2+ In addition to supporting the finding that inflow was a causative (inducing and / or maintaining factor) for MDD registered in our studies (a novel pathological mechanism for MDD and related disorders), dextromethadone is also found to be beneficial for MDD, MDD-related disorders, and pathologically hyperactive NMDARs and excess Ca 2+It has also been shown to be potentially curative for other neuropsychiatric disorders, including hypothalamic-pituitary system disorders induced and / or maintained by inhibition of influx and neuroplasticity or impairment of other cellular functions (see, for example, Example 5 in which gentamicin acts as a PAM, and thus the diseases and disorders described by Du et al., 2016).

[0133] In the case of CNS damage, excess Ca in selected neurons prior to the onset of excitotoxicity 2+ Invasion can also lead to excessive inhibitory activity, such as inhibitory interneurons projecting to medial prefrontal cortex (mPFC) neurons. By blocking pathologically hyperactive NMDAR channels, such as selected persistently hyperactive NMDARs, dextromethadone can reduce or halt excessive inhibitory activity by interneurons and mitigate excessive inhibition of mPFC neurons. Control of inhibitory activity using the reciprocal effects of 1) GABAaR dispersion or 2) GABAaR clustering is a consequence of stimulation-induced NMDAR activity [Bannai H, Niwa F, Sherwood MW, Shrivastava AN, Arizono M, Miyamoto A, Sugiura K, Levi S, Triller A, Mikoshiba K. Bidirectional control of synaptic GABAAR clustering by glutamate and calcium. Cell reports. December 29, 2015; Vol. 13 (No. 12): pp. 2768-2780]. Therefore, the inhibitory activity present on the homeostatic rhythms of brain networks is determined by NMDARs. 2+ It is controlled by inflow. In excess, these Ca 2+ The inward current can potentially be modulated by dextromethadone. Therefore, not only excitatory activity but also inhibitory activity can be observed in NMDAR and Ca 2+ It is regulated by signal transduction. The NMDAR framework is therefore Ca 2+It is regulated not only by excitatory effects but also by inhibitory effects, by modulating the framework of all other receptors, including inhibitory receptors such as GABAaR, via signal transduction.

[0134] NMDAR therefore receives environmental input and Ca 2+ We hypothesize a central regulatory position that translates this input into finely tuned neuroplasticity by controlling and modulating the entire synaptic framework through signal transduction and its downstream effects. Such downstream effects include transcription, synthesis, transport, and assembly of NGF and synaptic proteins, as well as transcription of receptor subunits for AMPAR, NMDAR, GABAaR, and substantially all other CNS receptors. NMDARs, therefore formed by environmental stimuli, control the lifetime evolution of the synaptic framework, including NMDARs.

[0135] Therefore, diseases and disorders may be induced, maintained, or exacerbated by excessive activation of one or more NMDAR subtypes expressed by selected neurons essential to one of several different circuits (e.g., activation induced by lifestyle stress, other stimuli, or glutamate-mediated stimuli, including endogenous or exogenous PAMs containing endogenous or exogenous agonists and / or toxins). This excessive NMDAR activation leads to excessive Ca in the postsynaptic neurons via NMDARs. 2+ It leads to influx. Presynaptic glutamate receptors also play a role in neuronal plasticity (Baretta and Jones, 1996; Bouvier G, Bidoret C, Casado M, Paoletti P. Presynaptic NMDA receptors: Roles and rules. Neuroscience. 2015; Vol. 311: pp. 322-340), and can therefore be regulated by dextromethadone. Ca in selected neurons 2+When the influx of Ca is excessive, this deregulates the neural plasticity activity of the neural circuit, reducing or hindering its connectivity and altering its functionality (reducing the structure and strength of synapses) (excessive Ca 2+ The influx can even affect the critical structure and function of neurons if the excitotoxicity progresses toward apoptosis of cells. Drugs like dextromethadone have their own unique molecular action as NMDAR blockers (Examples 1 and 5), and without having an effect on physiologically functioning NMDARs, they have an effect on excess Ca in pathologically hyperactive NMDARs. 2+ It downregulates cell influx (this was first demonstrated in a Phase 2a trial, Example 3, showing no cognitive side effects at therapeutic doses). Thus, cells (previously damaged by excitotoxicity) resume neuroplastic function and restore the NS circuit with recovery of circuit dysfunction (recovery of neuropsychiatric symptoms as well as neuropsychiatric disorders: this disease-modifying effect is due to neuroplasticity, not just receptor occupancy and Ca, as demonstrated by the sustained efficacy after abrupt discontinuation of the treatment shown in Example 3, and with the reduction in plasma dextromethadone concentration and the resulting reduction in receptor occupancy). 2+ (This is not due to a temporary effect from the downward adjustment of inflows.)

[0136] Drugs like dextromethadone, which are well-tolerated at disease-modifying effective doses, were first confirmed in patients by the Phase 2a results presented in this application (Example 3), as demonstrated in the presence of PAM and other agonists (Example 5) and different, unique actions in NMDAR subtypes (Examples 1, 5), unique "on"-"off" NMDAR dynamics (Example 6, Part I) and "capture" profiles (Example 6, Part II) and physiological concentrations of Mg at resting membrane potential. 2+ Disclosed are different Ca2+ stimuli (including very low levels of glutamate), including unique effects in the presence of (Example 6, Part III). 2+It has a downmodulatory effect and is a potential disease-modifying treatment for a number of diseases and disorders. Importantly, the blocking activity of dextromethadone at NMDAR channels does not interfere with physiological activity at effective doses, as demonstrated by the results described in Examples 1-11 (as demonstrated by the absence of side effects at therapeutic doses in Example 3). Therefore, dextromethadone is a novel tool for exploring brain function both during physiological manipulation and under pathological circumstances. In addition, researchers and practitioners will use this novel diagnostic tool to select a subset of patients with NMDAR hyperfunction that causes, maintains, or exacerbates one of a number of diseases and disorders.

[0137] Based on findings from in vitro and in vivo experiments using dextromethadone in healthy subjects and patients with MDD, the inventors hereby propose that the shared epigenetic code, which forms the basis of the G+E paradigm, has different Ca dynamics determined by the NMDAR framework. 2+ It is possible to hypothesize that the pattern of cell influx is determined by the presynaptic release of glutamate induced by stimulation (environmental stimuli reaching the cell) (e.g., activation of the polyamine site of the NMDAR or other allosteric or agonist site by other NMDAR modulators or toxins) integrated by agonists, PAM, and NAM. 2+ The influx patterns, in both healthy and diseased states, determine postsynaptic and presynaptic neural plasticity modulation in the brain (other effects may exist in other cells / tissues): for example, excess Ca 2+ Influx demodulates neural plasticity, for example, excessive Ca by the non-competitive channel blocker dextromethadone. 2+ The reduction in inflow potentially leads to a resumption of physiological neuroplasticity, as observed in the experimental tests presented throughout this application. 2+The shared code for brain activity, which is a differential pattern of influx, was shown by the inventors to regulate NMDAR expression (NMDAR framework) (Example 2). Postsynaptic Ca after presynaptic glutamate release 2+ The influx pattern is regulated by postsynaptic AMPAR and NMDAR expression (and presynaptic NMDAR expression, as shown by Berretta and Jones, 1996), and this postsynaptic AMPAR and NMDAR receptor expression (and presynaptic glutamate release) then Ca 2+ It is regulated by influx. Therefore, NMDARs are regulatory factors as well as Ca 2+ It is regulated by inflow. Stimulation induces differential patterns of Ca that flow across the entire NMDAR. 2+ This regulation of NMDAR expression by influx (the NMDAR framework) is the basis of neural plasticity and the basis for each individual's unique connectome. Each environmental interaction with the individual thus affects a different NMDAR framework, resulting in different amounts of Ca with different downstream consequences. 2+ This will lead to an influx of excess (pathological) Ca via NMDARs. Dextromethadone will cause an influx of excess (pathological) Ca via NMDARs. 2+ The inflow can be corrected. [Examples]

[0138] (Example 1) - Mechanism of action of fluorescence imaging plate reader (FLIPR) calcium assay using GluN1-GluN2A, -2B, -2C, and -2D cell lines on the human NMDA receptor. The following is a list of abbreviations used in this embodiment and in this application.

[0139] [Table 1]

[0140] A. Introduction Example 1 demonstrates the mechanism of action of dextromethorphan in NMDAR subtypes and the relative potencies in each channel subtype, and compares it with other channel blockers. The example also provides information about the ability of dextromethorphan to affect Ca 2+ influx induced by very low ambient glutamate. This, together with other evidence disclosed herein, corroborates the novel pathophysiology of MDD (persistence and excessive Ca 2+ influx through pathologically activated NMDARs) disclosed by the inventors.

[0141] The mode of action of the FLIPR-calcium assay described herein was designed to demonstrate the effect of the test items on the fitting parameters of the L-glutamate concentration-response curve at six selected concentrations in four human recombinant NMDA receptor types: GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, GluN1-GluN2D.

[0142] B. Test and control items Five test items were selected for this study: dextromethorphan hydrochloride (CAS#15284-15-8, supplied by Padova University), memantine hydrochloride (CAS#41100-52-1, supplied by Bio-Techne Tocris), (±)-ketamine hydrochloride (CAS#1867-669, supplied by Merck Sigma-Aldrich), (+)-MK801 maleate (CAS#77086-22-7, supplied by Bio-Techne Tocris), and dextromethorphan hydrobromide monohydrate (CAS#6700-34-1, supplied by Merck Sigma-Aldrich).

[0143] The vehicle used was DMSO (CAS#67-68-5; supplied by Merck Sigma-Aldrich).

[0144] The formulations of the test items are shown in Table 1 (Table 2) below.

[0145] [Table 2]

[0146] C. Examination System The test items were assessed using FLIPR to evaluate the ability to regulate L-glutamate and glycine-induced calcium intrusion in four CHO cell lines expressing dihetothermic human NMDA receptors (NMDARs): GluN- / GluN2A-CHO, GluN1-GluN2B-CHO, GluN1-GluN2C-CHO, and GluN1-GluN2D-CHO.

[0147] D. Experimental Design The study aimed to monitor the effects of five test items on L-glutamate CRC in the presence of a fixed 10 μM glycine concentration.

[0148] Six different concentrations—50 μM, 12.5 μM, 3.13 μM, 0.781 μM, 0.195 μM, and 0.049 μM—were tested for each test item.

[0149] Eleven CRCs of L-glutamic acid contained the following final concentrations: 100 mM, 1 mM, 100 μM, 10 μM, 3.3 μM, 1.1 μM, 370 nM, 123 nM, 41 nM, 13.7 nM, and 4.6 nM.

[0150] FLIPR determination of intracellular calcium levels was used as a readout for NMDAR activation.

[0151] E. Methods and Procedures 400× compound plates were prepared using a Labcyte Echo system, with each well containing 300 nl of 400× L-glutamic acid / glycine solution in H2O and 300 nl of 400× test item solution in DMSO. The 400× compound plates were stored at -20°C until the day of the FLIPR experiment.

[0152] 4× compound plates were prepared from 400× compound plates by adding compound buffer up to 30 μl / well on the day of the FLIPR experiment. 4× L-glutamic acid solution was directly prepared at a concentration of 400 mM and divided into columns 1 and 12 of the 4× compound plate.

[0153] Using the FLIPR system, Fluo-4 was pre-loaded for 1 hour, intracellular calcium levels in NMDAR cell lines were monitored, and the cells were then washed with assay buffer. Intracellular calcium levels were monitored 10 seconds and 5 minutes before the addition of the test items, in the presence of L-glutamate and glycine.

[0154] F. Data Handling and Analysis The fluorescence AUC value was measured using ScreenWorks 4.1 (Molecular Devices) FLIPR software, and calcium levels were monitored for 5 minutes after adding the test sample. Subsequently, data were standardized using Excel 2013 (Microsoft Office) software, using wells (column 23) containing 10 μM L-glutamic acid and 10 μM glycine as a high control, and wells (column 24) containing only assay buffer as a low control.

[0155] To evaluate the plate quality Z', calculations were performed in Excel. Z' was calculated according to the following equation: Z'=1-3(σ h +σ l ) / |μ h -μ l | Where μ and σ are the mean and standard deviation of the mean of the high (h) control and low (l) control, respectively.

[0156] Four-parameter logistic equations were used with Prism 8 (GraphPad) software to calculate the EC 50 and maximum effect under different experimental conditions: Y = Bottom + (Top - Bottom) / (1 + 10^((LogEC 50 - Log[A]) * Hill slope)) Where Y is the % effect of L-glutamic acid and [A] is the molar concentration of L-glutamic acid.

[0157] The equations for allosteric modulators (Leach K, Sexton PM and Christopoulos A, Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology, Trends Pharmacol. Sci. 28: 382-389, 2007; Kenakin TP, Overview of receptor interaction of agonists and antagonists, Curr. Protoc. Pharmacol. Chapter 4: Unit 4.1, 2008, Kenakin TP, Biased signalling and allosteric machines: new vistas and challenges for drug discovery, Br. J. Pharmacol. 165:1659-1669, 2012) were generated with Prism 8 (GraphPad) software to estimate the K B and α parameters for all test items, assuming that all test items, like pore blockers, can produce competitive blockade of agonist responses at sufficiently high concentrations:

[0158]

Number

[0159] In the formula, Y is the percentage effect of L-glutamic acid; [A] is the molar concentration of L-glutamic acid; E MAX This is the maximum possible effect of L-glutamate, estimated from four types of parameterized logistic equations; EC 50 τ is half of the maximum effective concentration of L-glutamate, estimated from four parameterized logistic equations; τ is the efficacy value of any L-glutamate in NMDARs (fixed τ = 100 for all receptors, in the absence of a consistent value for the L-glutamate dissociation equilibrium constant in human diheteromeric NMDARs, EC2). 50 [B] may be needed to estimate τ from; [B] is the molar concentration of the test item; K B is the estimated equilibrium dissociation constant of the test item; α is the estimated cooperativity term indicating the effect of the test item on the L-glutamate equilibrium dissociation constant at the receptor (i.e., α is the estimated ratio between the L-glutamate equilibrium dissociation constants in the absence and presence of the test item, and is expected to be 0 < α ≤ 1 for negative allosteric modulators that affect the agonist's equilibrium dissociation constant).

[0160] The % affinity rate is calculated from the estimated affinity, and this is K B It is the reciprocal of and the highest affinity in the NMDAR subtype is set to 100%.

[0161] G. Protocol deviation The preparation of the 400× concentrated solutions of L-glutamic acid and glycine was carried out in H2O instead of DMSO due to the low solubility of L-glutamic acid in DMSO. This protocol deviation does not affect the overall interpretation or impair the completeness of the study.

[0162] H. Results 1. Plate Z' value Five cell plates for all cell lines (GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, GluN1-GluN2D) were tested against the same compound plate containing all test items.

[0163] All cell plates had a Z' value > 0.4, which was accepted. The Z' values ​​for GluN1-GluN2A in plates 1 to 5 were 0.82, 0.80, 0.83, 0.83, and 0.83, respectively. The Z' values ​​for GluN1-GluN2B in plates 1 to 5 were 0.80, 0.77, 0.77, 0.81, and 0.83, respectively. The Z' values ​​for GluN1-GluN2C in plates 1 to 5 were 0.73, 0.53, 0.74, 0.71, and 0.76, respectively. The Z' values ​​for GluN1-GluN2D in plates 1 through 5 were 0.70, 0.74, 0.65, 0.44, and 0.64, respectively.

[0164] Five additional cell plates using GluN1-GluN2C cells were discarded because they showed low fluorescence values ​​due to low receptor expression in this cell batch.

[0165] 2 L-Glutamate CRC L-glutamate CRC was obtained in all cell lines in the presence of 10 μM glycine, and relative plots using GraphPad Prism are shown in Figure 1. Data are reported as mean ± SEM, n=5.

[0166] At 100 mM L-glutamic acid, the % fluorescence values ​​decreased significantly in all cell lines except GluN2D, and the fluorescence time course differed from all other concentrations, with an initial transient peak lasting approximately 90 seconds. This transient peak was visible in all cell lines, particularly GluN2C and GluN2D cell lines, which is thought to be due to the low NMDAR expression levels in those cells, and even lower in the GluN2C batch of cells that express NMDAR at low levels (see traces in Figures 2A-2E). Therefore, although 100 mM L-glutamic acid is reported in the graph, it was excluded from the data analysis.

[0167] The best-fit values ​​for the four cell lines are shown in Table 2 (Table 3) as follows:

[0168] [Table 3]

[0169] 3 Dextromethadone The effects of dextromethadone on L-glutamate CRC in four NMDA receptor types are shown in Figures 3A–3D. 100 mM L-glutamate levels were not used for fitting. Data are reported as mean ± SEM, n=5.

[0170] The best-fit values ​​for the four parameterized logistic equations for dextromethadone were obtained from GraphPad's Prism data analysis, as shown in Tables 3-6 (Tables 4-7) below.

[0171] [Table 4]

[0172] [Table 5]

[0173] [Table 6]

[0174] [Table 7]

[0175] Computational analysis with an allosteric modulator shows K as shown in Table 7 (Table 8). B The % affinity and alpha value were obtained.

[0176] [Table 8]

[0177] 4 Memantine The effects of memantine on L-glutamate CRC in four NMDA receptor types are shown in Figures 4A–4D. 100 mM L-glutamate levels were not used for fitting. Data are reported as mean ± SEM, n=5.

[0178] The best-fit values ​​for memantine's four parameterized logistic equations were obtained from GraphPad's Prism data analysis, as shown below in Tables 8-11 (Tables 9-12) (values ​​that are not considered to be reliable fits are typed in bold and underlined).

[0179] [Table 9]

[0180] [Table 10]

[0181] [Table 11]

[0182] [Table 12]

[0183] The computational analysis using allosteric modulators revealed the following K shown in Table 12 (Table 13): B The % affinity and alpha value were obtained.

[0184] [Table 13]

[0185] 5 (±)-Ketamine The effects of (±)-ketamine on L-glutamate CRC in four NMDA receptor types are shown in Figures 5A–5D. 100 mM L-glutamate levels were not used for fitting. Data are reported as mean ± SEM, n=5.

[0186] The best-fit values ​​for the four parameterized logistic equations for (±)-ketamine were obtained from GraphPad's Prism data analysis, as shown below in Tables 13-16 (Tables 14-17).

[0187] [Table 14]

[0188] [Table 15]

[0189] [Table 16]

[0190] [Table 17]

[0191] The computational analysis using allosteric modulators revealed the following K shown in Table 17 (Table 18): B The % affinity and alpha value were obtained.

[0192] [Table 18]

[0193] 6(+)-MK801 The effects of (+)-MK801 on L-glutamate CRC in four NMDA receptor types are shown in Figures 6A-6D. 100 mM L-glutamate levels were not used for fitting. Data are reported as mean ± SEM, n=5.

[0194] The best-fit values ​​for the four parameterized logistic equations for (+)-MK801 were obtained from GraphPad's Prism data analysis, as shown below in Tables 18-21 (Tables 19-22): (Values ​​that are not considered to be highly reliable fits are typed in bold and underlined):

[0195] [Table 19]

[0196] [Table 20]

[0197] [Table 21]

[0198] [Table 22]

[0199] Computational analysis with allosteric modulators revealed the following K shown in Table 22 (Table 23): B The % affinity and alpha value were obtained.

[0200] [Table 23]

[0201] 7 Dextromethorphan The effects of dextromethorphan on L-glutamate CRC in four NMDA receptor types are shown in Figures 7A–7D. 100 mM L-glutamate levels were not used for fitting. Data are reported as mean ± SEM, n=5.

[0202] The best-fit values ​​for the four parameterized logistic equations of dextromethorphan were obtained from GraphPad's Prism data analysis, as shown below in Tables 23-26 (Tables 24-27) (values ​​that are not considered to be highly reliable fits are typed in bold and underlined).

[0203] [Table 24]

[0204] [Table 25]

[0205] [Table 26]

[0206] [Table 27]

[0207] Analysis of the allosteric modulator revealed the following K shown in Table 27 (Table 28): B The % affinity and alpha value were obtained.

[0208] [Table 28]

[0209] I. Discussion The effect of L-glutamate on calcium mobilization shows differential activation of NMDAR heterodimer receptors, and EC 50 The ranking is GluN2A > GluN2B ≥ GluN2C > GluN2D, with EC values ​​of 2.5e-7, 1.3e-7, 8.7e-8, and 3.4e-8 respectively. 50 The values ​​were as follows. The ranking of efficacy obtained is consistent with those described in the literature for various methodologies (Paoletti P, Bellone C, and Zhou Q, NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease, Nat. Rev. Neurosci, 14: pp. 383-400, 2013).

[0210] 100 mM L-glutamate induced a transient peak in calcium lasting approximately 90 seconds in all cell lines, and this was more pronounced in GluN2C batches of cells expressing low levels of NMDAR. It can be hypothesized that the effect of 100 mM L-glutamate on intracellular calcium levels is not mediated by NMDAR, but rather by osmotic cellular responses that may lead to the metabolite reaching such high concentrations. The pathways involved in the 100 mM L-glutamate-induced increase in intracellular calcium remain uninvestigated.

[0211] Five test items—dextromethadone, memantine, (±)-ketamine, (+)-MK801, and dextromethorphan—were investigated for their effects on L-glutamate CRC at six selected concentrations. All five test items showed sustained profiles, which was typical for NMDAR pore blockers in the FLIPR calcium assay. (+)-MK801 showed the highest estimated affinity across all NMDAR subtypes, and compared to the other test items, it was able to reduce the % effect of L-glutamate to less than 50% across all NMDAR subtypes at 781 nM. The estimated K of (+)-MK801 was... B The values ​​were ≤150 nM in all NMDAR subtypes. Memantine and (±)-ketamine were within the micromolar range. B The K levels for memantine against GluN2B, GluN2C, and GluN2D, and for (±)-ketamine against GluN2C, were less than micromolar. Dextromethadone and dextromethorphan were estimated to be within the micromolar range for all NMDAR subtypes. B That's what happened.

[0212] None of the compounds were selective in NMDARs containing specific GluN2 subunits, although most compounds showed some preference for the GluN2 subunit. Of all the compounds tested, dextromethadone showed the lowest preference for the subunit. All compounds except (+)-MK801 showed preference for the GluN2C-containing subtype compared to other subtypes containing GluN2A, B, or D (for example, with 100% being the estimated % affinity in NMDARs containing GluN2C, then the estimated % affinity in NMDARs containing GluN2A was 51%, 13%, 11%, and 8% for dextromethadone, dextromethorphan, (±)-ketamine, and memantine, respectively). Only (+)-MK801 showed some preference in NMDARs containing GluN2B.

[0213] [Table 29] TIFF0007869138000031.tif36162

[0214] Fluorescent Imaging Plate Reader (FLIPR) Ca 2+ Assay: Effect of L - Glutamate on Calcium Mobilization. The inventors examined the effect of L - Glutamate at 10 concentrations: 1 mM, 100 μM, 10 μM, 3.3 μM, 1.1 μM, 370 nM, 123 nM, 41 nM, 14 nM, and 4.6 nM. The inventors also examined the effect of 5 compounds (MK - 801, memantine, ketamine, dextromethorphan, and dextromethadone) at 6 concentrations (50 μM, 12.5 μM, 3.1 μM, 781 nM, 195 nM, and 49 nM; 0 concentration is also shown) on 10 concentrations of glutamate listed above (in addition to 0 concentration). Figures 8A - 12J show the % effect of various compounds at various concentrations on L - Glutamate.

[0215] The effect of L - Glutamate on calcium mobilization indicates differential activation of NMDA heterodimer receptor subtypes, and the EC 50 rank was GluN2A > GluN2B ≧ GluN2C > GluN2D. The EC 50 for NMDARs containing GluN2A, GluN2B, GluN2C, and GluN2D were 2.5 μM, 1.3 μM, 870 nM, and 340 nM, respectively. The rank of potency is consistent with that described in the literature (Paoletti et al., 2013) for various methodologies.

[0216] EC 50 By calculating the value for the e - Hill slope (H), the inventors also calculated ECF (where 0 < F < 100, for example, 5, 10, 20, 30, 40, 90, 95, 99) using the following formula.

[0217]

Equation

[0218] In Example 1, the present inventors have reported on EC for NMDAR 50 By applying the e-hill slope value, the following ECF values ​​were obtained, as shown in Table 29 (Table 30).

[0219] [Table 30]

[0220] Under physiological conditions, total Ca2+ ions to cells following excitatory stimulation. 2+ Influx is via different NMDAR subtypes activated by glutamate. 2+ This is the total inflow. Also, Ca 2+ Inflow generally increases in proportion to the concentration of L-glutamic acid up to the maximum effect, as seen in Example 1. In our experiments, Ca 2+ The maximum (99%) effect of glutamate concentration on influx is observed at 250 μM, 45 μM, 19 μM, and 6 μM in NMDAR subtypes expressing GluN2A, GluN2B, GluN2C, and GluN2D heterogeneous cells, respectively: at L-glutamate concentrations higher than the maximum effect concentration, Ca 2+ The inflow did not increase, which is consistent with the literature (Paoletti et al., 2013).

[0221] From the ECF table (Table 29 (Table 30)), it can be seen that lower glutamate concentrations preferentially activate GluN2C and GluN2D subtypes compared to GluN2A and GluN2B subtypes. The preferential activity of dextromethadone against GluN2C (K B Table 28 (Table 29)) and the distribution of GluN2C subtypes in the brain (Hansen et al., 2019) showed that persistent activation (in the presence of low concentrations of glutamate and Mg) was observed. 2+This potentially supports the hypothesis of blockade of a pathologically highly active GluN2C channel (or GluN2D channel) (at resting membrane potential in the presence of blockade), as evidenced by the absence of cognitive side effects (see Example 3). Damage to the glutamate / glutamine cycle and dysfunctional astrocytes (or a decrease in the number of functional astrocytes) accompanied by excessively persistent extracellular synaptic glutamate (even at very low concentrations) are associated with excess Ca 2+ Inflow (in detail, in GluN2C and GluN2D subtypes as disclosed above) can be determined, which can cause neuronal damage, induce MDD and related disorders, and / or reduce neuronal plasticity (with or without PAM and agonists). By preferentially targeting the neuronal portion of the endorphin pathway that is persistently and pathologically activated (shepherding affinity, Example 10), dextromethadone can reduce excess Ca in selected NMDARs. 2+ By downward regulating influx, cellular functionality is restored via the endorphin pathway, and MDD is improved as seen in Example 3.

[0222] Fluorescence Imaging Plate Reader (FLIPR) Ca 2+ In the assay, the effect of L-glutamate on calcium mobilization was observed to be similar to that of physiological Mg 2+ It is not the primary cause of the blocking effect, and the preference of open channel blockers for GluN2C and GluN2D in vivo is compared to 1 mM Mg 2+It should be noted again that in the physiological presence of Mg2+, the performance is improved several times over (Kotermanski SE, Johnson JW. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci. 2009;29(9):2774~2779). Also, NMDAR tri-ethelomers (e.g., NR1-NR2A-NR2B), as well as tri and di-ethelomers containing the NR3A-B subunit, were not tested. Different splice variants of NR1 were also not tested. These additional potential subtypes and isoforms of NMDARs add complexity in many ways, but Ca 2+ This also allows for fine-tuning of the inflow, making downstream results increasingly precise [environment-induced (stimulus-induced) Ca 2+ Defined above as a differential pattern of cell influx, the dynamics of which are determined by the NMDAR framework are epigenetic codes.

[0223] The following is about this FLIPR Ca 2+ These are nine points that can be inferred from the assay and Examples 2-7.

[0224] (1) Ca 2+ The L-glutamate concentration-dependent (M) effect on mobilization differs for each subtype of NMDAR tested, A-D, according to the subtype's dependency order. Other NMDAR subtypes and isoforms, such as tri-etheromers (e.g., NR1-NR2A-NR2B), as well as the NR3A-B subunits containing di- and tri-etheromers, and different splice variants of NR1, also differ. 2+ It is easy to show a differential ranking of mobilization effects. The following are examples of known and promising tetrameric NMDAR subtypes (a possible NMDAR subtype requires a tetrameric structure and at least two NR1 subunits; each possible subtype has potentially unique functional characteristics, as well as expression and regional distribution): (NR1-NR1 tetrahomomer) NR1-NR2A diheteromer NR1-NR2A-NR2B triheteromer NR1-NR2A-NR2C triheteromer NR1-NR2A-NR2D triheteromer NR1-NR2B Dietelomer NR1-NR2B-NR2C triheteromer NR1-NR2B-NR2D triheteromer NR1-NR2C diheteromer NR1-NR2C-NR2D triheteromer NR1-NR2D diheteromer NR1-NR3A diheteromer NR1-NR2A-NR3A triheteromer NR1-NR2B-NR3A triheteromer NR1-NR2C-NR3A triheteromer NR1-NR2D-NR3A triheteromer NR1-NR3B diheteromer NR1-NR2A-NR3B triheteromer NR1-NR2B-NR3B triheteromer NR1-NR2C-NR3B triheteromer NR1-NR2D-NR3B triheteromer NR1-NR3A-NR3B triheteromer

[0225] (2) Total postsynaptic Ca at a given synapse 2+ Influx is a function of L-glutamate (M) concentration / time in the synaptic cleft, i.e., the amount of glutamate released by the presynaptic axon terminal (and its clearance by EAAT) (stimulus-dependent).

[0226] (3) Except for the amount of presynaptic glutamate release, Ca in postsynaptic cells 2+Influx is also a function of the NMDAR framework (the NMDAR framework is closely related to postsynaptic density) of NMDARs (and AMPAR under physiological conditions) expressed by the postsynaptic cell membrane in the synaptic cleft (including NMDAR density and subtypes within the synaptic "hotspot," the density, subtypes, and location of postsynaptic glutamate receptors, and the area of ​​approximately 100 nm closest to presynaptic glutamate release). AMPAR expression determines the voltage-dependent activation of NMDARs (Mg 2+ Deactivation of blockage): In this experiment, Mg 2+ The absence of is assumed to be because the voltage gating has been surpassed or is not required (Mg 2+ There are NMDAR subtypes that are independent of or not very dependent on blockade, such as subtypes containing GluN2C, GluN2D, and GluN3 subunits: Dextromethadone is incomplete Mg in the NMDAR channel pores at resting membrane potential. 2+ (These subtypes are more likely to be activated due to blockade). The NMDAR framework measures the total Ca over a given time period in a predetermined amount of glutamate released presynaptically and present in the synaptic cleft (e.g., remaining surrounding glutamate and potential defects in astrocytes and EAATs). 2+ Determine the inflow (epigenetic code) (specific Ca 2+ Fine-tuning of the inflow rate.

[0227] (4) More generally, the total Ca 2+ The influx is related to the concentration of L-glutamate reaching the NMDAR framework and the time constant of glutamate clearance from the synaptic cleft by EAAT.

[0228] (5) Ca 2+ The postsynaptic influx pattern has an effect on neuronal plasticity, namely the total Ca to the relative expression of synaptic proteins, including AMPAR, and more importantly, NMDAR (see Example 2), which are essential for the assembly of glutamate receptors. 2+Determine the LTP and / or LTD, including the effect of inflow: total Ca 2+ Influx is therefore regulated by NMDARs, and modulates NMDARs. This working hypothesis provides the backbone for neuroplasticity (LTP / LTD, memory, connectome, personality, self-awareness), and, from a broader perspective, for Ca as a process that continues from conception to death. 2+ Through influx, it provides a backbone to NMDARs, which are central to the epigenetic regulation of the genetic code.

[0229] (6)Ca 2+ When the influx is excessive (high concentration / prolonged glutamate exposure or glutamate + PAM or glutamate + agonist or glutamate clearance deficiency), cellular function is impaired (including synaptic protein production and, consequently, neural plasticity), and this excess Ca 2+ When the influx reaches a certain level, cells may undergo apoptosis (excitotoxicity).

[0230] (7) Ca 2+ Differential inflow patterns (Ca 2+ The sum of (invading via different NMDARs at a given synapse) modulates downstream effects. In some neurons, x mEq of Ca to postsynaptic (and presynaptic) neurons 2+ Inflow [For example, x = mEq amount of Ca] 2+ Influx is determined by EC100 with phasic glutamate (for example, a physiological amount of 1 mM released by the presynaptic cell, or even as little as 6 μM shown in the ECF table above for the GluN2D subtype (Table 29 (Table 30)) can determine sufficient activation) and determines LTP, i.e., synaptic potentiation. In the same neuron, x mEq of Ca 2+ Ca exceeding 2+ Inflow [For example, x = mEq amount of Ca] 2+Influx is determined by EC100 glutamate maintained over a long period (e.g., physiological 1 mM or even as low as 6 μM, as shown in the ECF table above - Table 29 (Table 30)), which can instead determine LTD and synaptic fragility. The NMDAR framework, which is variable in different neurons and regions of the brain and has different expression phases (e.g., switching of expression), is important for determining LTP or LTD (Sava A, Formaggio E, Carignani C, Andreetta F, Bettini E, Griffante C. NMDA-induced ERK signalling is mediated by NR2B subunit in rat cortical neurons and switches from positive to negative depending on stage of development. Neuropharmacology. 2012;62(2):925-932).

[0231] (8) Each cell line tested in the FLIPR assay overexpresses one NMDAR subtype. Different cell lines, such as ARPE-19 expressing all four subtypes (A-D) (and possibly other subtypes and different isoforms) at differential densities (NMDAR framework), express similar Ca 2+ For mobilization and downstream effects, differential concentrations (EC100) of L-glutamic acid are required (see Example 2).

[0232] (9) Finally, presynaptic NMDAR receptors are also important for their regulatory effects on the amount of presynaptic glutamate released in response to stimulation.

[0233] Dextromethadone and four other test compounds showed L-glutamate concentration response curves (CRCs) at 11 concentrations in each heterogeneous cell line expressing one of four different NMDAR subtypes A-D, at six selected concentrations (50 μM, 12.5 μM, 3.1 μM, 781 nM, 195 nM, and 49 nM; 0 is also shown). 2+ The effects of these on influx were investigated. For all compounds tested, including dextromethadone, and for all NMDAR subtypes (A-D) tested, dextromethadone showed a low micromolar range of K B Using (M) (calculated estimate of receptor affinity), a sustained profile typical of NMDAR pore blockers in the FLIPR calcium assay was demonstrated.

[0234] Same FLIPR Ca 2+ In the assay, the inventors tested the NMDAR pore blockers memantine, ketamine, and dextromethorphan, all of which are currently approved by the FDA, and found that +)-MK-801 had a higher affinity for the experimental NMDAR pore blockers. B Table 28 (Table 29) shows extracellular Mg 2+ We report the calculated estimate of NMDAR binding affinity without any modifications.

[0235] None of the tested compounds were selective for NMDARs containing a specific GluN2 subunit; however, all compounds containing dextromethadone showed preference for some NMDAR subtypes.

[0236] The inventors disclose that all FDA-approved NMDAR blockers and dextromethadone tested showed a relative preference for subtypes containing the 2C subunit. MK-801, an NMDAR blocker with high affinity and low tolerance, instead shows a preference for subtypes containing the 2B subunit. Initially, the inventors disclose that dextromethadone shows a preference for subtypes containing the 2C subunit (K BTable 28 (Table 29) discloses the following. In the same table, the inventors also show that dextromethadone exhibits minimal variability across all tested subtypes, which may be an important feature for safety as implied by Example 3 (similar side effect profile to placebo at the MDD effective dose). As shown in the above ECF table (Table 29 (Table 30)), the glutamate concentrations required for sustained activation of subtypes containing 2C and 2D subunits are extremely low, suggesting the potential importance of dextromethadone's action in these subtypes.

[0237] The clinically well-tolerated NMDAR channel blockers, dextromethadone and dextromethorphan, are therapeutically administered in all subtypes for MDD at low micromolar ranges. B This shows that ketamine is therapeutic for MDD, and nanomolar K in GluN2C B (Furthermore, GluN2D shows approximately five times higher affinity compared to dextromethadone and dextromethorphan), suggesting that excessive blockade of Glu2NC and / or GluN2D may cause cognitive side effects, as suggested by the dissociative effects observed in over 70% of patients treated with esketamine for MDD.

[0238] If the estimated % affinity for GluN2C-containing NMDARs is set to 100%, then the estimated % affinity for GluN2A-containing NMDARs was 51%, 13%, 11%, and 8% for dextromethadone, dextromethorphan, (±)-ketamine, and memantine, respectively.

[0239] Memantine, which is ineffective against MDD, is found in nanomolar forms of GluN2B, GluN2C, and GluN2D. B This indicates.

[0240] Notably, all approved NMDAR blockers have a micromolar K in the GluN2A subtype. BThis is shown, however, not in MK-801, which is clinically poorly tolerated, suggesting that this subtype may be particularly important for cognitive function. A similar argument can be applied to the high affinity of MK-801 for the GluN2B subtype. Both of these subtypes, GluN2a and GluN2B, have physiological Mg compared to the GluN2C and GluN2D subtypes. 2+ They are highly sensitive to blockade, which makes the GluN2C and GluN2D subtypes less likely to be targeted by channel pore blockers: the channel is Mg 2+ If the pores are already completely blocked, the effects of other pore-blocking agents may be irrelevant.

[0241] Three NMDAR blockers effective for MDD are GluN2B and micromolar K B However, memantine, which is ineffective against MDD, is present in nanomolar K in GluNB. B MK-801, which exhibits poor clinical tolerance, also has a low nanomolar K in the same subtype. B This indicates.

[0242] In summary, these data suggest that clinically tolerable NMDAR blockers effective for MDD may preferentially act on GluN2C and / or GluN2D subtypes, while relatively conserving GluN2A and GluN2B. Notably, this conservative effect of clinically tolerable NMDAR blockers effective for MDD is related to physiological magnesium. 2+ Due to the blockage, the correlation is even more likely to occur in vivo.

[0243] As expected, the high-potency channel blocker (+)-MK-801 showed the best estimated affinity across all NMDAR subtypes, reducing the % effect of L-glutamate to less than 50% across all NMDAR subtypes at 781 nM. B The value was ≤150 nM for all NMDAR subtypes tested.

[0244] Compared to other tested NMDAR pore blockers, dextromethadone is K B It showed the least NMDAR subtype preference. This relative lack of NMDAR subtype selectivity may also explain the excellent tolerability and safety profile, indistinguishable from placebo at therapeutic doses for MDD, while maintaining a slight preference for GluN2C over 2A (a property common to dextromethorphan, ketamine, and memantine) (see Example 3). This superior tolerability and safety profile, indistinguishable from placebo at therapeutic doses for MDD, suggests that in tested MDD patients [Example 3, patients screened at SAFER (Desseilles et al., Massachusetts General Hospital SAFER Criteria for Clinical Trials and Research. Harvard Review of Psychiatry. Psychopharmacology, September-October 2013; 21(5) pp. 1-6)], dextromethadone can selectively block only highly active (pathologically highly active) NMDARs without interference to physiologically acting NMDARs, and therefore without side effects including the cognitive side effects typical of NMDAR blockers (more than 70% of MDD patients treated with therapeutic doses of esketamine experienced “schizoid” cognitive side effects, suggesting that this drug actually acts on physiologically acting NMDARs instead). GluN2C and 2D subtypes (compared to GluN2A and GluN2B, as seen in our ECF table, Table 29 (Table 30)) may exhibit sustained high activity at low concentrations of glutamate. These two subtypes, 2A and 2B, are instead further dependent on phasic stimulation (depolarization) induced by stimulus-dependent presynaptic release of high concentrations of glutamate, and a constant Ca 2+ Before allowing inflow, Mg 2+Reversal of blockade is required (Kuner T, Schoeffer R. Multiple structural elements determine subunit specificity of Mg2+ block in NMDA receptor channels. J Neurosci. 1996;16(11):3549~3558). Mg 2+ Persistence of GluN2C and GluN2D in the presence of blockade 2+ Permeability (low levels) for ketamine, dextromethorphan, and memantine (all FDA-approved drugs) was determined by the inventors' FLIPR assay (Mg 2+ These subtypes (specifically the GluN2C type) disclosed by [Name of Distributor] improve relative preference several times over (Kotermanski et al., 2009), and in the case of dextromethadone, it supports the mechanism of action disclosed by the inventors for disease-modifying effects.

[0245] The relatively weak blockade of the GluN2A subtype induced by dextromethadone at higher glutamate concentrations, compared to the blockade of the GluN2C (and GluN2D) subtype at lower concentrations, suggests a preferential effect against persistently pathologically active NMDARs compared to physiologically phasic active NMDARs (see the table above and Example 5).

[0246] Another possible explanation for the superior safety and tolerability of dextromethadone may involve the "on," "off," and "trapping" modes of interaction between dextromethadone and NMDARs (see Example 6): Dextromethadone exhibits a 1 / 10th GluN-GluN2C NMDAR subtype potency compared to ketamine, as disclosed by the inventors in these experiments (Example 1, Table 28 (Table 29) and Example 6, Part I: similar "onset" compared to dextromethadone at 1 / 10th ketamine concentration (Example 6, Part I). Dextromethadone matches ketamine in "trapping" (Example 6, Part II)). When this finding is compared to the lower "trapping" of memantine, the relatively high "trapping" and relatively low micromolarity are both desirable features for a clinically effective drug for MDD and a safe NMDAR channel blocker. Memantine, which exhibits relatively low "trapping" (Mealing GA, Lanthorn TH, Small DL et al., Structural modifications to an N-methyl-D-aspartate receptor antagonist result in large differences in trapping block. J Pharmacol Exp Ther. 2001;297(3):906~914), does not act in MDD, but this is likely to result in relatively better tolerability compared to ketamine, a drug with similar affinity but higher trapping compared to memantine. Ketamine, which has both high potency and high "trapping," has a dissociative effect. Dextromethadone, which exhibits "trapping" similar to ketamine but with lower potency, is instead well-tolerated at therapeutic doses without cognitive side effects.

[0247] Furthermore, the absence of cognitive side effects at therapeutic doses (see Example 3) suggests that physiological NMDAR functional values, such as phasic Glu2A-D activity, are not affected by dextromethadone. In Example 6, Part III, the inventors used Mg 2+And in the presence of low glutamate concentrations, the effect of dextromethadone is Mg 2+ This shows how it relates to membrane polarity, as well as the blockage caused by it. This novel disclosure also relates to physiological Mg 2+ Dextromethadone acts best near the resting potential, and is precisely Mg during the voltage-dependent phase of NMDAR activation. 2+ This explains that dextromethadone does not have cognitive side effects, such as being excreted through pores.

[0248] Furthermore, dextromethadone, with or without PAM and / or agonists, is ca with extremely low concentrations of glutamate. 2+ By reducing the inflow (Example 5), it is again shown that when high concentrations of glutamate are present in the presence of Mg2+, its action may not be involved in physiologically phased NMDAR function. Very low concentrations of glutamate do not activate AMPAR, and consequently Mg 2+ Because it does not reduce the blockade, in vivo this Ca 2+ The decrease in inflow may therefore not be related to the GluN2A and GluN2B subtypes, and these subtypes may be related to Ca 2+ While it is impermeable to Mg 2+ It is blocked by Mg 2+ Since it is relatively independent of blockade, it may be related to GluN2C and Glun2D (low level Ca 2+ This is due to its permeability (Kuner et al., 1996; Kotermanski et al., 2009). In summary, these findings and observations suggest that the effect of dextromethadone is sustained and pathologically activated by low concentrations of glutamate, including NMDARs containing GluN2C and GluN2D (Example 6, Part III), and / or Mg 2+ This suggests that other NMDAR subtypes that are not significantly affected by the blockade, or are not affected at all (e.g., subtypes containing the Glun3 subunit), may become preferred.

[0249] To simplify further, voltage-gated NMDARs, which physiologically open and close in response to various stimuli and are directed by highly physiologically phaotic glutamate concentrations, may be relatively unaffected by dextromethadone channel blockade. Furthermore, the "on" phase (several seconds) of dextromethadone is induced by the stimulus Ca 2+ It may not be fast enough to block the flow (this timing hypothesis for dextromethadone "on" is based on Example 6 Part I, and Ca by dextromethadone in different NMDAR subtypes following the known dynamics of NMDAR GluN2D>GluN2C>GluN2B>GluN2A). 2+ As supported by the prioritization of inflow blockade, subtypes that remain open longer after stimulation can be blocked more effectively, thus allowing Ca through these channels to be blocked. 2+ Inflow is more effectively reduced with dextromethadone (Example 1), and the cause of dextromethadone's blocking activity is more likely to be the resting membrane potential. Therefore, dextromethadone is persistent and pathologically highly active in NMDARs, namely PAM and other agonists, in the presence or absence of 0.04 and 0.2 microM L-glutamic acid, as seen in Example 5, in the presence or absence of gentamicin and / or quinolinic acid, and MG 2+ In the absence of blockade, it is potentially selective for NMDARs that are persistently activated by chronically low concentrations of glutamate.

[0250] The short-term physiological concentration of L-glutamate (e.g., 1 mM phasic glutamate) (the physiological decay time constant for glutamate is 1 ms) may, instead, be unaffected by dextromethadone, as suggested by the absence of cognitive side effects of dextromethadone at doses effective for treating MDD (Example 3) and the long "onset" required for the action of dextromethadone (Example 6). The preference of the GluN2C subtype observed in ketamine is in the nanomolar range, and this difference compared to micromolar dextromethadone and dextromethorphan may explain the dissociative effect of ketamine at therapeutic doses for MDD. The effect of dextromethadone was also evident when PAM and / or agonists were added (see Example 5). Ca 2+ The effect of dextromethadone on downregulation of influx can be mediated not only by excitotoxicity, but also by excitotoxicity, as chronically low extracellular glutamate concentrations are likely to be evident due to poor clearance (e.g., due to poor EAAT activity), for several reasons including astrocyte dysfunction or death, including apoptosis, which can be potentially prevented by dextromethadone. The effects of dextromethadone as described herein include:

[0251] (1) Dextromethadone provides sustained blocking of NMDARs, similar to ketamine, dextromethorphan, and memantine, which are FDA-approved NMDA channel blockers (Example 1).

[0252] (2) Dextromethadone, in patients with MDD, provides a rapid and robust therapeutic effect at doses with side effects comparable to placebo (see Example 3), suggesting selectivity for pathologically highly active NMDARs.

[0253] (3) The therapeutic efficacy of dextromethadone for MDD persists beyond receptor occupancy after discontinuation of treatment (see Example 3), which suggests a neuroplastic effect that persists beyond receptor occupancy (including beyond any occupancy of receptors other than NMDARs).

[0254] Based on the points above, the inventors believe that in at least a subset of patients diagnosed with MDD, the impairment is due to excess Ca after high-activity NMDAR. 2+ We conclude that this is potentially caused by inflow. 2+ The influx impairs neuronal function, including synaptic plasticity, in the select neuronal portion of the selection circuit involved in the memory of emotional states (impairing homeostasis, synaptic protein assembly, and BDNF release) (this damage to the formation of new memories of emotional states can be a determinant of mood disorders). Excess Ca caused by non-competitive channel blockers (dextromethadone, ketamine, dextromethorphan) 2+ Blocking the inflow, excess Ca 2+Downregulating influx restores neuronal plasticity, including the synthesis of NMDAR proteins (Example 2). When environmental stimuli reach neurons in the endorphin pathway with restored synaptic capacity (synaptic proteins are ready to assemble and express as functional receptors, and BDNF is ready for release), new emotional memories are generated and the MDD phenotype is weakened. Excessive opening of NMDARs may be caused by excessive stimulation-induced release of presynaptic glutamate (e.g., psychological stressors) and / or decreased glutamate clearance (EEAT deficiency, astrocytic cell pathology), or high NMDAR activity may be caused by PAM or agonists, or by a combination of excess glutamate and PAM or agonists, such as quinolinic acid, as shown with gentamicin in Example 5. The concept of "excessive" glutamate may therefore be more related to exposure time (pathological and sustained activation) rather than the concentration (e.g., 1 mM) reached in a short time (e.g., 1 ms) during physiological and phasic activity. Dextromethadone is caused by Ca toxicosis induced by PAM gentamicin, a known ototoxic and nephrotoxic agent. 2+ The influx (Example 5) can be effectively reduced, and therefore these toxins, and similar toxins caused by PAMs, can potentially be prevented in various cells, including CNS cells. Similarly, in a subset of patients with MDD (or other disorders and diseases), one or more known PAMs (e.g., opioids) of NMDARs may be selective to neurons linked to the plasticity of emotional memory. Lupine, or any other unknown PAM (or agonist), may be linked to the induction or maintenance of disorders or diseases. Excess Ca 2+ Dextromethadone that effectively inhibits the entry of [unclear] is determined by the PAM and agonist of NMDAR (Example 5).

[0255] Furthermore, dextromethorphan is FDA approved (in combination with quinidine) to treat PBA, and in at least a subset of patients with pseudobulbar palsy, it has been shown to catalyze Ca after high-activity NMDARs. 2+The excessive influx of these molecules suggests that it impairs neural function (including neural plasticity) in the selective neuronal portion of the circuit that regulates (influences) emotional expression, which is an essential part of the emotional "memory" circuit.

[0256] Finally, the inventors' FLIPR Ca 2+ Memantine, as tested in the assay, also exerts non-competitive (sustained) NMDAR channel blocking activity, similar to dextromethadone (as shown in Example 1). Memantine is FDA approved for the treatment of moderate to severe dementia and is thought to selectively modulate highly active glutamatergic pathways in these patients [Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease. Int J Geriatr Psychiatry. January 1999;14(1):3-47]. The inventors have shown that in at least a subset of patients with Alzheimer's disease, Ca through highly active NMDARs... 2+ It can be hypothesized that excessive influx of β-amyloid impairs neuronal function (including neuronal plasticity) in the selection neuronal portions of selection circuits involved in cognitive memory processes. The hyperglutamatergic state in Alzheimer's disease is also consistent with the increase in beta-amyloid observed in these patients (Zott B, Simon MM, Hong W et al., A vicious cycle of β-amyloid-dependent neuronal hyperactivation. Science. 2019;365(6453):559-565).

[0257] All of the above evidence suggests that clinically tolerable, non-competitive NMDAR channel blockers may be potentially therapeutic for a great many diseases and disorders induced or maintained by NMDAR dysfunction. Of all known agonists, dextromethadone may be quite useful due to its favorable PK and PD profile at therapeutic doses, as shown in Example 3. For the first time, we disclose the disease-modifying effects of dextromethadone and provide a novel mechanism that explains these novel effects (Examples 1-11). As disclosed by us, the common therapeutic effect brought about by all NMDAR channel blockers is the reaction of Ca through highly active NMDARs. 2+ This is a downward regulation of the excess inflow of Ca. 2+ Inflow impairs the neural plasticity mechanism in the selected neuron portion of the selection circuit. This involves the opening of NMDAR channels and subsequent Ca 2+ The influx is dependent on the glutamate concentration (as shown in Example 1), but under physiological conditions, high concentrations of glutamate lead to excessive (pathological) Ca in a short time (e.g., 1 ms). 2+ It does not cause influx. On the other hand, chronic (persistent) low concentrations of glutamate instead do not cause influx, for example, Mg 2+ Not 100% dependent on blocking (within channel pores, Mg 2+ Low levels of Ca in the presence of 2+ (Permeable) NMDAR, excess (pathological) Ca 2+ Influx can be prolonged. Dextromethadone is likely to selectively act on persistently highly active NMDARs, particularly NR1-GluN2C and NR-1GluN2D, or NR1-GluN3 subtypes, including in the presence or absence of one or more PAMs or agonists (Example 5) (Example 3, no side effects at therapeutic doses).

[0258] Furthermore, in the case of dextromethadone, we are the first to demonstrate that one of the mechanisms of plasticity in rescued neurons is the regulation of selective NMDAR subunits (enhanced transcription and synthesis of NR1 and NR2A subunits, Example 2). This finding not only contributes to explaining the potential therapeutic effects of dextromethadone for treating, preventing, and diagnosing a great many diseases and disorders, but also clarifies the underlying principles and mechanisms of neuronal plasticity: Ca 2+ The influx patterns are regulated not only by NMDARs but also by subsequent NMDAR synthesis and expression, resulting in molecules based on the concept of developmental plasticity, including neural plasticity, which is directed by environmental (epigenetic) stimuli during the process (from conception to death) (G+E paradigm).

[0259] Based on the above evidence, the inventors have found that common codes in neuroplasticity (LTP / LTD, memory, connectome, personality, self-awareness) are not only modulated by NMDARs, but also subsequently modulate NMDARs. 2+ It is assumed that this is represented by a differential pattern. Each subsequent stimulus (glutamate release by the presynaptic neuron) is received separately by the postsynaptic neuron (this results in various patterns of Ca 2+ Because intrusion occurs, stimulation has a unique effect on neural plasticity. 2+ The differential (intrinsic) effects of this pattern occur constantly throughout the lifespan of an individual (at any given moment when many different stimuli reach the neuron) (Ca 2+ Each inflow pattern (which differs from those mentioned above and below due to its impact on the NMDAR framework) determines the individual's constantly reconstructing connectome (memory), and therefore determines their personality and consciousness.

[0260] J. Conclusion (1) The FLIPR calcium assay demonstrated sustained profiles of dextromethadone, memantine, (±)-ketamine, (+)-MK 801, and dextromethorphan against dihetomer human recombinant NMDARs containing GluN1 and one of the GluN2A, GluN2B, GluN2C, or GluN2D subunits. Differential preferences for specific GluN2 subunits were also demonstrated.

[0261] (2) Dextromethadone has low affinity (calculated K) as seen in Example 1. B It acts as a non-competitive (sustained) blocker (low micromolar) as indicated by [the relevant formula]. This finding, along with the results in Examples 2-11, suggests the selectivity of dextromethadone for highly irritating, pathologically highly active NMDARs.

[0262] (3) Ca of dextromethadone, depending on the concentration of glutamic acid (Example 1), after NMDAR analysis. 2+ Differential regulation of inflow is high-stimulation NMDAR (excess Ca 2+ As confirmed by the findings outlined in Example 5, which show that influx of (pathologically highly active) is more effectively blocked than physiologically active NMDARs, this suggests a similar mechanism for other stimuli that potentially activate NMDARs, including PAMs, toxins, and other agonists. Dextromethadone (and potentially other NAMs disclosed by the inventors) blocks Ca from the sum of various stimuli (glutamate, PAMs, and toxins). 2+ If the net effect on inflow is excessive, the pores can only be blocked in the case of extended (persistent) openings.

[0263] (4) Compared to other tested NMDAR pore blockers, dextromethadone has lower potency and lowest potassium content. BThis demonstrated the variability of NMDAR subtypes (in Example 1). This is likely due to the relative lack of NMDAR selectivity of dextromethadone pore channel blockade (along with points 1-2 above), which could potentially contribute to explaining the superior tolerability and safety profile (indistinguishable from placebo) at doses that effectively treat MDD (Example 3, MDD) by selectively blocking only a subset of highly active (sustained and pathologically active) NMDARs.

[0264] (5) Despite point 3, 2C is relatively preferred. Subtype 2C preference may suggest that dextromethadone activity is pathologically and persistently preferred for the highly active 2C subtype [physiologically functioning receptor opening / closing, depolarization and Mg 2+ Because the blockage is regulated by measuring it in milliseconds (e.g., NR1-NR2A subtype) compared to seconds (e.g., NR1-NR2D subtype), the on / off kinetics in dextromethadone (Example 6) can constrain the molecule to a persistently highly active channel (Hansen et al., 2018). The preference in subtypes containing 2C and 2D subunits is relatively weak in these subtypes, due to the presence of Mg 2+ The presence of blockade enhances the effect in vivo (Kotermanski and Johnson, 2009; Example 6). Furthermore, the “on” / “off” kinetics in dextromethadone (Example 6) may not affect the much faster activation / inactivation of phasic NMDARs. The phasic openings of the GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D subtypes were 50 msec, 400 msec, 290 msec, and over 2 seconds, respectively (Hansen et al., 2018). The “onset” in dextromethadone was measured in tens of seconds (Example 6), making it difficult for this molecule to enter the opening channel during stimulus-induced phasic opening. However, in the GluN1-GluN2C and GluN1-GluN2D subtypes (or subtypes containing the N3 subunit), Mg is present within the NMDAR channel. 2+In the presence of Ca, excess inward-facing Ca at the resting membrane potential 2+ When a flow occurs, dextromethadone is responsible for this excess Ca 2+ This could potentially block the inflow (Example 6).

[0265] (Example 2) A. Overview In the experimental studies of this embodiment, the inventors were asked to determine whether (1) the membrane of human retinal pigment epithelial cells (cell line ARPE-19) expresses NMDAR receptor subtypes (GluN1, GluN2A, GluN2B, GluN2C, and GluN2D), (2) dextromethadone mitigates L-glutamate-induced cytotoxicity, (3) dextromethadone modulates the transcription and synthesis of selected NMDAR protein subunits, and (4) dextromethadone increases NMDAR expression. The experiments detailed below demonstrate that dextromethadone upregulates NMDAR membrane expression and, consequently, the NR1 subunit, which is essential for neural plasticity.

[0266] B. Methods and Results 1. Expression of NMDAR subtypes in ARPE-19 cells First, the inventors evaluated the expression of five NMDAR subunits (GluN1, GluN2A, GluN2B, GluN2C, and GluN2D) using immunofluorescence combined with confocal microscopy.

[0267] 7,500 cells / well were seeded on sterile glass coverslips in 24-well plates. Immunofluorescence analysis was performed the following day. The following primary antibodies were used: anti-NMDAR1A (Abcam, ab68144), anti-NMDAR2A (Bioss, bs-3507R-TR), anti-NMDAR2B (Bioss, bs-0222R-TR), anti-NMDAR2C (Invitrogen, PA5-77423), and anti-NMDAR2D (Invitrogen, PA5-77425), and the secondary antibody goat anti-rabbit IgG (GeneTex, GTX213110-04). Images of immunostained cells (see Figures 13A-C) were acquired using a Zeiss LSM800 confocal microscope at 63x magnification. The intensity of the fluorescence signal was quantified using ImageJ software.

[0268] 2. The effect of dextromethadone on glutamate-induced cytotoxicity To confirm the effect of dextromethadone on L-glutamate-induced cytotoxicity in ARPE-19 cells, the inventors performed a cell viability assay. In this experiment, ARPE-19 cells were seeded in 96-well plates (7000 cells / well). These were left overnight in a 37°C incubator with 5% CO2. The following day, the cells were pretreated with dextromethadone solution. After 6 hours, all wells (except control cells) were replaced with 10 mM L-glutamate dissolved in Tris-buffered control salt (CSS). After 5 minutes, the exposure solution was thoroughly washed off and replaced with standard medium. After a 24-hour rest period, cell viability was evaluated by the crystal violet assay. The inventors observed that dextromethadone, tested at 30 microM, suppressed the observed decrease in cell viability induced by L-glutamate treatment, as shown in Figure 14 [this illustrates the cell viability of ARPE-19 cells after treatment with the NMDAR agonist L-glutamate alone (10 mM L-Glu) or in combination with dextromethadone]. ***P<0.001 vs. vehicle-treated control cells (one-way ANOVA, followed by Tukey post-hoc test).

[0269] 3. Effect of dextromethadone on protein expression of NMDAR subunits The inventors conducted additional immunocytochemical studies to determine whether dextromethadone induces the synthesis of selective proteins that form NMDARs.

[0270] In these additional studies, 7,500 cells / well were seeded on sterile glass coverslips in 24-well plates. The following day, the cells were treated with 10 μM dextromethadone for 24 hours, followed by rescue in standard medium for 5 days or 0.05 μM dextromethadone for 6 consecutive days. After 6 days, immunofluorescence analysis was performed using the first and second antibodies described above, in conjunction with confocal microscopy.

[0271] The results are shown in Figures 15A-C. ARPE-19 cells exposed to 0.05 μM dextromethadone for 6 days showed a dramatic increase in NMDAR1 and NMDAR2A subunits, while the inventors observed a significant decrease in NMDAR2B expression. ARPE-19 cells exposed to 10 μM dextromethadone for 24 hours also showed a significant increase in NMDAR1 and NMDAR2A, although this increase was not as pronounced compared to the increase observed in routine incubation. The NMDAR2B subunit did not change with acute treatment.

[0272] C. Discussion and Conclusion Based on the experimental work of this study, it was shown that ARPE-19 cells express all tested NMDAR subunits (NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D). Dextromethadone prevents glutamate excitotoxicity in ARPE-19 cells, and at the tested concentrations (10 μM and 0.05 μM), dextromethadone dramatically upmodulates the NR1 and NR2A subunits but has no effect (10 μM), or downmodulates the NR2B subunit (0.05 μM).

[0273] The observed modifying effect on the NMDAR subunit is due to the non-competitive NMDAR blockade and excess calcium of dextromethadone. 2+ This is potentially determined by the downward regulation of inflow (see Example 1). Without glutamate stimulation, we found that excess Ca is inhibited by dextromethadone. 2+ We hypothesize that the influx is mediated by an agonist effect resulting from a deficiency of NMDARs expressed on the membrane of ARPE-19 cells.

[0274] Further excess calcium via pathologically highly active NMDARs, which were excessively stimulated by high concentrations of glutamic acid (10 mM). 2+ Invasion causes excitotoxicity resulting from a decrease in ARPE-19 cell viability (as shown in Figure 14).

[0275] Dextromethadone, which has been found to provide a rapid, sustained, and robust antidepressant effect in patients diagnosed with MDD (see Example 3 below), is disclosed for the first time in this application. The therapeutic effect in MDD appears to be due to a prolonged sharp drop in plasma levels after abrupt discontinuation of dextromethadone (as shown in Example 3), suggesting a mechanism of action based on neuroplasticity.

[0276] Furthermore, dextromethadone, which has been shown to differentially regulate subunits in ARPE-19 cells, including GluN2C and GluN2D subunits, is disclosed herein for the first time.

[0277] The regulation of transcription and synthesis of NMDAR subunits, which potentially regulate NMDAR expression (the NR1 subunit is required for NMDAR expression in the cell membrane), not only contributes to explaining the mechanism of action of dextromethadone and other non-competitive NMDAR channel blockers in the therapeutic effect of MDD, but may also provide important insights into the physiological and pathological roles of NMDARs. The inventors of the present invention have found that Ca 2+ The differential pattern of influx is regulated by NMDARs activated by glutamate (with or without PAM or other glutamate agonists) or other stimuli (e.g., light), and Ca 2+ These influx patterns suggest that they subsequently regulate NMDAR expression in the cell membrane (NMDAR framework). Neural plasticity is regulated, and also via NMDARs. 2+ It is regulated (encoded) by differential patterns of influx (a common epigenetic code for neural plasticity).

[0278] Based on these experimental results in ARPE-19, the inventors hypothesize that different glutamate concentrations may act as shown in Figure 16.

[0279] NR1 was selected as a measure of neural plasticity because this subunit is required for the expression of all NMDAR subtypes NR1-NR2A, NR1-NR2B, NR1-NR2C, and NR1-NR2D.

[0280] The Y-axis in Figure 16 shows hypothetical values, where the formula represents the minimum environmental stimulus (assumption) "e.g., no light exposure in a dark room," and 8000 = NR1 at glutamate concentrations of 0 or very low nM; 10000 = NR1 at 0.37 μM glutamate concentrations; 12000 at 1-10 mM glutamate concentrations such as 1.1: Around this glutamate concentration, and especially when prolonged, NR1 (as a measure of neuronal plasticity) begins to decrease to baseline levels (no glutamate) and lower.

[0281] The X-axis in Figure 16 shows glutamic acid at different concentrations (M): 0.001, 0.37 μM, 1.1 μM, 3.3 μM, 10 μM, 50 μM, 100 μM, 300 μM, 1 mM, 5 mM, 10 mM, 50 mM, and 100 mM.

[0282] The X values ​​(glutamate μM) and Y values ​​(assumed) for the NR1 subunit at different glutamate concentrations are shown in the legend of Figure 16.

[0283] in vivo Ca 2+ The amount of influx is relatively low, and the extracellular glutamate concentration in the synaptic cleft is low, for example, low nM, Mg 2+ Given the relatively insensitive nature of GluN2C to blockade, and even when mediated through pathologically activated NMDARs, it should be considered that this can lead to "excess" (causing excitotoxicity and cessation of neuroplasticity mechanisms).

[0284] Therefore, in summary, (1) dextromethadone differentially prevents glutamate-induced excitotoxicity, (2) dextromethadone differentially regulates mRNA and NMDAR receptor subunit synthesis, and (3) dextromethadone induction of mRNA and NMDAR receptor subunit synthesis are differential with respect to different subtypes and levels of stimulation.

[0285] (Example 3) A. Overview This embodiment describes a phase 2 trial of two doses of dextromethadone in MDD patients screened by SAFER. Through this trial, the inventors demonstrate that dextromethadone is effective as a disease-modifying treatment for MDD. In particular, the inventors determined that: (1) Dextromethadone is safe and well-tolerated in MDD patients, has an indistinguishable side effect profile from placebo at disease-modifying doses, preserves physiologically active NMDARs, and treats hyperstimulated NMDARs (pathologically hyperactive, excessive Ca...). 2+(2) This suggests a selective effect on (influx of) the receptor; and (3) Dextromethadone exhibits a sustained therapeutic effect for at least 7 days after discontinuation of treatment, and this therapeutic effect is attributed to neuroplasticity that persists beyond the occupancy of NMDAR or other receptor pore channel sites by dextromethadone.

[0286] Therefore, (1) the known role of NMDAR in the formation of memory including LTP, LTD, and affective memory (a subset of the target memory in light of Example 3) (Baez et al., 2018); (2) the effect of dextromethadone, particularly the NMDAR GluN1-GluN2C subtype (Example 1) on the activation of genes for the production of synaptic proteins including the GluN2C subunit (Example 2) (excess Ca via NMDAR) 2+ In light of (3) increased neurotrophic factors, including BDNF, induced by dextromethadone in both humans and experimentally; (4) improvement of experimental depressive phenotype; and (5) results of the Phase 2a trial of Example 3, we have for the first time determined that dextromethadone is disease-modifying, and therefore potentially curative, for MDD.

[0287] Furthermore, dextromethadone can be transmitted via NMDAR to Ca 2+ By downwardly regulating the inflow (see Example 1) and consequently regulating NMDAR (see Example 2), the inventors have found that Ca as an epigenetic code related to neuronal plasticity in health and disease 2+ We will observe the significant impact of differential inflow patterns.

[0288] Furthermore, in consideration of these new findings, the inventors have determined that excess Ca is detrimental to the impairment of the physiological activity of cells. 2+ By reversing the influx effect, we can reverse the overstimulation / overactivity of NMDARs and excess Ca in selected cells (including extra-CNS cells) that express NMDARs on the cell membrane. 2+It is also disclosed that this can be applied to numerous diseases and disorders that are induced, maintained, or aggravated by influx. In the case of neurons, the inventors have shown that cellular functions related to neuronal plasticity (LTP+LTD) can be restored at the molecular level in vitro. This has been demonstrated in both experimental models (see Example 2) and patients (see Example 3) without affecting normally (physiologically) functioning neurons, as indicated by a placebo-equivalent side effect profile observed in MDD patients (as shown in Example 3).

[0289] B. Lessons from Dextromethadone in Health and Disease The molecular effects of dextromethadone outlined above are useful in explaining brain activity not only in pathological states but also in healthy conditions, and the imbalances potentially induced, maintained, or exacerbated by hyperactive NMDARs support the concept of a continuum between health and disease.

[0290] This disclosure demonstrates that dextromethadone can protect “normal” healthy subjects from potential CNS damage caused by severe psychological stress by preferentially blocking the pathologically hyperactive NMDAR subtype GluN1-GluN2C (Example 1). When a sufficient number of NMDARs are pathologically hyperactive in a sufficient number of neurons as part of discrete CNS circuits for a sufficient period of time (e.g., during pathologically persistent activation of a particular GluN2C subtype that may result from a stressful state), those neurons and their circuits are impaired, and clusters of symptoms (disease or impairment) specific to the impaired circuit appear.

[0291] During "mental health" (a balanced mental state that is not altered by excessive or abnormal stimuli, including allosteric modulators), the intensity and frequency of stimulation (presynaptic glutamate release) induce Ca 2+The differential influx patterns are regulated by the "normal" postsynaptic glutamate framework. This framework depends on genetic determinants present from conception [seven genes: GRIN1 (with eight splice variants), Grin2A, 2B, 2C, 2D, 3A, and 3B], and simultaneously on epigenetic determinants, initiating at conception and constantly shaping the framework. The different subunits encoded by the seven genes assemble into tetramers with the essential NR1 subunit (required for NMDAR membrane expression), as well as the 2A-D and / or 3A-B subunits. The 3A and 3B subunits, which lack glutamate agonist sites, may also potentially substitute for the NR1 subunit in the tetrameric structure.

[0292] Ca containing NMDAR 2+ Ca through channels 2+ The differential inflow is an epigenetic determinant that directs cellular translational and synthetic activity, including the formation of the synaptic framework itself, in the self-learning paradigm (see Example 2). Environmental stimuli, via glutamate-mediated excitatory stimuli, Ca 2+ This is converted into a differential inflow. Environmental stimuli begin at conception (NMDAR channels are present in gametocytes and zygotes) and continue throughout the lifespan of the individual, directing the framework of NMDAR synapses (along with other epigenetic directives that direct development, they also direct the transcription of seven NMDAR genes, as seen in Example 2). This continuous exposure to environmental stimuli, which begins at conception, including embryonic exposure in the uterus (the precise amount of Ca regulated by NMDARs in cells). 2+ Ca (which is always translated into influx) constantly regulates cellular function and simultaneously auto-regulates the NMDAR framework. Even the same (identical) stimulus can have differential Ca reactions on the synaptic framework, including NMDAR expression. 2+It exerts differential effects due to its pattern-modulating action. (Differential effects generally fall within physiological parameters that manifest due to widespread individual variation within a species: the greater the possible variation in NMDAR subtypes and their combinations, the greater the individual differences that can occur within a given species sharing a similar NMDAR framework.) The code (Ca) regulated by this ion channel (NMDAR) 2+ The influx pattern instructs gene activation from conception and forms individuals based on continuous interaction with the environment (by selecting which genes to activate). This supports the long-held assumption that humans (and other species) are not only shaped by the environment but are also integrated with it (although each individual represents only a small contribution to that whole).

[0293] (1) Environmental stimuli (translated into impulses to presynaptic neurons resulting in presynaptic axonal glutamate release) and (2) a constant, continuous interaction between the postsynaptic (and presynaptic, Baretta and Jones 1996) received synaptic glutamate framework (mediated by glutamate in the presence of glycine and modulated by numerous PAMs and NAMs, as well as potentially other agonists) Ca 2+ Adjust the differential patterns of inflow. At the same time (i.e., then), the same framework of NMDAR adjusts these Ca 2+ Because it is regulated by differential patterns of inflow, Ca 2+ The pattern precisely modulates cellular activity based not only on the current stimulus [glutamate + mediator (agonist) + modulator (PAM and NAM)] but also on past environmental stimuli, including the immediate preceding stimulus. Learning / memory, including emotional memory and prediction (a form of learning / memory that creates the future based on past experiences, as opposed to recollection which similarly creates the past based on past experiences), is Ca 2+ This is a form of structural (synaptic) neuronal plasticity precisely etched by environmental stimuli converted into inflow patterns. 2+The inflow pattern modulates the effects of environmental inputs (the effects of each stimulus) by constantly forming the framework of NMDARs. Dextromethadone is a pathologically hyperactive NMDAR Ca 2+ By adjusting the inflow pattern downwards (Examples 1 and 3), we determine long-term modifications of the NMDAR framework, such as neuroplasticity (Example 2), including neuroplastic effects (induction of synaptic proteins and neurotrophic factors) that manifest themselves as therapeutic agents for MDD (as shown in Example 3).

[0294] Based on our experimental findings in vitro (Examples 1, 2, 5, 6) and in MDD patients treated with dextromethadone (Example 3), we have determined that Ca 2+ We can hypothesize here that not only are differential influx patterns regulated by the NMDAR framework, but these same patterns, in turn, regulate and determine the NMDAR framework over time [neural plasticity (LTP and LTD) occurring throughout the lifespan of an individual from conception to death]. Ca via selective NMDARs 2+ This modulatory effect of dextromethadone on inflow (Example 1) and downstream neuroplasticity (Example 2) may lead to a cure for MDD (Example 3) by enabling cells to restart neuroplastic mechanisms (synaptic protein synthesis and assembly, neurotrophic factor synthesis and release), as well as by enabling the formation of new layers of emotional memory, neutralizing, or reversing previous pathological emotional memories and their effects.

[0295] Physiological LTD (pruning) that occurs during specific phases of sleep can also be explained by the same mechanism. Ca 2+ The differential pattern is regulated by NMDAR expression, and dextromethadone may have therapeutic effects even during sleep.

[0296] Memory formation, including cognitive, motor, emotional, and social memories, including constructed memories [memories built for prediction / expectation and during recollection (learning, LTP)], as explained by NMDAR-dependent LTP and LTD, is regulated by Ca. 2+ It starts with differential patterns of inflow. These Ca 2+ The differential patterns of influx, under physiological conditions, are determined by stimulus-induced (environmental) presynaptic release of glutamate, leading to the transcription, synthesis, assembly, expression (e.g., AMPAR and NMDAR), and release (neurotrophic factors) of synaptic proteins and neurotrophic factors. This physiological memory formation (LTP and LTD) forms the connectome (the wiring and unwiring of neurons through synapses), which is the basis of individuality and consciousness (see below).

[0297] Affective memory may be conscious: current mood, i.e., mood at any given moment, is determined by existing memories (connectome) + current environmental stimuli (external and internal) reaching the brain, including bodily sensations, and is generally governed by the instinct for species preservation (perception of danger - stress; thoughts about food and sex). Affective memory may also be subconscious (moods that can be retrieved when prompted) or unconscious [synapses that are unstructured (immature) and cannot reach consciousness at a given point in time, but may appear at different points in time due to ongoing (additive - LTP or subtractive - LTD) neuroplasticity and synaptic maturation]. The predictive nature of these emotional memory constructs, and their importance in determining mood and behavior, is well described in Pontius, AA, *Overwhelming Remembrance of Things Past: Proust Portrays Limbic Kindling by External Stimulus-Literary Genius Can Presage Neurobiological Patterns of Puzzling Behavior*, Psychological Reports, 73(2), 1993, pp. 615-621. This study can be re-examined here in light of disclosures presented by the inventors, including the selectivity of dextromethadone and certain open channel blockers to pathological and persistently hyperactive channel subtypes (Examples 1, 3, 5) and / or further selectivity of selective pore blockers to the NMDAR channel portion of the endorphin system (Example 10). Dysfunctional emotional memory (conscious, subconscious, and unconscious, representing an interplay continuum) which may manifest as selective neuropsychiatric disorders, including MDD and related disorders, is of interest to this disclosure.

[0298] The known role of NMDARs in LTP, LTD, and therefore in memory formation is confirmed by the disclosed effects of dextromethadone on NMDARs in Examples 1-11: the effects of dextromethadone are selective and differential with respect to the intensity and frequency of stimulation and the received NMDAR framework (including the effects of agonists and modulators), including selective blockade of persistent and pathologically hyperactive NMDAR pore channels and Ca on neuronal plasticity. 2+ This includes the downstream consequences of differential inflow patterns. In particular, the disclosed therapeutic effect of dextromethadone without cognitive side effects in MDD patients disclosed herein is due to excess Ca 2+ Dextromethadone exerts a selective re-equilibrium effect on hyperactivated NMDARs expressed by cells that have become dysfunctional due to influx (unable to function for the generation of new emotional memories: transcription-synthesis and aggregation-membrane expression of synaptic proteins, and transcription-synthesis and release of neurotrophic factors). 2+ This supports the inventors' hypothesis regarding the downward regulation of entry. Excess Ca via hyperactivated NMDARs 2+ These CNS cells, rendered dysfunctional by influx, are part of a neuronal circuit [a continuously evolving (sustained stimulus-induced LTP-LTD) circuit in the same patient over time], are targets of dextromethadone, and explain its efficacy against MDD, particularly its efficacy against MDD-related disorders and its potential efficacy against numerous neuropsychiatric disorders.

[0299] Without being bound by any theory, the inventors believe that one reason for the rapid therapeutic effect in MDD patients may be the activation of neurons in the mPFC by neurotrophic factors such as BDNF. Another possible explanation for the rapid effect in MDD patients is the interruption of sustained stimulation of inhibitory interneurons projecting to the mPFC (NMDAR blockade). Hyperactive NMDARs cause the cessation of neuroplastic mechanisms in the dendrites of postsynaptic neurons, but they may also allow for depolarization and electrochemical transmission along the axon of the postsynaptic neuron to reach inhibitory interneurons projecting to mPFC neurons. Dextromethadone is Ca 2+ Downregulating inflow may not only allow for the resumption of neuroplastic mechanisms in these persistently hyperstimulated neurons, but also reduce electrochemical transmission, thereby potentially quiescent inhibitory interneurons projecting to mPFC neurons. Furthermore, hyperactivation of NMDARs may lead to clustering of GABAaRs with excessive inhibitory activity reaching selective neurons, such as those in the mPFC. Generally, under chronic stress conditions, activation of interneurons that inhibit mPFCs is thought to serve an evolutionary (species-preserving) purpose by reducing active decision-making during prolonged stress. In MDD, chronic hyperactivation of inhibitory interneurons may be part of a pathological process that is potentially modified instead by dextromethadone.

[0300] C. dextromethadone modulates NMDARs and neuroplasticity. In light of the above observations and experimental results, the inventors hypothesize that in health and disease, emotions (e.g., satisfaction, happiness, sadness, anxiety, etc.) originate from conscious, latent, or unconscious emotional memories (LTP and LTD in neurons, which are part of the emotional circuit). These emotional memories enter the cell via NMDAR and are induced by glutamate, which determines structural LTP and LTD. 2+They are "learned" through inflow patterns (these cells include neurons, which are part of neural circuits). These circuits are Ca via NMDARs. 2+ Through continuous neural plasticity regulated by differential inflow patterns, it evolves during lifespan. Learned emotions (emotions are learning circuits like other learning neuronal circuits such as cognitive, motor, and social memory circuits) are stimulus-driven, NMDAR-regulated Ca 2+ Differential patterns of inflow (as shown above, these Ca 2+ The differential pattern of influx also modulates regulators, i.e., it modulates the NMDAR framework by inducing the production of NMDAR subunits and nerve growth factor, as shown in Example 2, which is encoded via this process. Virtually all stimuli from the external environment, including stimuli entering through sensory organs such as light and sound, as well as other stimuli, are translated into glutamate release, which activates NMDARs, and Ca 2+ It induces differential patterns of influx. Other external environmental stimuli, including pH, may be molecules that enter the individual's bloodstream or are formed by metabolic pathways, and can function as NMDAR agonists or PAMs and / or NAMs. Learning (neural plasticity) circuits that control emotions and their manifestation (emotional states) are affected when NMDARs are excessively stimulated, altering the functionality and structure of cells and their circuits. 2+ This can be impaired by causing inflow patterns (for example, excessive Ca 2+ This influx leads to decreased neural plasticity, including reduced transcription and production of synaptic proteins, including NMDAR subunits and BDNF.

[0301] Furthermore, the present inventors have shown that the pathological hyperactivity of selected neurons (excessive Ca 2+ The inflow NMDAR channel is blocked by dextromethadone, Ca 2+ Inflow (inward Ca) 2+Lowering the current (as seen in Example 1) restarts the neural plasticity mechanism [synthesis of synaptic proteins containing NMDAR subunits (Example 2) and neurotrophic factors such as BDNF], and modifies the MDD phenotype (Example 3).

[0302] Interruption of NMDAR hyperstimulation can occur without pharmacological NMDAR blockade. For example, in mild cases of depression or anxiety, the removal of the triggering stressful psychological stimulus itself leads to a sharp decrease in presynaptic glutamate release, and this decrease in "excessive" glutamate release is exerted by dextromethadone's NMDAR channel blockade. 2+ Similar to the effect on neural plasticity caused by the decrease in inflow, the previously excess Ca 2+ It downregulates inflow. As a result, cells resume neural plasticity, new channels are formed, BDNF is produced and released, new “healthy” emotional memories are formed, and previous “pathological” emotional memories are neutralized. This explains the spontaneous recovery of patients with MDD and related neuropsychiatric disorders (e.g., GAD), as well as the high placebo response commonly seen in the study shown in this Example 3 (and other clinical trials), where 15% and 5% of patients treated with placebo achieved remission on days 7 and 14, respectively. The use of SAFER in our Phase 2a trial (to exclude a subset of patients that may confound clinical trial results) was able to exclude some patients who were likely to respond to placebo, but not all of them.

[0303] The continuous epigenetic reformation of neuronal plasticity (memory formation) is determined by experiences mediated by presynaptic glutamate release [environmental stimuli reaching the individual through various means (not limited to sensory organs) (initiated at conception)], and the resulting Ca2+ regulating neuronal plasticity. 2+ Differential inflow patterns (Ca to postsynaptic neurons) 2+The differential kinetics of influx is regulated by neuronal plasticity through a differential NMDAR framework that constantly changes throughout lifespan. This multi-year change in the membrane expression of the NMDAR framework includes the NMDAR generation switch (Hansen et al., 2018), which underlies all forms of learning (cognitive, motor, emotional, and social memory / learning). Cognitive (e.g., language learning), motor (e.g., walking), emotional (e.g., satisfaction), and social (e.g., starting with nonverbal "imitation" as a communication tool) memory manifests structurally and functionally as stronger or weaker synapses within more (stronger) or less (weaker) connected neuronal circuits. These circuits may be stronger or weaker, and more or less interconnected (connectome individuality). Therefore, memories (the basis of personality), including, but not limited to, emotional memories (the emotional circuit has been studied in more detail in our experimental findings), are constantly shifting from consciousness to the subconscious and then to the unconscious (personality and consciousness are regulated by continuous LTP and LTD and change throughout life).

[0304] Ca regulated by NMDAR via glutamate and / or PAM or NAM 2+ Exposure to specific stimuli that determine specific differential patterns of influx and, consequently, modulate the NMDAR framework, constantly reshapes synapses structurally and functionally (e.g., through synaptic protein synthesis and membrane expression, as well as NGF synthesis and release, including BDNF).

[0305] Ca via NMDAR 2+ The differential patterns of influx are ultimately shared codes that determine differences and similarities between individuals of the same species (individuals of the same species have similar NMDAR frameworks, and individuals of the same society are exposed to similar environmental stimuli, including cultural stimuli that involve the imitation of similar behaviors). 2+ The differential patterns of influx represent epigenetic codes that determine and explain individuality, consciousness, learning and memory, emotions, and preferential communication both within and between species, as will be further discussed below.

[0306] (1) Individuality: Even identical twins with the same NMDAR gene, subtype, and isoform will begin to have different differential experiences (exposure to environmental influences, i.e., exposure to epigenetic influences) when the zygote divides into two separate embryos. Differential exposure to environmental influences (anything outside the zygote and embryo) is mediated by NMDARs and Ca 2+ Differential patterns of influx are determined, differentially regulating development, including neural plasticity, and determining the individuality of the CNS in identical twins (while demonstrating structural differences in the CNS in humans can be difficult, it is a well-known fact that identical twins have different fingerprints at birth, and differential environmental exposure (and their epigenetic effects) has been shown to begin immediately after zygote division). Mutations also differentially affect embryonic development and can explain some differences between identical twins.

[0307] (2) Consciousness: not only the ability to recall learning and learned memories, but also the ability to "reason," create, project, and predict based on learned memories.

[0308] (3) Learning memory: These memories include cognitive, motor, emotional (individual), and social (collective) circuits.

[0309] (4) Personal and social emotions, as well as behaviors, beliefs, religious, political and cultural movements.

[0310] (5) Intraspecies preferential communication: Similar NMDAR frameworks (genetic and epigenetic) expressed on cell membranes generate learning memories that become recognizable and predictable among individuals of the same species living in contact with one another (e.g., tribes, local and regional communities, and nations), and Ca generated by similar environmental stimuli (epigenetic). 2+ It will be translated into similar patterns of inflow.

[0311] (6) Preferential communication between different species: Similar environmental stimuli (epigenetic) fostered by intimacy (e.g., humans and dogs) generate recognizable and predictable learning memories across NMDARs (genetic and epigenetic) Ca 2+ It will be translated into inflow patterns.

[0312] All of the above are Ca2+, which regulates gene expression and neural plasticity. 2+ This is an example of molecular-level learning and memory formation determined by differential patterns of influx. Structural (synaptic / connectome) and functional (acting NMDAR framework) neural plasticity (memory formation) is a continuous, real-time effect of the external environment on the individual's nervous system, and Ca across NMDARs 2+ It is coded by the differential pattern of inflow. Ca of the same pattern 2+ The inflow modulates itself by modulating the NMDAR framework. 2+ The inflow pattern functions as an epigenetic code. Also, in CNS, the epigenetic code is Ca through the pores of NMDAR. 2+ It is represented by differential patterns of inflow.

[0313] Finally, the complex (but seemingly simply chaotic) constant brain activity throughout the lifespan of any individual is elicited by environmental stimuli (epigenetic stimuli) via glutamate / glycine (agonist, mediator) and via PAM-NAM (allosteric modulator) which gates NMDARs. 2+ This can best be understood as the reverberation of downstream effects (mediated by multiple neurotransmitters) of differential inflow patterns. This includes Na via AMPA receptors. + Voltage gating of the NMDAR due to inflow is caused by Mg from holes in the NMDAR channel. 2+ It is important to release the blockage, but cellular activities, including gene regulation, Ca 2+ It is controlled by differential patterns of inflow. The NMDAR framework uses these Ca 2+These Ca are regulators of (and are regulated by) differential patterns of inflow. 2+ The differential patterns of influx function as a shared code for translating environmental stimuli into finely tuned neural plasticity (presynaptic and postsynaptic), and thus play a role in constantly reshaping connectomes (structural memories) in humans and other species.

[0314] Environmental stimuli that translate to glutamate release are first Mg 2+ It may affect persistently active NMDAR channels that are not completely closed by (e.g., C and D), and low concentrations of glutamate (Mg via AMPA activation) 2+ The blockage cannot be released, but persistent Ca 2+ This physiological enhancement of sustained NMDAR activation (as seen in our Example 1 at very low glutamate concentrations) at concentrations high enough to cause / enhance influx (e.g., 40-200 nM) may modulate the neural plasticity mechanism by LTP production (synaptic maturation: by the production of synaptic proteins and neurotrophic factors, and spine formation / enhancement). However, Ca 2+ Excessive influx can disrupt the physiological mechanisms of neuronal plasticity. The novel data disclosed by the inventors in Examples 1-10, along with the potential therapeutic, prophylactic, and diagnostic applications of dextromethadone and related compounds disclosed by the inventors, suggests the potential of excessive Ca through hyperactivated NMDARs. 2+ Dextromethadone exhibits disease-modifying effects on numerous diseases and disorders that are induced, maintained, or exacerbated by ingestion.

[0315] Therefore, dextromethadone, a highly tolerable drug at doses that selectively target persistently and pathologically hyperactive NMDAR channels, is essential for understanding brain function in health and disease, and for identifying pathologically hyperactive NMDARs and excess Ca in select cells essential to tissues, organs, and circuits in humans and other species. 2+Disclosed herein by the inventors as a powerful research and clinical tool for preventing, treating, and diagnosing numerous diseases and disorders caused by ingestion (as discussed in the following "Lessons from Dextromethadone" section).

[0316] D. Lessons from dextromethadone in “disease”: A Phase 2a Trial in MDD Patients In a Phase 2a trial, the oral doses of 25 mg and 50 mg of dextromethadone administered daily to hospitalized MDD patients (diagnosed by SAFER) were investigated.

[0317] 1. Method A Phase 2a, multicenter, RDBPC 3-arm trial evaluated the safety, tolerability, and pharmacokinetics of dextromethadone and explored the efficacy of two oral doses of dextromethadone (also referred to in this example as REL-1017) as a treatment for MDD patients. Patients were adults aged 18–65 years who were unresponsive to appropriate antidepressant treatment in categories 1 (87.1%), 2 (11.3%), or 3 (1.6%). Patients included in the study were those who met the criteria for TRD. After the screening period, 62 patients (x - Age = 49.2 years old, x - HAMD score = 25.3, x -Patients with a MADRS score of 34.0 were randomized in a 1:1:1 ratio to either placebo or dextromethadone 25 mg QDay or dextromethadone 50 mg QDay, in addition to ongoing treatment with SSRIs, SNRIs, or bupropion (in particular, 62 patients were taking one or more of the following: fluoxetine, paroxetine, sertraline, escitalopram, citalopram, bupropion, vortioxetine, venlafaxine, and duloxetine). Patients in the dextromethadone group received a single loading dose of 75 mg (25 mg group) or 100 mg (50 mg group). All patients completed 7 days of hospitalization and were discharged 2 days later, returning for follow-up on days 14 and 21. Potential efficacy was assessed on days 2, 4, 7, and 14 using the MADRS, SDQ, and CGI scales. Safety measures included the 4-PSRS for psychotic symptoms, the CADSS for dissociative symptoms, the COWS for withdrawal symptoms, and the CSSRS for suicidal tendencies. All 62 randomized patients were part of the ITT population analysis.

[0318] Figure 17 shows an overview of the screening and medication regimen for patients in this study. Patient characteristics, demographic features, and MDD severity were homogeneously distributed across the arms, as shown in Table 30 (Table 31) below.

[0319] [Table 31]

[0320] Furthermore, patients in the Phase 2 trial had previously experienced failure with antidepressant treatment. The number of previous failed antidepressant treatments per group is shown in Table 31 (Table 32) below.

[0321] [Table 32]

[0322] Figure 18 shows a table of adverse events that occurred during treatment (a summary of the entire safety analysis population). Figures 19A and 19B show tables of adverse events that occurred during treatment in the safety analysis population, categorized by organ system and basic terminology. Figure 20 shows a table of particularly noteworthy adverse events (AESI) in the safety analysis population, categorized by organ system and basic terminology.

[0323] 2.Results The data from this Phase 2a trial showed very positive efficacy results, with highly statistically significant p-values ​​for all depression measures performed, large effect sizes, rapid efficacy (surprisingly, the first signal of efficacy began on day 2 with the 25 mg dose, and was statistically significant on day 4 for both the 25 mg and 50 mg doses), and sustained efficacy lasting at least one week after abrupt discontinuation of the one-week treatment course (long-lasting / sustained, statistically significant clinically meaningful therapeutic effect, and large effect size).

[0324] This study also confirmed the favorable safety, tolerability, and PK profile of dextromethadone observed in the Phase 1 trial. Patients experienced mild to moderate adverse events (AEs), with no single-acting emergencies (SAEs), and there was no higher prevalence of related organ AEs in the REL-1017 (dextromethadone) group compared to the placebo group. There was no evidence of treatment-induced psychosis or dissociative AEs, or narcotic effects or withdrawal signs and symptoms. There was no evidence of clinically significant QTc prolongation, defined as an increase of ≥500 msec or 60 msec compared to baseline. Patients in the dextromethadone 25 mg and 50 mg groups experienced rapid (started on day 2), sustained (up to day 14, final efficacy assessment), and statistically significant improvements with large t-effect sizes compared to patients in the placebo group in all efficacy endpoints, including the MADRS, CGI-S scale, CGI-I scale, and SDQ. Improvement in the MADRS score appeared on day 2 in the 25 mg group and was statistically significant in both dextromethadone dose groups on day 4, with a P-value < 0.03 and an effect size of 0.7–1.0, continuing until day 7 and day 14 (7 days after discontinuation of treatment). Similar findings were observed from the CGI and SDQ scales.

[0325] Figure 21 shows a table of the Clinician Administration Dissociation Scale scores during this study. Figures 22 and 23 show the plasma concentrations of dextromethadone at each dose level (25 mg or 50 mg) on ​​day 1 (Figure 22), and the trough plasma concentration levels of dextromethadone at both dose levels (Figure 23). The findings in both of these figures are consistent with the results of the Phase 1 trial.

[0326] Furthermore, a better efficacy signal was observed from the 25 mg dose compared to the 50 mg dose. The drug was well-tolerated at the effective dose, with side effects at the 25 mg dose being comparable to those in placebo-treated patients, and a higher incidence of side effects at the 50 mg dose compared to placebo and compared to the 25 mg dose. In patients diagnosed with MDD and subsequently screened with SAFER, the placebo response was lower than the characteristic placebo response (usually -9 to 12 points on MARDS) (-7.4 points on MADRS). Moreover, the magnitude of this response was greater than the characteristic response (usually -12 to 14) (-17.8), independently of the placebo effect. Figure 24 shows that the MADRS scores in the treatment group achieved a statistically significant difference compared to placebo from day 4 to day 14. Figure 25 shows the percentage of patients in remission with a MADRS reduction of <50% from baseline.

[0327] E. Safety and tolerability findings The trial results confirm the favorable tolerability and safety profiles observed in the Phase 1 SAD and MAD trials. These include: (1) only mild and moderate AEs—no SAEs; (2) no increased prevalence of AEs in particularly relevant organ groups compared to treatment group versus placebo; (3) no evidence of treatment-induced dissociative symptoms compared to treatment group versus placebo; (4) no evidence of treatment-induced psychotic symptoms compared to treatment group versus placebo; and (5) no evidence of opioid withdrawal symptoms compared to treatment group versus placebo.

[0328] F. Effectiveness Insights Dextromethadone 25 mg and 50 mg demonstrate rapid onset and sustained antidepressant efficacy in MDD patients, with statistically significant differences compared to placebo across all efficacy endpoints. These include: (1) solid efficacy results in MADRS with p-values ​​< 0.03 and large effect sizes (0.7 to 1.0) from day 4 to day 14; (2) solid findings in CGI-S and CGI-I consistent with the MADRS results with similar p-values ​​and effect sizes; (3) SDQ scores with moderate effect size differences (d=0.4 and 0.5) from day 4 to day 7 and statistically significant differences and large effect sizes in both the 25 mg arm (P=0.0066, d=0.9) and the 50 mg arm (P=0.0014, d=1.1) on day 14; (4) rapid onset and long-lasting antidepressant efficacy; and (5) findings that strongly support the efficacy of dextromethadone as a monotherapy for MDD, and indicate continued clinical development.

[0329] G. Discussion and Conclusion REL-1017 (dextromethadone) 25 mg and 50 mg demonstrated very favorable safety, tolerability, and PK profiles. Unexpectedly, the response and remission in MDD patients induced by REL-1017 (dextromethadone) 25 mg and 50 mg were rapid, statistically significant with large effect sizes, clinically meaningful, and persisted after treatment discontinuation. Sustained improvements in multiple aspects of MADRS, CGI-S scale, CGI-I scale, and SDQ observed at day 14 (one week after the final treatment dose) of dextromethadone plasma levels that did not result in effective NMDAR occupancy indicate a disease-modifying effect and mechanism of action not previously demonstrated. Therefore, the findings of this study suggest that dextromethadone may be effective in treating MDD and related disorders (e.g., excess Ca in selected cells). 2+ This study is the first to demonstrate that dextromethadone represents disease-modifying treatment for other disorders caused by influx, and not merely symptomatic treatment limited to receptor binding. In addition to the disease-modifying effect of dextromethadone as an adjunct treatment for MDD, the results strongly demonstrate a similar effect as monotherapy of dextromethadone in MDD and related disorders.

[0330] The unexpected efficacy results of this Phase 2a trial, supported by findings regarding the mechanism of action and its downstream effects (disclosed by the inventors in Examples 1-11 of this specification), should be interpreted together with other evidence presented throughout this application to suggest the following:

[0331] (1) In at least a subset of patients (who have been diagnosed with MDD and further screened according to the SAFER criteria), excessive Ca in selection neurons, which are part of the selection circuit involved in emotional processing. 2+ The inflow causes and / or maintains the disruption.

[0332] (2) The clinical effects of dextromethadone are longer than the receptor occupancy period, and may be due to the resumption of neuronal function, including the synthesis of synaptic proteins and neurotrophic factors, as well as the resumption of neuronal plasticity and the restoration of neuronal circuits.

[0333] (3) A 25 mg dose of dextromethadone resulting in plasma levels of approximately 50–150 ng / ml or approximately 150–500 nM delivers a potentially more potent and rapid onset of therapeutic effect compared to a 50 mg dose resulting in plasma levels of 150–450 ng / ml or approximately 500–1300 nM. This signal suggests that for the average patient, lower concentrations of dextromethadone may be associated with excess Ca 2+ This is sufficient to block the influx and pathologically hyperactive NMDAR channels that cause MDD, suggesting that in most MDD patients, a daily oral dose higher than 25 mg may not be necessary to achieve therapeutic efficacy.

[0334] (4) The inventors conducted an additional sub-analysis of the Phase 2a study data. This sub-analysis correlated BMI, dose, response [Table 32 (Table 33) below], and plasma levels. Interestingly, patients defined as normal or overweight by the CDC according to their BMI responded very well to dextromethadone 25 mg, while patients defined as obese (BMI ≥ 30) did not respond well. However, unexpectedly, plasma levels did not change with BMI in both the 25 mg and 50 mg dose groups. Normal and overweight patients administered the higher dose of dextromethadone, 50 mg, responded less well than patients with the same BMI who were administered 25 mg. Furthermore, obese patients administered 50 mg responded much better than obese patients administered 25 mg. However, as mentioned above, even at the 50 mg dose, plasma levels did not change with BMI. Tables 32-34 (Tables 33-35) below show the effects of BMI on clinical outcomes and plasma levels.

[0335] [Table 33]

[0336] [Table 34]

[0337] [Table 35]

[0338] The inventors have conducted research on dextromethadone and its isomers for several decades. In particular, Charles Inturrisi, one of the inventors, previously defined the role of plasma proteins in the pharmacology of methadone and its isomers [Inturrisi CE, Colburn WA, Kaiko RF, Houde RW, Foley KM. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther. 1987;41(4):392~401], and has studied the effects of diet on methadone metabolism, finding that methadone clearance was faster in patients on a Western diet compared to those on a macrobiotic diet [Wissel PS, Denke M, Inturrisi CE. A comparison of the effects of a macrobiotic diet and a Western diet on drug metabolism and plasma lipids in man. Eur J Clin Pharmacol. 1987;33(4):403~407].

[0339] The CNS permeability of certain drugs, including methadone, is determined by the level of alpha-1-glycoprotein (AAG) [Jolliet-Riant P, Boukef MF, Duche JC, Simon N, Tillement JP. The genetic variant A of human alpha 1-acid glycoprotein limits the blood to brain transfer of drugs it binds. Life Sci. 1998;62(14):PL219~PL226]. Racemic methadone and its isomers primarily bind to AAG, particularly the orosomucoid 2A variant. [Eap CB, Cuendet C, Baumann P. Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein. Clin Pharmacol Ther. 1990 Mar;47(3):338~46; Herve F, Duche JC, d'Athis P, Marche C, Barre J, Tillement JP, Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine, and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for presence of two separate drug-binding sites on alpha 1-acid glycoprotein.] Pharmacogenetics.1996;6(5):403~415].AAG levels influence the effects of methadone in preclinical experimental settings [Garrido MJ, Jiminez R, Gomez E, Calvo R. Influence of plasma-protein binding on analgesic effect of methadone in rats with spontaneous withdrawal. J Pharm Pharmacol. 1996;48(3):281~284]. In patients with withdrawal symptoms, AAG levels increase and free methadone levels decrease [Garrido MJ, Aguirre C, Troconiz IF, Marot M, Valle M, Zamacona MK, Calvo R. Alpha 1-acid glycoprotein (AAG) and serum protein binding of methadone in heroin addicts with abstinence syndrome. Int J Clin Pharmacol Ther. 2000 Jan;38(1):35~40]. Finally, alpha-1-glycoprotein levels increase in obese individuals, meaning alpha-1-glycoprotein levels are influenced by diet [Benedek IH, Blouin RA, McNamara PJ. Serum protein binding and the role of increased alpha 1-acid glycoprotein in moderately obese male subjects. Br J Clin Pharmacol. 1984;18(6):941~946], and diet affects methadone PK (Wissel et al., 1987). Furthermore, the free fraction of methadone is not significantly affected by increased methadone concentration or substitution by other drugs that also bind to AAG [Abramson FP. Methadone plasma protein binding: alterations in cancer and displacement from alpha 1-acid glycoprotein. Clin Pharmacol Ther. 1982;32(5):652~658].

[0340] Based on the points in (3) and (4) above, as well as other data disclosed throughout this application, and the inventors' shared knowledge regarding methadone and its isomers, particularly dextromethadone, the inventors disclose that the therapeutic range of dextromethadone is narrower than its safe range, a fact unknown prior to the inventors' Phase 2a trial and subsequent detailed analysis of the Phase 2a data. Furthermore, this therapeutic range can be better defined by measuring free dextromethadone levels and / or AAG and / or its variants, rather than by measuring total plasma levels (as had been done until this unexpected discovery). Furthermore, the therapeutic free level of dextromethadone for MDD and related disorders, and possibly other neuropsychiatric disorders (approximately 10% of total plasma levels) is defined as being within the range of 5–30 ng / ml or approximately 15–100 nM. Furthermore, the inventors disclose that the potential therapeutic effect of dextromethadone in MDD may be attributable to its metabolites, particularly EDDP. The inventors believe that further research will reveal a direct correlation between free dextromethadone and EDDP levels and the therapeutic response, and an inverse correlation between AAG levels and the therapeutic response (based on the data herein).

[0341] Continuing from the above list of points (1) to (4) of the conclusions obtained from the inventors' research, the results of the Phase 2 trial, as well as other examples and evidence presented herein, also suggest the following:

[0342] (5) Excess Ca in some selection neurons of the selection circuit 2+ There may be patients diagnosed with MDD who are less responsive to drugs that block the inflow. Based on the low placebo response and robust efficacy results in our Phase 2 trial, the SAFER screening tool can block excess calcium, such as dextromethadone. 2+This may be useful in screening MDD patients who are less responsive to drugs that selectively downregulate inflow. This effect of SAFER screening suggests that researchers and clinicians may be able to identify excess Ca in neurons that are part of the emotional processing circuit (emotional memory circuit). 2+ This may help to better define a subset of MDDs with inflow-induced and / or sustained failures.

[0343] (6) The outcomes for subjects and patients treated with dextromethadone are determined by researchers and physicians not only by a subset of neuropsychiatric disorders but also by excessive Ca in selected neurons or other cell populations, which are determined by the overactivation of NMDARs by glutamate and / or PAM and / or agonists. 2+ Metabolic disorders (e.g., diabetes, NAFLD-NASH, osteoporosis), cardiovascular disorders (e.g., angina pectoris, CHF, HTN), immune disorders, inflammatory disorders, infectious disorders, oncological disorders, otological disorders, and renal disorders that are induced, maintained, or worsened by influx may also be helpful in defining.

[0344] (7) Aside from the absence of side effects at the effective dose, the selectivity of dextromethadone for pathologically hyperactive NMDARs is also demonstrated by the absence of withdrawal (signs and symptoms) observed in the phase 2a trial. Drugs that exert their clinical effects by directly acting on receptors or receptor pathways, such as opioids, benzodiazepines, dopamine agonists or anti-dopaminamine agonists, or SSRIs [Henssler J, Heinz A, Brandt L, Bschor T. Antidepressant Withdrawal and Rebound Phenomena. Dtsch Arztebl Int. 2019;116(20):355~361] generally produce clinically significant withdrawal signs and symptoms upon abrupt discontinuation.

[0345] The fact that NMDARs are shared among vertebrates [Teng H, Cai W, Zhou L, Zhang J, Liu Q, Wang Y et al. (2010) Evolutionary Mode and Functional Divergence of Vertebrate NMDA Receptor Subunit 2 Genes. PLoS ONE 5(10)] also suggests potential therapeutic uses of dextromethadone for the treatment of numerous veterinary diseases and disorders induced, exacerbated, or maintained by NMDAR hyperactivation.

[0346] Furthermore, our research also discloses in vitro results showing that dextromethadone can potentially modulate inflammatory biomarkers that are abnormal in neuropsychiatric disorders and conditions including MDD and TRD, neurodegenerative diseases such as dementia including Alzheimer's disease, neurodevelopmental disorders such as Parkinson's disease and autism spectrum disorder, and other neuropsychiatric disorders and conditions such as schizophrenia. These potential anti-inflammatory effects of dextromethadone may be attributable to dextromethadone's blockade of NMDARs (representing potential NMDAR blockade of NMDARs expressed by immune cells, including glial immune cells), and may also help explain its efficacy against a wide range of neuropsychiatric, metabolic, cardiovascular, inflammatory, immunological, and neoplastic disorders. In light of the known mechanism of action of dextromethadone as a non-competitive NMDAR channel blocker, these anti-inflammatory effects of dextromethadone may be due to excess Ca in immune-modulating cells. 2+ This could be the effect of downward adjustment of inflows.

[0347] The inventors confirmed the anti-inflammatory in vitro effects detailed in Example 11 in a series of clinical measurements of markers in patients with MDD treated with dextromethadone (see also Example 7 below). The inventors hypothesize that these effects on inflammatory markers are caused by the modulation of NMDARs expressed on the cell membranes of immune cells, including selective neurons and glial cells, by dextromethadone. The modulation of inflammatory markers in patients with neuropsychiatric disorders treated with dextromethadone may result from the effect of dextromethadone on immune cell effects (modulation of immunological memory), which is observed in neurons for different types of memory (cognitive, emotional, and motor memory) and reflects effects mediated by increases in BDNF and synaptic proteins. If dextromethadone can improve the functionality of immune cells (e.g., immunological memory and inflammatory response), it could be a therapeutic agent at appropriate doses for diseases and disorders affected by dysregulation of the immune system, including inflammatory disorders, autoimmune disorders, and tumor disorders, among others.

[0348] In addition to the results presented in this Example 3 regarding dextromethadone as an adjunctive treatment in MDD patients, we also disclose dextromethadone monotherapy in MDD patients. The effects of dextromethadone are very robust in patients receiving MDD treatment and antidepressant treatment in combination, and dextromethadone exhibits a potentially curative effect on CNS abnormalities not only associated with MDD but also potentially associated with MDD treatment (as shown in this Example 3). In other words, excessive Ca in select neurons with pathologically hyperactive NMDARs 2+ The downward regulation exerted by dextromethadone in response to inflow can occur regardless of whether concomitant neuropharmacological treatments are used.

[0349] The inventors of this invention have found that excess Ca 2+We hypothesize that the selective modulating effect of dextromethadone on inflow may be particularly useful for patients who have not yet received treatments that could potentially alter CNS neurotransmitter pathways. Furthermore, we disclose that dextromethadone can be successfully combined with behavioral psychotherapy.

[0350] As previously disclosed, dextromethadone had not been considered a potentially safe and effective drug due to concerns regarding abuse liability, as well as concerns regarding QTc prolongation and arrhythmias. In this Example 3, we hereby provide additional data to address these concerns. In particular, the data of Example 3 demonstrate the absence of opioid effects (narcotic effects) on cognitive and respiratory function, as well as the absence of dissociative and / or psychedelic effects typical of some NMDAR channel blockers such as MK-801, PCP, and ketamine. Furthermore, there were no clinically significant signs and symptoms of opioid withdrawal (measured by COWS) upon abrupt discontinuation. The data of Example 3 also confirmed overall cardiac safety and the absence of clinically significant QTc prolongation with dextromethadone.

[0351] The following Examples 6 (electrophysiological testing to establish "on" and "off" rates and "trapping") and 3 (absence of psychotic and psychedelic side effects in addition to the absence of narcotic side effects at therapeutic doses) suggest that non-competitive blockade of selected hyperactive NMDAR channels at the intramembrane MK-801 site by dextromethadone allows cells to resume physiological LTP cell activity necessary for physiological brain function (e.g., synaptic protein production and assembly, as well as BDNF production and release).

[0352] This disclosure of our clinical and experimental data strongly signals a novel pathophysiological understanding of MDD, related disorders, and other disorders. This novel pathophysiological understanding could have profound and direct impacts on therapeutic, preventive, and diagnostic strategies, as well as the development of new treatment agents. Dextromethadone may restore functionality to neurons and circuits that cause, induce, maintain, and / or exacerbate neuropsychiatric disorders and other disorders, as highlighted by its mechanism of action outlined in Examples 1-11, by selectively targeting hyperactivated ion channels (e.g., NMDARs) without interfering with physiologically active NMDARs, and by exhibiting, at therapeutic doses, the absence of psychotropic side effects and a very favorable tolerability profile, as well as rapid, robust, and sustained efficacy.

[0353] A similar mechanism of action (NMDAR blockade) has been disclosed for esketamine, which was recently approved by the FDA for TRD. However, the blockade provided by esketamine (and ketamine), while effective in treating MDD / TRD, does not appear to be selective for hyperactivated NMDARs (or, if selective, the blockade does not have substantially useful "on" / "off" and / or related "trapping" properties as disclosed in Example 6), because esketamine and ketamine, being more high-affinity non-competitive channel blockers, cause more severe psychotic symptoms (dissociative effects) than competitive NMDAR channel blockers, indicating interference with physiological NMDAR activity by ketamine and esketamine.

[0354] The unique effects of dextromethadone in NMDARs [e.g., a more homogeneous effect on different NMDAR subtypes A-D with a preference for the GluN1-GluN2C subtype (Example 1)], its specific "on"-"off" kinetics and "trapping" properties in channel pores, and physiological amounts of Mg 2+The preference for GluN1-GluN2C subtypes in the presence of (Example 6), or its affinity for other receptors (Example 10), may be "just right" for selectively targeting and blocking pathologically hyperactive NMDARs and other receptors in selective CNS circuits, and importantly, its features may be "just right" for deblocking NMDAR channels during physiological activity (e.g., phasic glutamatergic neurotransmission).

[0355] The combination of behavioral psychotherapy and dextromethadone can be a highly effective strategy for treating neuropsychiatric disorders: Dextromethadone, through its stepwise selective blockade, allows psychotherapy-induced "healthy" neuroplasticity to occur in cells that previously exhibited pathologically hyperactive NMDAR channels before treatment with dextromethadone, and in circuits (in the case of MDD, the emotional memory circuit) that were refractory to stimuli including positive psychotherapy stimuli that could otherwise potentially produce therapeutic neuroplastic effects. In other words, the emotional memory circuit, impaired by neurons with pathologically hyperactive channels, is refractory to psychotherapy [and may also be refractory to stress-reducing (i.e., favorable) life experiences, as in the case of MDD]. On the other hand, the circuit that is currently blocked by dextromethadone (excess Ca 2+ By blocking the inflow, the same circuits containing cells that previously exhibited hyperactive NMDARs may provide fertile ground for psychotherapy-induced "healthy" neuroplasticity (LTP) (production of synaptic proteins and BDNF).

[0356] Differential cellular expression of NMDAR subtypes 2A-D (part of the NMDAR framework) on the cell membrane is associated with the experience-driven release of glutamate from presynaptic cells (with or without the action of PAM or other agonists) and Ca 2+We describe how specific patterns of CaMKII influx are determined, and how this subsequently leads to downstream effects (e.g., CaMKII-mediated) including reverberation effects by other neurotransmitters on transcription (mRNA induction) and protein synthesis and assembly (the basis for LTP and LTD for learning and memory formation), which regulate synaptic activity and strength. All of these effects ultimately determine the continuous evolution / regression (reformation) of the connectome throughout the lifespan of the individual. Based on our preclinical in vitro and in vivo data as well as clinical data, NMDAR is Ca 2+ It adjusts the differential patterns of inflow, and is thereby regulated.

[0357] Interneuronal communication, essential for the continuous reshaping of the connectome, is determined by presynaptic action (experience-driven presynaptic glutamate release by excited presynaptic neurons—including NMDAR modulation by endogenous or exogenous PAMs, e.g., polyamines, gentamicin, or agonists, e.g., quinolinic acid) and postsynaptic action: differentially expressed NMDAR channel openings, including CaMKII-mediated effects and downstream effects including neuroplastic effects, including effects on the NMDAR framework. 2+ This creates differential patterns of inflow.

[0358] Therefore, glutamate release from presynaptic cells is a strictly regulated Ca2+ release that depends on the differential postsynaptic NMDAR framework (e.g., variations in NR1-2A-D, NR1-3A-B, and their potential trihetomers). 2+ This results in influx over a certain period of time. (1) Deactivation kinetics (GuN2D is the slowest, allowing calcium influx for a longer time when the 2D receptor is activated, while GluN2A is the fastest, allowing calcium influx for a shorter time when these channels are activated by glutamate), and (2) Voltage-dependent Mg between all four GluN2 subunits. 2+ Blocking strength [2D and 2C are the weakest Mg 2+There are subtype-dependent differences in that, due to the presence of blockage, opening can be induced by even slight depolarization, or it may even occur spontaneously in the synaptic cleft by low ambient concentration agonists (e.g., glutamate or quinolinic acid) in the absence of membrane depolarization. Other subtypes, including those containing splice variants (isoforms) of the NR1 subunit, or tr-heteromers (e.g., NR1-NR2A-NR2B), and / or subtypes containing the NR3A-B subunit, are PAM, Mg 2+ Blocking and Ca 2+ They have different tolerances to permeability.

[0359] Dextromethadone selectively interacts with and modulates pathologically hyperactive NMDAR channels in a way that allows for the resumption of physiological cellular activity. [The "on" velocity of dextromethadone allows for channel blockade only when the channel is pathologically hyperactive, while the "off" velocity (and receptor interaction "trapping" properties) allows for the efflux of dextromethadone (MG).] 2+ [Similar to the elimination of waste products,] under physiological conditions, for example, under environmental stimuli, the reactivation of cellular ionic currents and associated cellular activity.

[0360] Intrinsic differential receptor subtype blocking properties (Example 1), just the right "on" / "off" and "trapping" kinetics (Example 6), and action with or without PAM and agonists (Example 5), as well as effects on synaptic protein induction, aggregation and release (Example 2), and selectivity for hyperactivated pathologically hyperactive NMDARs (Example 3), and consequently, excess Ca 2+Dextromethadone, a highly tolerable NMDAR channel blocker with selective downmodulation of inflow, is revealed here (by the inventors' research disclosed herein) as a “best-in-class” (novel emerging class of non-competitive NMDAR blockers) for patient treatment, use as a research tool in healthy subjects (physiology of memory), and for the prevention, treatment, and diagnosis of patients with numerous disorders associated with NMDAR hyperactivation.

[0361] Dextromethadone is Ca 2+ This could facilitate progress in understanding the role of tightly regulated patterns of influx (regulated by differential stimulation of presynaptic cells and differential cellular expression of NMDAR 2A-D in postsynaptic cells). 2+ The inflow patterns may represent shared (interspecies) codes that enable the connectome to constantly self-reform (synaptic evolution and regression, LTP and LTD). Synaptic strengthening and formation are the basis of memory and learning, including the learning of emotions and social interactions, emotional engagement with events and interpersonal relationships, or engagement with religious and political movements, and are the cause of confused pathological behaviors and activities ranging from ego-affiliative / socio-affiliative ("mentally healthy") to ego-dysphoric / socio-dysphoric ("mentally unhealthy"), as well as moods, behaviors and activities and moods that are sources of individual and societal distress. Therefore, glutamate-induced Ca 2+ The pattern of invasion is regulated not only by the amount of glutamate released presynaptically [potentially similar among individuals of the same species (who have similar NMDAR frameworks) in response to similar environmental stimuli], but also precisely by the postsynaptic NMDAR framework.

[0362] The expression of this synaptic protein (NMDAR framework) is similar among individuals of the same species, but differs depending on the individual's NMDAR gene and environmental factors (G+E). Epigenetic (environmental) effects include Ca by NMDAR. 2+This is converted into neural plasticity through influx patterns. Even among cells of the same type and distributionally close to each other, differential expression of NMDAR (part of the NMDAR framework) results in specific Ca after stimulation and presynaptic glutamate release. 2+ An inflow pattern emerges. Dextromethadone's selectivity appears to be directed towards pathologically hyperactive NMDARs, but because its affinity for different subtypes differs, it may differentially block different pathologically hyperactive receptor subtypes.

[0363] Furthermore, different doses of dextromethadone (plasma levels, see Example 3, and also Figures 22 and 23) may have differential effects on different subtypes. If fully elucidated, these differential effects could reveal the full potential of dextromethadone and related compounds for the treatment of selected disorders and diseases.

[0364] In experimental models, NMDAR channel blockers have been associated with neuronal vacuolation and other cytotoxic changes ("Olney's lesions"). The efficacy of the drugs in producing these neurotoxic changes is related to their efficacy as NMDA antagonists: namely, MK-801 > PCP > tiretamine > ketamine [Olney JW, Labruyere J, Price MT (1989) "Pathological Changes Induced in Cerebrocortical Neurons by Phencyclidine and Related Drugs". Science. 244: 1360~1362]. Dextromethorphan has been shown to induce vacuolation in the brains of rats when administered at a dose of 75 mg / kg [Hashimoto, K; Tomitaka, S; Narita, N; Minabe, Y; Iyo, M; Fukui, S (1996) "Induction of heat shock protein Hsp70 in rat retrosplenial cortex after administration of dextromethorphan". Environmental Toxicology and Pharmacology. 1 (4): 235~239]. The development of NMDAR antagonists as therapeutic agents has been hindered due to the potential for NMDAR antagonists to cause permanent brain lesions. The inventors conducted the first rat studies to investigate the potential chronic CNS toxicity of dextromethadone. The doses of dextromethadone were 0, 31.25, 62.5, and 110 mg / kg / day in males and 0, 20, 40, and 80 mg / kg / day in females. As a control, methadone racemic mixture was administered at 31.25 mg / kg / day for males and 20 mg / kg / day for females. MK-801 was tested as a positive control at 5 mg / kg (males) and 2 mg / kg (females). Notably, the minimum test dose of dextromethadone (32.25 mg / kg / day) was more than 10 times the equivalent human therapeutic dose. Drug administration was daily, and autopsies were performed 8, 48, and 96 hours after the initial dose.The brain was evaluated by a neuropathologist familiar with identifying Olney's lesions (hematoxylin & eosin + Fluoro Jade B staining). Dextromethadone did not induce Olney's lesions at any test dose, while the active control MK-801 did in all test animals (Relmada internal data). These data indicate that dextromethadone can be safely used in humans without the concerns of potential CNS damage seen with other NMDAR channel blockers under development for MDD, including dextromethorphan.

[0365] Furthermore, the NMDAR framework on the cell membrane of an individual's selected neurons, determined both genetically [seven genes encoding different subunits, numerous splice variants (isoforms), and a vast number of mutation possibilities] and epigenetically (environmental influences from embryogenesis), determines that individual's "mental characteristics" (the individual's response to environmental stimuli). Continuous experience-driven neuroplasticity (Ca in postsynaptic cells via postsynaptic NMDARs, induced by presynaptic glutamate release) 2+ The differential patterns of influx (modulated by the differential patterns of influx) and other environmental effects on NMDAR (e.g., modulosites, e.g., PAM and NAM at the polyamine site, or agonists at the agonist site, e.g., quinolinic acid at the NMDA / glutamate site) contribute to the determination of an individual's “mental state” (“characteristics” and “state” include the definitions by Desseilles et al., 2013), and, considering our current and past disclosures, reflect the G+E paradigm underlying learning (memory formation, LTP, LTD) and each individual’s unique connectome.

[0366] The availability of a new class of highly tolerable, safe, and effective NMDAR blockers (e.g., dextromethadone and compounds and methods previously and currently disclosed by the inventors) that are differentially acting on different NMDAR subtypes and preferentially target specific circuits, could potentially treat, prevent, and diagnose mental disorders, and improve social functioning and work capacity, which may be part of undesirable “mental traits” (e.g., reduced ability to perform tasks requiring a certain level of mental concentration) caused by dysfunctional NMDARs that result in pathologically hyperactive NMDAR channels in selected cells that are part of a selection circuit.

[0367] NMDARs play a central role in learning (memory formation, LTP, LTD). Certain learning disorders may be secondary to dysfunction determined by the G+E of NMDARs. In addition to addressing and modifying environmental factors that induce and / or maintain certain learning disorders (e.g., ADHD), well-tolerated and safe drugs such as dextromethadone can effectively modulate pathologically hyperactive NMDARs expressed by neurons that are part of the neural circuits assigned to learning cognitive, social, and motor skills. For example, aside from modulating hyperactive NMDARs that disrupt specific neural circuits involved in learning cognitive and motor skills and memory formation, the preferential induction of NR1 and NR2A subunit synthesis by dextromethadone (as seen in Example 2 for ARPE-19 cells, and potentially differential if different cell lines are tested) may have a favorable effect on CNS maturation (e.g., NMDAR generation switches), potentially leading to further disease-modifying effects on ADHD.

[0368] The spectrum encompassing normal and pathological mental development, as well as cognitive, social, emotional, sensory, and motor functions and skills, depends on the NMDAR framework and its operating state, i.e., physiological activity versus deregulated pathological activity, for example, pathologically hyperactive NMDARs of the NMDAR framework. When a specific threshold for hyperactivated NMDAR channels expressed by neurons (or astrocytes or extra-CNS cells) that are part of a circuit (or tissue or organ) is exceeded for that cell (or multiple cells, since it appears that one or more cells must become dysfunctional before the tissue, organ, or circuit is affected), the circuit (organ or tissue) may cease to function, and disease or impairment may manifest. For example, in the case of neurons involved in specific cognitive circuits related to academic performance, ADHD may manifest. In the case of hair cells in the inner ear, hearing loss may manifest (Example 5), etc.

[0369] Abnormal background electrical activity and connectivity in the central nervous system (CNS), explained in certain neurodevelopmental and neurodegenerative diseases as well as in aging brains, may be secondary to abnormally functioning NMDARs and may be correctable, at least initially (before neuronal loss occurs), with drugs such as dextromethadone.

[0370] The results of our Phase 2a trial (rapid onset, robust and sustained disease-modifying effect) not only provide the first confirmation that NMDAR hyperactivation is responsible for MDD in a significant subset of patients, but also potentially shed light on the pathophysiology of MDD-related disorders. For example, we hereby disclose that in bipolar disorder, the manic phase is triggered by pathologically hyperactive channels that allow for an influx of excess calcium, initially resulting in some degree of function (in some milder cases, very mild hypomania, the functionality of circuits related to personal and social well-being is "improved" by hypomania, possibly due to a very slight increase in Ca beyond physiological levels). 2+ (This can be caused by inflow.)

[0371] However, due to either increased presynaptic release of glutamate (experience-driven release), impaired reuptake by astrocytes, the action of PAM or agonists, or postsynaptic changes in the absolute number or relative subtype of NMDARs, "excess" Ca 2+ If the influx increases beyond a certain limit, it can lead to circuit disruption, which in turn manifests as cellular dysfunction (alterations in LTP signaling) and dysfunctional manic episodes. Furthermore, excess Ca 2+ As the influx progresses and cellular functions, including the LTP mechanism (transcription, synthesis, assembly, and transport of synaptic proteins), are gradually impaired, in bipolar disorder, a manic episode is followed by a depressive phase (MDE). Excess Ca 2+ Cellular dysfunction caused by influx can further progress to apoptosis and cell death, which may explain neuroimaging and postmortem findings of brain atrophy in MDD patients and bipolar disorder patients. Drugs such as dextromethadone can cause excess calcium 2+ It may prevent influx, dysfunctional manic and depressive phases, and neuronal death, potentially altering the course of the disorder.

[0372] Another example of a related disorder that may be improved by dextromethadone is PTSD. This disorder shares some phenotypic features with MDD, and its cause is excessive Ca in selective neurons, which are part of the emotional circuit. 2+ This could be event-driven activation of NMDARs that leads to influx. Anothe...

Claims

1. A composition for use in a method for modifying the course and severity of neuropsychiatric disorders, The method comprises the step of administering a composition to a subject suffering from a neuropsychiatric disorder, wherein the neuropsychiatric disorder is selected from persistent depressive disorder, severe mood dysregulation, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, overactive bladder disorder, and substance use disorder; The composition comprises a substance selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The step of administering the composition is performed at a dose of 25 mg per day. A composition wherein the administration of the composition includes a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition, the loading dose of the composition being 75 mg.

2. The substance is the sole active agent in the composition for the treatment of the neuropsychiatric disorder, or A substance is isolated from its enantiomer, or newly synthesized, or The step of administering the composition is carried out under conditions that are effective for the substance to bind to the target NMDA receptor, thereby providing relief to the subject by modifying the course and severity of the neuropsychiatric disorder. The composition according to claim 1.

3. The step of administering the composition is performed as monotherapy, or The step of administering the composition is performed as part of an auxiliary treatment for the second substance, or The composition according to claim 1, wherein the step of administering the composition is carried out under conditions effective for action at ion channels, neurotransmitter systems, neurotransmitter pathways, or receptors selected from ion channel-type glutamate receptors, 5-HT2A receptors, 5-HT2C receptors, opioid receptors, AChR, SERT, NET, sigma-1 receptors, K channels, Na channels, and Ca channels.

4. The composition according to claim 3, wherein the action at an ion channel glutamate receptor includes induction of the synthesis of an NMDAR subunit or other synaptic protein that contributes to neuronal plasticity, and contributes to the membrane expression of the synaptic protein, or the receptor is an opioid receptor selected from MOR, KOR and DOR.

5. The composition according to claim 1, wherein the step of administering the composition modifies the course and severity of the neuropsychiatric disorder in the subject, and the relief begins within a period selected from two weeks or less after the first administration of the substance, seven days or less after the first administration of the substance, four days or less after the first administration of the substance, and two days or less after the first administration of the substance.

6. The composition according to claim 1, wherein the substance is dextromethadone, and the step of administering the composition results in disease modification of the neuropsychiatric disorder.

7. On the first day of administration of the composition, a steady state or higher plasma level is reached, or within 4 hours of administration of the composition, The composition according to claim 1.

8. After the administration of the composition, the total plasma level of the substance in question is within the range of 5 ng / ml to 3000 ng / ml, or after the administration of the composition, the unbound level of the substance in question is within the range of 0.1 nM to 1500 nM, or the administration of the composition is performed as an intermittent treatment schedule selected from every other day, once every 3 days, once a week, every other week, every two weeks, once a week per month, every other month, every two months, every three months, once a week per year, and once a month per year. The composition according to claim 1.

9. A composition for use in methods for treating neuropsychiatric disorders, The method described above is The process of diagnosing an individual with a neuropsychiatric disorder selected from persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement-related depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder and substance use disorder; and A method comprising the step of administering a composition to the individual as at least part of a course of treatment for the individual's neuropsychiatric disorder, wherein the composition comprises one or more substances selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol and pharmaceutically acceptable salts thereof, The step of administering the composition is performed at a dose of 25 mg per day. A composition wherein the administration of the composition includes a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition, the loading dose of the composition being 75 mg.

10. A composition for use in methods for treating neuropsychiatric disorders, The method described above is The process includes inducing the transcription, synthesis, and membrane expression of NMDAR subunits, AMPAR subunits, or other synaptic proteins that contribute to neural plasticity and organizing NMDAR channels in the target; The subjects suffer from a neuropsychiatric disorder, which is selected from persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement-related depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, overactive bladder disorder, and substance use disorder; A method for inducing the transcription, synthesis, and membrane expression of NMDAR subunits, AMPAR subunits, or other synaptic proteins contributing to neuronal plasticity, by administering a composition to a subject comprising one or more substances selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The step of administering the composition is performed at a dose of 25 mg per day. A composition wherein the administration of the composition includes a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition, the loading dose of the composition being 75 mg.

11. The composition according to claim 10, wherein the treatment of the neuropsychiatric disorder results in the alleviation of the neuropsychiatric disorder, the alleviation being selected from the following: cure of the neuropsychiatric disorder, prevention of the neuropsychiatric disorder, reduction of the severity of the neuropsychiatric disorder, and reduction of the incidence of the neuropsychiatric disorder.

12. The composition according to claim 1 or 11, wherein the subject is a vertebrate, or the substance is dextromethadone, or dextromethadone is delivered in a total daily dose of 0.1 mg to 5,000 mg.

13. The composition according to claim 10, wherein the relief from the target neuropsychiatric disorder begins within two weeks or less after the first administration of the substance, or the relief from the target neuropsychiatric disorder begins within seven days or less after the first administration of the substance.

14. The composition according to claim 10, wherein the therapeutic effect of dextromethadone reaches an effect size greater than or equal to 0.3 in a phase 2 clinical trial, or greater than or equal to 0.5 in a phase 2 clinical trial, or greater than or equal to 0.7 in a phase 2 clinical trial, or the duration of the therapeutic effect after discontinuation of treatment is equal to or greater than the duration of treatment.

15. The step of administering the composition is carried out in combination with the administration of an antidepressant to the subject, or The step of administering the composition is carried out in combination with the administration of one or more of magnesium, zinc, or lithium to the subject. The composition according to claim 1 or 10.

16. The composition according to claim 12, wherein dextromethadone is used as a disease modifier or cure for patients having the diagnosis of the neuropsychiatric disorder and having an obesity index of 35 or less.

17. The process of administering the composition is used to improve cognitive function, improve social function, improve sleep, improve sexual function, improve the ability to work, or The composition according to claim 1 or 10, wherein the step of administering the composition is performed orally, intraoral, sublingually, rectally, vaginally, nasally, via aerosol, percutaneously, parenterally, intravenously, subcutaneously, epidurally, intrathecally, intraauricularly, intraocularly, or locally.

18. The process of administering the composition is carried out in doses of 0.01 to 1000 mg per day, or The composition according to claim 10, wherein the administration of the composition comprises a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition.

19. A steady state is reached on the first day of administration of the composition, or A steady state is reached within 4 hours of administration of the composition, or After administration of the composition, the unbound level of the substance in the target is 5 ng / ml to 3000 ng / ml, or After administration of the composition, the unbound level of the substance in the target is 0.5 nM to 1,500 nM, or The composition according to claim 10, wherein the step of administering the composition is performed as an intermittent treatment schedule selected from once a week, every other day, once every three days, once a week, every other week, every two days, every three days, every two weeks, and every other month.

20. The composition according to claim 1 or 10, wherein the method further relates to a digital application for monitoring the course of a disability, including digital monitoring of symptoms and signs, and outcomes of functional and disability.

21. A composition for use in treating a disease or disorder characterized by ion channel dysfunction, wherein the treatment A step of diagnosing an individual with a disease or disorder characterized by ion channel dysfunction, wherein the disease or disorder is selected from persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, overactive bladder disorder, and substance use disorder. ; A step of treating a disease or disorder of the said individual, the step of restoring the dysfunction of ion channels; and A step of administering a composition to the individual as at least part of a step of restoring ion channel dysfunction, wherein the composition comprises one or more selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol and pharmaceutically acceptable salts thereof. Includes, The step of administering the composition is performed at a dose of 25 mg per day. A composition wherein the administration of the composition includes a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition, the loading dose of the composition being 75 mg.

22. Ion channels are essential for one or more NMDARs, or Ion channels are essential for NMDARs, including the Glun2C subunit, or Ion channels are essential for NMDARs, including the Glun2D subunit, or Ion channels are essential for NMDARs, including the Glun2B subunit, or Ion channels are essential for NMDARs, including the Glun2A subunit, or The ion channel is essential for NMDARs, including the Glun3A subunit, or Ion channels are essential for NMDARs, including the GluN3B subunit. The composition according to claim 21.

23. A composition for diagnosing a disorder as a disorder caused, exacerbated, or maintained by pathologically hyperactive NMDAR channels, The diagnosis comprises the step of administering a composition to a subject, wherein the composition comprises a substance selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol and pharmaceutically acceptable salts thereof, and the subject is diagnosed with at least one neuropsychiatric disorder, wherein the neuropsychiatric disorder is selected from persistent depressive disorder, severe mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depressive disorder, bipolar disorder, hypomania and mania, generalized anxiety disorder, social anxiety disorder, somatic symptom disorder, bereavement depressive disorder, adjustment disorder, post-traumatic stress disorder, obsessive-compulsive disorder, chronic pain disorder, overactive bladder disorder and substance use disorder; A step of determining the effectiveness of the composition in at least one disorder by measuring endpoints specific to each disorder before and after administration of the composition; and A process for diagnosing a subject showing improvement in a specific endpoint as having a disorder caused, exacerbated, or maintained by pathologically hyperactive NMDAR channels. Includes, The step of administering the composition is performed at a dose of 25 mg per day. A composition wherein the administration of the composition includes a step of administering a loading dose of the composition, followed by the administration of a daily dose of the composition, the loading dose of the composition being 75 mg.

24. A composition for use in a method of disease modification for major depressive disorder, The method is a step of administering a composition to a subject suffering from major depressive disorder; The composition comprises a substance selected from dextromethadone, d-metadol, d-alpha-acetylmetadol, d-alpha-normetadol, l-alpha-normetadol, and pharmaceutically acceptable salts thereof. The step of administering the composition is performed at a dose of 25 mg per day. A composition in which administration of the composition includes a step of administering a loading dose of the composition, followed by an administration of a daily dose of the composition, wherein the loading dose of the composition is 75 mg.

Images