NMDA modulators for the treatment of neurological disorders

Abstract

In some aspects, the present disclosure provides methods of treatment comprising zelquisintel or a pharmaceutically acceptable salt thereof. In some aspects, the present disclosure provides methods of treatment comprising a loading dose of zelquisintel or a pharmaceutically acceptable salt thereof. In some embodiments, the methods further comprise a maintenance dose of zelquisintel or a pharmaceutically acceptable salt thereof. In some aspects, the present disclosure provides methods of treatment comprising monitoring electrical brain activity in a subject in need thereof and administering zelquisintel or a pharmaceutically acceptable salt thereof or apimostinel or a pharmaceutically acceptable salt thereof.

Description

NMDA MODULATORS FOR THE TREATMENT OF NEUROLOGICAL DISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 653,610 filed on May 30, 2024, and U.S. Provisional Application No. 63 / 727,561 filed on December 3, 2024, each of which is incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] N-methyl-D-aspartate receptor (NMDA receptor) is believed to play a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory acquisition, retention and learning, as well as in certain cognitive pathways and in the perception of pain. The NMDA receptor also appears to be involved in a broad spectrum of CNS disorders. NMDA receptor modulators therefore can provide pharmaceutical benefits to subjects in need thereof.SUMMARY OF THE INVENTION

[0003] In certain aspects, the present disclosure provides method of treating a diseases or disorder using an NMDA modulator. In some embodiments, the NMDA modulator is zelquistinel (Gate- 251, AGN-241751) or a salt thereof. In some embodiments, the NMDA modulator is apimostinel (Gate-202, NRX-1074) or a salt thereof.

[0004] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, or three times a week. In some embodiments, the at least four weeks is from about 4 weeks to 52 weeks. In some embodiments, each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, the administering is orally administering. In some embodiments, the method further comprises monitoring the electrical brain activity of the subject.

[0005] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising (a) administering a loading dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof; and (b) administering a maintenance dose of zelquistinel or a pharmaceutically acceptable salt thereof after the loading dose, the maintenance dose is selected from an amount less than the loading dose. In some embodiments, the loading dose is administered once a week over the course of about 1 to 4 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 week to about 2 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 week to about 2 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to 52 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to 52 weeks. In some embodiments, each loading dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, the administering is orally administering.

[0006] In some embodiments, the method further comprises monitoring the electrical brain activity of the subject. In some embodiments, electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, the electrical brain activity is monitored with EEG. In some embodiments, the EEG is quantitativeelectroencephalography (qEEG). In some embodiments, the electrical brain activity is monitored with PSG. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof comprising (a) monitoring the electrical brain activity of the subject; and (b) administering to the subject a starting dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, the electrical brain activity is monitored with EEG. In some embodiments, the EEG is quantitative electroencephalography (qEEG). In some embodiments, the electrical brain activity is monitored with PSG. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, the starting dose is administered once a week over the course of about 1 to 4 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 week to about 2 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 week to about 2 weeks. In some embodiments, wherein each starting dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 5 mg apimostinel or apharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the method further comprises administering to the subject a maintenance dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to 52 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to 52 weeks. In some embodiments, each maintenance dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 5 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, the administering of zelquistinel or a pharmaceutically acceptable salt thereof is orally administering. In some embodiments, apimostinel or a pharmaceutically acceptable salt thereof is formulated as an intravenous formulation. In some embodiments, the administering of apimostinel or a pharmaceutically acceptable salt thereof is intravenous administering. In some embodiments, the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the electrical brain activity of the subject comprises monitoring during the administering ofzelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the electrical brain activity of the subject comprises monitoring prior to the administering of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the electrical brain activity of the subject comprises monitoring during the administering of apimostinel or a pharmaceutically acceptable salt thereof.

[0009] In some aspects, the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto- cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the disease or disorder is Mild Cognitive Impairment.

[0010] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of at least four weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 208 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 104 weeks. In some embodiments, the at least four week is from above 4 weeks to about 104 weeks. In some embodiments, each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 3 mg of zelquistinel or a pharmaceuticallyacceptable salt thereof. In some embodiments, each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, the administering is orally administering.

[0011] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of more than four weeks. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, every three weeks, monthly, or bimonthly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt weekly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt biweekly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt monthly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt bimonthly. In some embodiments, each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, the administering is orally administering.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The novel features of the invention are set forth with particularity in the appended claims.A better understanding of the features and advantages of the present invention will be obtained byreference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0014] FIG. 1 illustrates that the enhancement of metaplasticity is occluded by co-administration of isoflurane, demonstrating that formation of zelquistinel metaplasticity is activity dependent.

[0015] FIGS. 2A-C illustrate the effect of zelquistinel on synaptic strength or metaplasticity over various dosing regimens. FIG. 2A illustrates that a single dose of zelquistinel increases medial prefrontal cortex (MPFC) synaptic strength for over one week. FIG. 2B illustrates that repeated daily dosing of zelquistinel actively suppresses the increase of synaptic strength. FIG. 2C illustrates that a single dose of zelquistinel enhances metaplasticity for at least one week, while 5 daily doses of zelquistinel are less effective.

[0016] FIGS. 3A-3B illustrate the effects of once weekly dosing of zelquistinel over 6 weeks. FIG. 3A illustrates that once weekly zelquistinel administration for 6 weeks maintains or enhances an increase of MPFC synaptic strength. FIG. 3B illustrates that once weekly zelquistinel administration for 6 weeks enhances and prolongs the magnitude and duration of metaplasticity.

[0017] FIGS. 4A-4D illustrate the effect of zelquistinel on positive emotional learning over various dosing regimens. FIG. 4A illustrates that a single dose of zelquistinel enhances positive emotional learning. FIG. 4B illustrates that once daily dosing over five days of the maximally efficacious Zelquistinel single dose (0.3mg / kg) is less effective than the single dose of zelquistinel at enhancing positive emotional learning. FIG. 4C illustrates that once weekly dosing of zelquistinel for six weeks maintains the enhancement of positive emotional learning. FIG. 4D illustrates that a single dose of zelquistinel enhances positive emotional learning for over one week.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0019] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0020] In this application, the use of “or” means “and / or” unless stated otherwise. The terms “and / or” and “any combination thereof’ and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated.Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof’ can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0021] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, z.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 15%, up to 10%, up to 5%, or up to 1% of a given value. In some embodiments, “about” refers to a range of up to 10% of a given value. In some embodiments, “about” refers to a range of up to 5% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value.

[0022] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0023] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open- ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions of the present disclosure can be used to achieve methods of the present disclosure.

[0024] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but notnecessarily all embodiments, of the present disclosures. To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below. As used herein, the terms "treatment," "treat," and "treating" are meant to include the full spectrum of intervention for the cancer from which the subject is suffering, such as administration of the combination to alleviate, slow, stop, or reverse one or more symptoms of the cancer and to delay the progression of the cancer even if the cancer is not actually eliminated. Treatment can include, for example, a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse, e.g., the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.

[0025] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0026] A “pharmaceutically acceptable salt” suitable for the disclosure may be an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethyl sulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH2)n- COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize from this disclosure and the knowledge in the art that further pharmaceutically acceptable salts include those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 ( 1985). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent.

[0027] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0028] The term “metaplasticity” as used herein refers to the term as defined in Richter-Levin G, Maroun M. “Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex.” Cerebral cortex. 2010; 20; 2433-2441; or Abraham WC, Bear MF. "Metaplasticity: the plasticity of synaptic plasticity". Trends Neurosci. 1996, 19(4); 126-30. In certain embodiments, the term refers to the modulation of the ability to induce synaptic plasticity of the form of long-term potentiation (LTP) or long-term depression (LTD) following prior activation of a synapse.

[0029] A “pharmaceutically acceptable excipient, carrier or diluent” refers to an excipient, carrier or diluent that can be administered to a subject, together with an agent, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent.

[0030] The terms "subject," "individual," and "patient" may be used interchangeably and refer to mammals the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like), and "mammal" includes, but is not limited to a human. In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0031] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0032] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0033] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeuticbenefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0034] Unless otherwise stated, structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13C- or 14C -enriched carbon are within the scope of the disclosure.

[0035] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0036] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0037] Methods of treating a disease or disorder

[0038] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg ofzelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0039] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0040] In one aspect, the present disclosure provides a method of enhancing metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0041] In one aspect, the present disclosure provides a method of enhancing metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0042] In one aspect, the present disclosure provides a method of improving metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0043] In one aspect, the present disclosure provides a method of improving metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of atleast four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0044] In one aspect, the present disclosure provides a method of enhancing synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0045] In one aspect, the present disclosure provides a method of enhancing synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0046] In one aspect, the present disclosure provides a method of improving synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0047] In one aspect, the present disclosure provides a method of improving synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0048] In one aspect, the present disclosure provides a method of enhancing synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In someembodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0049] In one aspect, the present disclosure provides a method of enhancing synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0050] In one aspect, the present disclosure provides a method of improving synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, four times a week, or five times a week. In some embodiments, the administering comprises administering the dose once a week, twice a week, three times a week, or four times a week.

[0051] In one aspect, the present disclosure provides a method of improving synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks. In some embodiments, the administering comprises administering the dose weekly, biweekly, monthly, every other month, or every six months. In some embodiments, the administering comprises administering the dose weekly, biweekly, or monthly.

[0052] In some embodiments, the administering comprises administering the dose once a week, twice a week, or three times a week. In some embodiments, the administering comprises administering the dose once a week or twice a week. In some embodiments, the administering comprises administering the dose twice a week or three times a week. In some embodiments, the administering comprises administering the dose twice a week, three times a week, or four times a week. In some embodiments, the administering comprises administering the dose twice a week. In some embodiments, the administering comprises administering the dose three times a week. In some embodiments, the administering comprises administering the dose four times a week. In some embodiments, the administering comprises administering the dose once a week. In some embodiments, the administering comprises administering the dose once a day. In some embodiments, the administering comprises administering the dose once every other day. In some embodiments, the administering comprises administering the dose once every other two days. In some embodiments, the administering comprises administering the dose once every other threedays. In some embodiments, the administering comprises administering the dose once every other four days.

[0053] In some embodiments, the administering comprises administering the dose once weekly, once biweekly, once a month, once every other month, once every three months, once every four months, once every five months, or once every six months. In some embodiments, the administering comprises administering the dose once weekly. In some embodiments, the administering comprises administering the dose once biweekly. In some embodiments, the administering comprises administering the dose once a month. In some embodiments, the administering comprises administering the dose once every other month. In some embodiments, the administering comprises administering the dose once every two months. In some embodiments, the administering comprises administering the dose once every three months. In some embodiments, the administering comprises administering the dose once every four months. In some embodiments, the administering comprises administering the dose once every five months. In some embodiments, the administering comprises administering the dose once every six months.

[0054] In some embodiments, the at most once a week is once weekly, once biweekly, once a month, once every other month, once every three months, once every four months, once every five months, or once every six months. In some embodiments, the at most once a week is once weekly. In some embodiments, the at most once a week is once biweekly. In some embodiments, the at most once a week is once a month. In some embodiments, the at most once a week is once every other month. In some embodiments, the at most once a week is once every two months. In some embodiments, the at most once a week is once every three months. In some embodiments, the at most once a week is once every four months. In some embodiments, the at most once a week is once every five months. In some embodiments the at most once a week is once every six months.

[0055] In some embodiments, the at least four weeks is from about 4 weeks to 104 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 78 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 52 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 50 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 48 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 46 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 44 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 42 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 40 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 38 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 36 weeks. In someembodiments, the at least four weeks is from about 4 weeks to about 34 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 32 weeks. In some embodiments, the at least four weeks is from about 4 weeks to 30 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 28 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 26 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 24 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 22 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 20 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 18 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 16 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 15 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 14 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 13 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 12 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 11 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 10 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 9 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 8 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 7 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 6 weeks.

[0056] In some embodiments, the at least four weeks is from 4 weeks to 104 weeks. In some embodiments, the at least four weeks is from 4 weeks to 78 weeks. In some embodiments, the at least four weeks is from 4 weeks to 52 weeks. In some embodiments, the at least four weeks is from about 4 weeks to 26 weeks. In some embodiments, the at least four weeks is from 4 weeks to24 weeks. In some embodiments, the at least four weeks is from 4 weeks to 20 weeks. In some embodiments, the at least four weeks is from 4 weeks to 16 weeks. In some embodiments, the at least four weeks is from 4 weeks to 12 weeks. In some embodiments, the at least four weeks is from 4 weeks to 10 weeks. In some embodiments, the at least four weeks is from 4 weeks to 9 weeks. In some embodiments, the at least four weeks is from 4 weeks to 8 weeks. In some embodiments, the at least four weeks is from 4 weeks to 7 weeks. In some embodiments, the at least four weeks is from about 4 weeks to 6 weeks.

[0057] In some embodiments, each dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 15 mg of zelquistinel or apharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 9 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0058] In some embodiments, each dose is selected from about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, and about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg and about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0059] In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a tablet. In some embodiments, the administering is orally administering.

[0060] In some embodiments, the method further comprises monitoring the electrical brain activity of the subject. In some embodiments, electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography(ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), or polysomnography (PSG). In some embodiments, electrical brain activity is monitored with electroencephalography (EEG) or polysomnography (PSG). In some embodiments, the electrical brain activity is monitored with EEG. In some embodiments, the EEG is quantitative electroencephalography (qEEG). In some embodiments, the electrical brain activity is monitored with PSG. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity comprises the subject wearing a device. In some embodiments, the device measures the EEG of the subject. In some embodiments, the device measures the PSG of the subject. In some embodiments, the device is a Dreem 3 headband (FDA 510(k) No.: K223539).

[0061] In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring after the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

[0062] As disclosed herein, zelquistinel or salt thereof is represented by the structure of

[0063] In some embodiments, the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto- cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium. In some embodiments, the disease or disorder is depression. In some embodiments, the depression is selected from major depressive disorder, refractory depression, and post-partum depression. In some embodiments, the depression is selected from major depressive disorder. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the disease or disorder is Cognitive Impairment. In some embodiments, the Cognitive Impairment is selected from Mild Cognitive Impairment. In some embodiments, the disease or disorder is Mild Cognitive Impairment.

[0064] Methods of treating a disease or disorder using a loading dose and maintenance dose.

[0065] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising (a) administering a loading dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof; and (b) administering a maintenance dose of zelquistinel or a pharmaceutically acceptable salt thereof after the loading dose, the maintenance dose is selected from an amount less than the loading dose.

[0066] In some embodiments, the loading dose is administered once a week over the course of about 1 to about 8 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 to about 7 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 to about 6 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 to about 5 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 to about 4 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 to about 3 weeks. In some embodiments, the loading dose is administered once a week over the course of about 2 to about 4 weeks. In some embodiments, the loading dose is administered once a week over the course of about 2 week to about 3 weeks.

[0067] In some embodiments, the loading dose is administered once a week over the course of about 1 week to about 2 weeks. In some embodiments, the loading dose is administered once a week over the course of about 1 week. In some embodiments, the loading dose is administered once a week over the course of about 2 weeks. In some embodiments, the loading dose is administered once a week over the course of about 3 weeks. In some embodiments, the loading dose is administered once a week over the course of about 4 weeks. In some embodiments, the loading dose is administered once a week over the course of about 5 weeks. In some embodiments, the loading dose is administered once a week over the course of about 6 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 to about 8 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 to about 7 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 to about 6 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 to about 5 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 to about 3 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 2 to about 4 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 2 week to about 3 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 week to about 2 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 1 week. In some embodiments, the loading dose is administered twice a week over the course of about 2 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 3 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 4 weeks. In some embodiments, the loading dose is administered twice a weekover the course of about 5 weeks. In some embodiments, the loading dose is administered twice a week over the course of about 6 weeks.

[0068] In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 104 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 78 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 52 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 50 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 48 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 46 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 44 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 42 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 40 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 38 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 36 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 34 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 32 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 30 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 28 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 26 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to 24 about weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 22 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 20 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 18 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 16 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 15 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 14 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 13 weeks. In someembodiments, the maintenance dose is administered once a week over the course of about 1 week to about 12 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 11 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 10 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 9 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 8 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 7 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 6 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 5 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 4 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 3 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 2 weeks.

[0069] In some embodiments, the maintenance dose is administered once biweekly over the course of about 104 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 78 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 52 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 50 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 48 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 46 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 44 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 42 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 40 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 38 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 36 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 34 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 32 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 30 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 28 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 26 weeks. In some embodiments, themaintenance dose is administered once biweekly over the course of about 24 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 22 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 20 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 18 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 16 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 15 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 14 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 13 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 12 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 11 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 10 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 9 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 8 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 7 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 6 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 5 weeks. In some embodiments, the maintenance dose is administered once biweekly over the course of about 4 weeks.

[0070] In some embodiments, the maintenance dose is administered once monthly over the course of about 104 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 78 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 52 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 50 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 48 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 46 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 44 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 42 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 40 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 38 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 36 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 34weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 32 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 30 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 28 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 26 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 24 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 22 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 20 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 18 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 16 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 15 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 14 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 13 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 12 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 11 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 10 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 9 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 8 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 7 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 6 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 5 weeks. In some embodiments, the maintenance dose is administered once monthly over the course of about 4 weeks.

[0071] In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 104 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 78 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 52 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 50 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 48 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 46 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 weekto about 44 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 42 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 40 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 38 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 36 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 34 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 32 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 30 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 28 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 26 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 24 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 22 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 20 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 18 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 16 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 15 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 14 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 13 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 12 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 11 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 10 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 9 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 8 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 7 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 6 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 5 weeks. In some embodiments, the maintenance dose isadministered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 3 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 2 weeks.

[0072] In some embodiments, each loading dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 1 mg to about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 1 mg to about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0073] In some embodiments, each loading dose is selected from about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, and about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg, about 6 mg, about 10 mg, about 12 mg, and about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg, about 6 mg, about 10 mg, and about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is selected from about 3 mg. In some embodiments, each loading dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each loading dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0074] In some embodiments, each maintenance dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0075] In some embodiments, each loading dose is selected from about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, and about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, about 15 mg, and about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, and about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, and about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg and about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, eachmaintenance dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0076] In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a tablet. In some embodiments, the administering is orally administering.

[0077] In some embodiments, the method further comprises monitoring the electrical brain activity of the subject. In some embodiments, electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), or polysomnography (PSG). In some embodiments, electrical brain activity is monitored with electroencephalography (EEG) or polysomnography (PSG). In some embodiments, the electrical brain activity is monitored with EEG. In some embodiments, the EEG is quantitative electroencephalography (qEEG). In some embodiments, the electrical brain activity is monitored with PSG. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring after the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity comprises the subject wearing a device. In some embodiments, the device measures the EEG of the subject. In some embodiments, the device measures the PSG of the subject. In some embodiments, the device is a Dreem 3 headband (FDA 510(k) No.: K223539).

[0078] As disclosed herein, zelquistinel or salt thereof is represented by the structure of

[0079] In some embodiments, the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto- cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium. In some embodiments, the disease or disorder is depression. In some embodiments, the depression is selected from major depressive disorder, refractory depression, and post-partum depression. In some embodiments, the depression is selected from major depressive disorder. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the disease or disorder is Cognitive Impairment. In some embodiments, the Cognitive Impairment is selected from MildCognitive Impairment. In some embodiments, the disease or disorder is Mild Cognitive Impairment.

[0080] Methods of treating a disease or disorder with monitoring of brain activity

[0081] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof comprising (a) monitoring the electrical brain activity of the subject; and (b) administering to the subject a starting dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, comprising (a) monitoring the electrical brain activity of the subject; and (b) administering to the subject a starting dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, comprising (a) monitoring the electrical brain activity of the subject; and (b) administering to the subject a starting dose of about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging. In some embodiments, electrical brain activity is monitored with electroencephalography (EEG), electrocorticography (ECoG), or polysomnography (PSG). In some embodiments, electrical brain activity is monitored with electroencephalography (EEG) or polysomnography (PSG). In some embodiments, the electrical brain activity is monitored with EEG. In some embodiments, the EEG is quantitative electroencephalography (qEEG). In some embodiments, the electrical brain activity is monitored with PSG. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping. In some embodiments, monitoring the electrical brain activity comprises the subject wearing a device. In some embodiments, the device measures the EEG of the subject. In some embodiments, the device measures the PSG of the subject. In some embodiments, the device is a Dreem 3 headband (FDA 510(k) No.: K223539).

[0082] In some embodiments, the starting dose is administered once a week over the course of about 1 to about 8 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 to about 7 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 to about 6 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 to 5 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 to 4 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 to about 3weeks. In some embodiments, the starting dose is administered once a week over the course of about 2 to about 4 weeks. In some embodiments, the starting dose is administered once a week over the course of about 2 weeks to about 3 weeks. In some embodiments, the starting dose is administered once week over the course of about 1 week to about 2 weeks. In some embodiments, the starting dose is administered once a week over the course of about 1 week. In some embodiments, the starting dose is administered once a week over the course of about 2 weeks. In some embodiments, the starting dose is administered once a week over the course of about 3 weeks In some embodiments, the starting dose is administered once a week over the course of about 4 weeks. In some embodiments, the starting dose is administered once a week over the course of about 5 weeks. In some embodiments, the starting dose is administered once a week over the course of about 6 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 to about 8 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 to about 7 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 to about 6 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 to about 5 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 to about 3 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 2 to about 4 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 2 weeks to about 3 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 week to about 2 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 1 week. In some embodiments, the starting dose is administered twice a week over the course of about 2 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 3 weeks In some embodiments, the starting dose is administered twice a week over the course of about 4 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 5 weeks. In some embodiments, the starting dose is administered twice a week over the course of about 6 weeks.

[0083] In some embodiments, each starting dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 6 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 10 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable saltthereof. In some embodiments, each starting dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 9 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg to about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 6 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 10 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg to about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 10 mg of zelquistinel or a pharmaceuticallyacceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0084] In some embodiments, each starting dose is selected from about 5 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 10 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 15 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 20 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 5 mg to about 15 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 5 mg to about 10 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 10 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 15 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each starting dose is selected from about 5 mg, about 10 mg, about 15 mg, about 20 mg, and about 25 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 5 mg, about 10 mg, and about 15 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 5 mg and about 10 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 15 mg and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is selected from about 10 mg and about 15 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 25 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 5 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each starting dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0085] In some embodiments, the method further comprises administering to the subject a maintenance dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a maintenance dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a maintenance dose of about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises apimostinel. In some embodiments, the dosing of apimostinel is based on the free base weight.

[0086] In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 104 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 78 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 52 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 50 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 48 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 46 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 44 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 42 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 40 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 38 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 36 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 34 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 32 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 30 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 28 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 26 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 24 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 22 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 weekto about 20 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 18 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 16 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 15 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 14 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 13 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 12 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 11 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 10 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 9 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 8 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 7 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 6 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 5 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 4 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 3 weeks. In some embodiments, the maintenance dose is administered once a week over the course of about 1 week to about 2 weeks.

[0087] In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 104 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 78 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 52 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 50 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 48 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 46 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 44 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 42 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 40 weeks. In someembodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 38 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 36 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 34 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 32 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 30 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 28 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 26 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 24 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 22 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 20 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 18 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 16 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 15 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 14 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 13 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 12 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 11 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 10 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 9 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 8 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 7 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 6 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 5 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 4 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 weekto about 3 weeks. In some embodiments, the maintenance dose is administered twice a week over the course of about 1 week to about 2 weeks.

[0088] In some embodiments, each maintenance dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, about 15 mg, and about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, and about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, about 10 mg, and about 12 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg, about 3 mg, and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 1 mg and about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 3 mg and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0089] In some embodiments, each maintenance dose is selected from about 5 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 10 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 15 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 20 mg to about 25 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 5 mg to about 15 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 5 mg to about 10 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 10 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 15 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof. In some embodiments, each maintenance dose is selected from about 5 mg, about 10 mg, about 15 mg, about 20 mg, and about 25 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 5 mg, about 10 mg, and about 15 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 5 mg and about 10 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 15 mg and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is selected from about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 5 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, each maintenance dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises apimostinel. In some embodiments, the dosing of apimostinel is based on the free base weight.

[0090] In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, zelquistinel or a pharmaceuticallyacceptable salt thereof is formulated as a capsule. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a tablet. In some embodiments, the administering of zelquistinel or a pharmaceutically acceptable salt thereof is orally administering.

[0091] As disclosed herein, zelquistinel or salt thereof is represented by the structure of

[0092] In some embodiments, apimostinel or a pharmaceutically acceptable salt thereof is formulated as an intravenous formulation. In some embodiments, the administering of apimostinel or a pharmaceutically acceptable salt thereof is intravenous administering.

[0093] As disclosed herein, apimostinel or salt thereof is represented by the structure of

[0094] In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping.

[0095] In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of apimostinel or a pharmaceutically acceptable salt thereof.In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring during the administering of apimostinel or a pharmaceutically acceptable salt thereof. In some embodiments, monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping.

[0096] In some embodiments, the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto- cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium. In some embodiments, the disease or disorder is depression. In some embodiments, the depression is selected from major depressive disorder, refractory depression, and post-partum depression. In some embodiments, the depression is selected from major depressive disorder. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the disease or disorder is Cognitive Impairment. In some embodiments, the Cognitive Impairment is selected from Mild Cognitive Impairment. In some embodiments, the disease or disorder is Mild Cognitive Impairment.

[0097] Methods of treating a disease or disorder with chronic administration of Zelquistinel

[0098] In one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of at least four weeks.

[0099] In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, about 4 weeks to about 156 weeks, about 4 weeks to about 184 weeks, and about 4 weeks to about 208 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, about 4 weeks to about 156 weeks, and about 4 weeks to about 184 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, and about 4 weeks to about 156 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, and about 4 weeks to about 130 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, and about 4 weeks to about 104 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, and about 4 weeks to about 78 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, and about 4 weeks to about 52 weeks. In some embodiments, the at least four weeks is selected from about 4 weeks to about 12 weeks and about 4 weeks to about 26 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 208 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 184 weeks.In some embodiments, the at least four weeks is from about 4 weeks to about 156 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 130 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 104 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 78 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 52 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 26 weeks. In some embodiments, the at least four weeks is from about 4 weeks to about 12 weeks.

[0100] In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, about 4 weeks to about 3 years, about 4 weeks to about 3.5 years, and about 4 weeks to about 4 years. In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, about 4 weeks to about 3 years, and about 4 weeks to about 3.5 years. In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, and about 4 weeks to about 3 years. In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, and about 4 weeks to about2.5 years, in some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, and about 4 weeks to about 2 years. In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year, and about 4 weeks to about1.5 years. In some embodiments, the at least four weeks is selected from about 4 weeks to about 1 year. In some embodiments, the at least four weeks is selected from about 4 weeks to about 0.5 year. In some embodiments, the at least four weeks is from about 4 weeks to about 4 years. In some embodiments, the at least four weeks is from about 4 weeks to about 3.5 years. In some embodiments, the at least four weeks is from about 4 weeks to about 3 years. In some embodiments, the at least four weeks is from about 4 weeks to about 2.5 years. In some embodiments, the at least four weeks is from about 4 weeks to about 2 years. In some embodiments, the at least four weeks is from about 4 weeks to about 1.5 years. In some embodiments, the at least four weeks is from about 4 weeks to about 1 year. In some embodiments, the at least four weeks is from about 4 weeks to about 0.5 year.

[0101] In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, about 4 weeks to about 36 months, about 4 weeks to about 42 months, and about 4 weeks to about 48 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, about 4 weeks to about 36 months, and about 4 weeks to about 42 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, and about 4 weeks to about 36 months. Insome embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, and about 4 weeks to about 32 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, and about 4 weeks to about 24 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, and about 4 weeks to about 18 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, and about 4 weeks to about 12 months. In some embodiments, the at least four weeks is selected from about 4 weeks to about 3 months and about 4 weeks to about 6 months. In some embodiments, the at least four weeks is from about 4 weeks to about 48 months. In some embodiments, the at least four weeks is from about 4 weeks to about 42 months. In some embodiments, the at least four weeks is from about 4 weeks to about 36 months. In some embodiments, the at least four weeks is from about 4 weeks to about 32 months. In some embodiments, the at least four weeks is from about 4 weeks to about 24 months. In some embodiments, the at least four weeks is from about 4 weeks to about 18 months. In some embodiments, the at least four weeks is from about 4 weeks to about 12 months. In some embodiments, the at least four weeks is from about 4 weeks to about 6 months. In some embodiments, the at least four weeks is from about 4 weeks to about 3 months.

[0102] In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of more than four weeks.

[0103] In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, about 4 weeks to about 156 weeks, about 4 weeks to about 184 weeks, and about 4 weeks to about 208 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, about 4 weeks to about 156 weeks, and about 4 weeks to about 184 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, about 4 weeks to about 130 weeks, and about 4 weeks to about 156 weeks. In someembodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, about 4 weeks to about 104 weeks, and about 4 weeks to about 130 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 78 weeks, and about 4 weeks to about 104 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, about 4 weeks to about 52 weeks, and about 4 weeks to about 78 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks, about 4 weeks to about 26 weeks, and about 4 weeks to about 52 weeks. In some embodiments, the more than four weeks is selected from about 4 weeks to about 12 weeks and about 4 weeks to about 26 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 312 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 260 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 208 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 184 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 156 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 130 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 104 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 78 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 52 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 26 weeks. In some embodiments, the more than four weeks is from about 4 weeks to about 12 weeks.

[0104] In some embodiments, the more than four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, about 4 weeks to about 3 years, about 4 weeks to about 3.5 years, and about 4 weeks to about 4 years. In some embodiments, the more than four weeks is selected from about 4 weeks to about1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, about 4 weeks to about 3 years, and about 4 weeks to about 3.5 years. In some embodiments, the more than four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, about 4 weeks to about 2.5 years, and about 4 weeks to about 3 years. In some embodiments, the more than four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, about 4 weeks to about 2 years, and about 4 weeks to about 2.5 years, in some embodiments, the more than four weeks is selected from about 4 weeks to about 1 year, about 4 weeks to about 1.5 years, and about 4 weeks to about2 years. In some embodiments, the more than four weeks is selected from about 4 weeks to about1 year, and about 4 weeks to about 1.5 years. In some embodiments, the more than four weeks is selected from about 4 weeks to about 1 year. In some embodiments, the more than four weeks is selected from about 4 weeks to about 0.5 year. In some embodiments, the more than four weeks is from about 4 weeks to about 6 years. In some embodiments, the more than four weeks is from about 4 weeks to about 5 years. In some embodiments, the more than four weeks is from about 4 weeks to about 4 years. In some embodiments, the more than four weeks is from about 4 weeks to about 3.5 years. In some embodiments, the more than four weeks is from about 4 weeks to about 3 years. In some embodiments, the more than four weeks is from about 4 weeks to about 2.5 years. In some embodiments, the more than four weeks is from about 4 weeks to about 2 years. In some embodiments, the more than four weeks is from about 4 weeks to about 1.5 years. In some embodiments, the more than four weeks is from about 4 weeks to about 1 year. In some embodiments, the more than four weeks is from about 4 weeks to about 0.5 year.

[0105] In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, about 4 weeks to about 36 months, about 4 weeks to about 42 months, and about 4 weeks to about 48 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, about 4 weeks to about 36 months, and about 4 weeks to about 42 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, about 4 weeks to about 32 months, and about 4 weeks to about 36 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, about 4 weeks to about 24 months, and about 4 weeks to about 32 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about4 weeks to about 6 months, about 4 weeks to about 12 months, about 4 weeks to about 18 months, and about 4 weeks to about 24 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, about 4 weeks to about 12 months, and about 4 weeks to about 18 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months, about 4 weeks to about 6 months, and about 4 weeks to about 12 months. In some embodiments, the more than four weeks is selected from about 4 weeks to about 3 months and about 4 weeks to about 6 months. In some embodiments, the morethan four weeks is from about 4 weeks to about 72 months. In some embodiments, the more than four weeks is from about 4 weeks to about 60 months. In some embodiments, the more than four weeks is from about 4 weeks to about 48 months. In some embodiments, the more than four weeks is from about 4 weeks to about 42 months. In some embodiments, the more than four weeks is from about 4 weeks to about 36 months. In some embodiments, the more than four weeks is from about 4 weeks to about 32 months. In some embodiments, the more than four weeks is from about 4 weeks to about 24 months. In some embodiments, the more than four weeks is from about 4 weeks to about 18 months. In some embodiments, the more than four weeks is from about 4 weeks to about 12 months. In some embodiments, the more than four weeks is from about 4 weeks to about 6 months. In some embodiments, the more than four weeks is from about 4 weeks to about 3 months.

[0106] In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt monthly, bimonthly, or every other month. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, every three weeks, monthly, bimonthly, or trimonthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, every three weeks, monthly, or bimonthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, every three weeks, or monthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, or every three weeks. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly or every three weeks. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly or biweekly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, every three weeks, or monthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt monthly or bimonthly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt weekly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt biweekly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt monthly. In some embodiments, the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptablesalt bimonthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once monthly, once bimonthly, or once every other month. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once weekly, once biweekly, once every three weeks, once monthly, once bimonthly, once every other month, or once trimonthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once weekly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once biweekly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once every three weeks. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once monthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once bimonthly. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once every other month. In some embodiments, the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt once trimonthly.

[0107] In some embodiments, the chronic administration has an occurrence selected from weekly, biweekly, every three weeks, bimonthly, monthly, and every other month. In some embodiments, the occurrence is selected from weekly, biweekly, every three weeks, bimonthly, and monthly. In some embodiments, the occurrence is selected from weekly, biweekly, and every three weeks. In some embodiments, the occurrence is selected from weekly and biweekly. In some embodiments, the occurrence is selected from biweekly, every three weeks, bimonthly, monthly, and every other month. In some embodiments, the occurrence is selected from every three weeks, bimonthly, monthly, and every other month. In some embodiments, the occurrence is selected from bimonthly, monthly, and every other month. In some embodiments, the occurrence is selected from monthly and every other month. In some embodiments, the occurrence is weekly. In some embodiments, the occurrence is biweekly. In some embodiments, the occurrence is every three weeks. In some embodiments, the occurrence is bimonthly. In some embodiments, the occurrence is monthly. In some embodiments, the occurrence is every other month.

[0108] In some embodiments, each dose is selected from about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 15 mg of zelquistinel or apharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 9 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg to about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0109] In some embodiments, each dose is selected from about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, and about 15 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg, about 3 mg, and about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg and about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof. In some embodiments, the dosing comprises zelquistinel. In some embodiments, the dosing of zelquistinel is based on the free base weight.

[0110] In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule. In some embodiments, zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a tablet. In some embodiments, the administering is orally administering.[OHl] As disclosed herein, zelquistinel or salt thereof is represented by the structure of

[0112] In some embodiments, the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive- compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto- cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium. In some embodiments, the disease or disorder is depression. In some embodiments, the depression is selected from major depressive disorder, refractory depression, and post-partum depression. In some embodiments, the depression is selected from major depressive disorder. In some embodiments, the disease or disorder is major depressive disorder. In some embodiments, the disease or disorder is autism. In some embodiments, the disease or disorder is schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia. In some embodiments, the schizophrenia is selected from Cognitive Impairment associated with Schizophrenia Negative Symptoms. In some embodiments, the disease or disorder is Cognitive Impairment. In some embodiments, the Cognitive Impairment is selected from MildCognitive Impairment. In some embodiments, the disease or disorder is Mild Cognitive Impairment.EXAMPLES

[0113] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.Example 1 - In Vivo Dose Dependent Studies Of Zelquistinel

[0114] Methods

[0115] Adult male rats were implanted with intracranial recording and stimulation electrode in the medial prefrontal cortex (MPFC). Three groups of implanted rats and non-surgical controls were administered either zelquistinel as a single dose, 5 days of daily repeat dosing, or once weekly dosing for six weeks. MPFC excitatory field potentials evoked by mixed deep white matter inputs to layer II / III were recorded from freely behaving rats at baseline, and 1 hr, 24 hr and 1 week after dosing. Input / output curves (VO) were generated during dosing, and 1 week after dosing I / O curves were measured, as well as long-term potentiation (LTP) induced by 6 Hz stimulation trains. Two weeks after dosing, I / O curves were recorded and LTP induced again. In a separate groups of rats, positive emotional learning was tested 1 and 2 weeks after single, daily or weekly dosing.

[0116] As shown in FIG. 1, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg). Isoflurane exposure: animals receiving isoflurane groups received 3 hrs of anesthesia (surgical plane) before or after zelquistinel administration. Metaplasticity: 20 min of baseline field potentials (70 ps pulse every 30 sec) were followed by theta train tetanus and an additional 60 minutes of field potential recordings (70 ps pulse every 30 sec).

[0117] In FIG. 2A, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg). I / O curves: excitatory field potentials were induced by bipolar stimulation (70 ps pulse every 5 sec) using a stimulation intensities from 0.1 to 2.0 mA in 0.1 mA steps. Data was normalized to pre dose levels. Displayed in FIG. 2B, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) as a single dose or daily for 5 days. I / O curves: excitatory field potentials were induced by bipolar stimulation (70 ps pulse every 5 sec) using a stimulation intensities from 0.1 to 2.0 mA in 0.1 mA steps. Data was normalized to pre dose levels. In FIG. 2C, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterilesaline vehicle (1 ml / kg) as a single dose or daily for 5 days. Metaplasticity: 20 min of baseline field potentials (70 ps pulse every 30 sec) were followed by theta train tetanus and an additional 60 minutes of field potential recordings (70 ps pulse every 30 sec).

[0118] In FIG. 3A, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) as a single dose or daily for 5 days. I / O curves: excitatory field potentials were induced by bipolar stimulation (70 ps pulse every 5 sec) using a stimulation intensities from 0.1 to 2.0 mA in 0.1 mA steps. I / O curve slopes were calculated as field excitatory postsynaptic potential (fEPSP) slope / mA and were normalized to pre dose levels. Shown in FIG. 3B, male 2-3 month old SD rats with MPFC stimulation and recording electrodes were dosed with zelquistinel (0.3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) as a single dose or daily for 5 days. Metaplasticity: 20 min of baseline field potentials (70 ps pulse every 30 sec) were followed by theta train tetanus and an additional 60 minutes of field potential recordings (70 ps pulse every 30 sec).

[0119] Displayed in FIG. 4A, naive male 2-3 month old SD rats were dosed with zelquistinel (0.003 - 3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) as a single dose and tested in the Positive Emotional Learning (PEL) assay 7 days after dosing. The PEL assay was conducted and analyzed exactly as describe in PMID: 21645591. In FIG. 4B, naive male 2-3 month old SD rats were dosed with zelquistinel (0.003 - 3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) as a single dose or 5 X daily dosing and tested in the PEL assay 7 days after the last dose. The PEL assay was conducted and analyzed exactly as describe in PMID: 21645591. In FIG. 4C, naive male 2-3 month old SD rats were dosed with zelquistinel (0.003 - 3 mg / kg PO) or 0.9% sterile saline vehicle (1 ml / kg) 6 X weekly and tested in the PEL assay 7 days after the last dose. The PEL assay was conducted and analyzed exactly as describe in PMID: 21645591. Whereas in FIG. 4D, naive male 2-3 month old SD rats were dosed with a single dose of zelquistinel (0.3 mg / kg PO), ketamine (10 mg / kg IP) or 0.9% sterile saline vehicle (1 ml / kg) and tested in the PEL assay 7 or 14 days after the last dose. The PEL assay was conducted and analyzed exactly as described in PMID: 21645591.

[0120] Results

[0121] A dose-response relation for zelquistinel was obtained in the MPFC-dependent PEL assay assessed 1 week post-dose. After a single dose, the 0.3 mg / kg PO dose was maximally effective (F (4, 25) = 48.29, P < .05; P < .05 Tukey post hoc test 0.3 mg / kg vs vehicle but not 0.3 mg / kg vs 3 mg / kg), while daily dosed animals exhibited an enhancement in PEL only at the lowest dose level of 0.003 mg / kg (F (4, 25) = 27.05, P < .05; P < .05 Tukey test 0.003 mg / kg vs vehicle) as compared to the single dose.

[0122] Once weekly dose animals exhibited a similar PEL response as a single administration, but with increased benefit at lower doses (F (4, 45) = 41.82, P < .05; P < .05 Tukey post hoc test 0.003, 0.03, 0.3, 3 mg / kg vs vehicle). Similar results were seen, in measures of synaptic strength as measured by I / O curves (F (3, 26) = 55.77, P < .05). Importantly, weekly dosing led to a larger and longer lasting facilitation of LTP for 2 weeks (i.e., metaplasticity), as compared to a single dose or daily (1 week) dose (F (3, 31) = 79.15, P < .05; P < .05 weekly dosing vs vehicle or daily dosing).

[0123] A similar shift in the dose response curve for single, daily and weekly dosing was observed with the metaplasticity assay as with the PEL and I / O curves. In addition, the metaplastic effect of zelquistinel was blocked by co-administration of isoflurane (F(3, 22) = 57.56, P < .05; m P < .05 Tukey test zelquistinel + isoflurane pre-dosing vs isoflurane post-dosing), and not isoflurane postdosing or vehicle), suggesting that the synaptic plasticity enhancing effects of zelquistinel are activity dependent.

[0124] Zelquistinel-mediated enhancement of in vivo plasticity and plasticity dependent behavior is both dose and dose frequency dependent. The increase in synaptic strength and learning seen with a single dose administration is (a) lost by too frequent (daily) dosing, and conversely (b) maintained or increased with a once-weekly dosing schedule. These data highlight the unexpected complexity and challenge of extrapolating synaptic plasticity effects from a single dose to clinical dosing strategies for plasticity enhancers.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a disease or disorder in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

2. The method of claim 1, wherein the administering comprises administering the dose once a week, twice a week, or three times a week.

3. The method of claim 2, wherein the administering comprises administering the dose once a week.

4. The method of any one of claims 1 to 3, wherein the at least four weeks is from about 4 weeks to 52 weeks.

5. The method of any one of claims 1 to 4, wherein each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

8. The method of claim 6, wherein each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

9. The method of claim 6, wherein each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1 to 9, wherein zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet.

11. The method of any one of claims 1 to 10, wherein the administering is orally administering.

12. A method of treating a disease or disorder in a subject in need thereof, comprising(a) administering a loading dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt thereof; and(b) administering a maintenance dose of zelquistinel or a pharmaceutically acceptable salt thereof after the loading dose, the maintenance dose is selected from an amount less than the loading dose.

13. The method of claim 12, wherein the loading dose is administered once a week over the course of about 1 to 4 weeks.

14. The method of claim 13, wherein the loading dose is administered once a week over the course of about 1 week to about 2 weeks.

15. The method of claim 12, wherein the loading dose is administered twice a week over the course of about 1 week to about 4 weeks.

16. The method of claim 15, wherein the loading dose is administered twice a week over the course of about 1 week to about 2 weeks.

17. The method of any one of claims 12 to 16, wherein the maintenance dose is administered once a week over the course of about 1 week to about 52 weeks.

18. The method of any one of claims 12 to 16, wherein the maintenance dose is administered twice a week over the course of about 1 week to about 52 weeks.

19. The method of any one of claims 12 to 18, wherein each loading dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein each loading dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

21. The method of claim 20, wherein each loading dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein each loading dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

23. The method of claim 21, wherein each loading dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 12 to 23, wherein each maintenance dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein each maintenance dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein each maintenance dose is about 1 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

27. The method of claim 25, wherein each maintenance dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

28. The method of claim 25, wherein each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 12 to 28, wherein zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet.

30. The method of any one of claims 12 to 29, wherein the administering is orally administering.

31. The method of any one of claims 1 to 30, wherein the method further comprises monitoring the electrical brain activity of the subject.

32. The method of claim 31, wherein electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging.

33. The method of claim 32, wherein the electrical brain activity is monitored with EEG.

34. The method of claim 32, wherein the EEG is quantitative electroencephalography(qEEG).

35. The method of claim 32, wherein the electrical brain activity is monitored with PSG.

36. The method of any one of claims 31 to 35, wherein monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping.

37. The method of any one of claims 31 to 36, wherein monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 31 to 37, wherein monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

39. A method of treating a disease or disorder in a subject in need thereof comprising(a) monitoring the electrical brain activity of the subject; and(b) administering to the subject a starting dose of about 1 mg to about 25 mg zelquistinel or a pharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein electrical brain activity is monitored with functional magnetic resonance imaging (fMRI), electroencephalography (EEG), electrocorticography (ECoG), polysomnography (PSG), or fluorescence imaging.

41. The method of claim 40, wherein the electrical brain activity is monitored with EEG.

42. The method of claim 41, wherein the EEG is quantitative electroencephalography(qEEG).

43. The method of claim 42, wherein the electrical brain activity is monitored with PSG.

44. The method of any one of claims 39 to 43, wherein monitoring the electrical brain activity of the subject comprises monitoring when the subject is sleeping.

45. The method of any one of claims 39 to 44, wherein the starting dose is administered once a week over the course of about 1 to about 4 weeks.

46. The method of claim 45, wherein the starting dose is administered once a week over the course of about 1 week to about 2 weeks.

47. The method of any one of claims 39 to 44, wherein the starting dose is administered twice a week over the course of about 1 week to about 4 weeks.

48. The method of claim 47, wherein the starting dose is administered twice a week over the course of about 1 week to about 2 weeks.

49. The method of any one of claims 39 to 48, wherein each starting dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein each starting dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein each starting dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein each starting dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

53. The method of claim 51, wherein each starting dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 39 to 48, wherein each starting dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof.

55. The method of claim 54, wherein each starting dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof.

56. The method of claim 54, wherein each starting dose is about 5 mg apimostinel or a pharmaceutically acceptable salt thereof.

57. The method of claim 54, wherein each starting dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof.

58. The method of claim 54, wherein each starting dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof.

59. The method of claim 54, wherein each starting dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof.

60. The method of any one of claims 39 to 59, wherein the method further comprises administering to the subject a maintenance dose of about 1 mg to about 25 mg zelquistinel or apharmaceutically acceptable salt thereof, or about 1 mg to about 25 mg apimostinel or a pharmaceutically acceptable salt thereof.

61. The method of claim 60, wherein the maintenance dose is administered once a week over the course of about 1 week to about 52 weeks.

62. The method of claim 60, wherein the maintenance dose is administered twice a week over the course of about 1 week to about 52 weeks.

63. The method of any one of claims 60 to 62, wherein each maintenance dose is selected from about 1 mg to about 20 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

64. The method of claim 63, wherein each maintenance dose is selected from about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein each maintenance dose is selected from about 6 mg and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

66. The method of claim 65, wherein each maintenance dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

67. The method of claim 65, wherein each maintenance dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

68. The method of any one of claims 60 to 62, wherein each maintenance dose is selected from about 5 mg to about 20 mg of apimostinel or a pharmaceutically acceptable thereof.

69. The method of claim 68, wherein each maintenance dose is selected from about 5 mg, about 10 mg, about 15 mg, and about 20 mg of apimostinel or a pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein each maintenance dose is about 5 mg apimostinel or a pharmaceutically acceptable salt thereof.

71. The method of claim 69, wherein each maintenance dose is about 10 mg apimostinel or a pharmaceutically acceptable salt thereof.

72. The method of claim 69, wherein each maintenance dose is about 15 mg apimostinel or a pharmaceutically acceptable salt thereof.

73. The method of claim 69, wherein each maintenance dose is about 20 mg apimostinel or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 39 to 53, or 60 to 67, wherein zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet.

75. The method of any one of claims 39 to 53, 60 to 67, or 74, wherein the administering of zelquistinel or a pharmaceutically acceptable salt thereof is orally administering.

76. The method of any one of claims 39 to 48, 54 to 62, or 68 to 73, wherein apimostinel or a pharmaceutically acceptable salt thereof is formulated as an intravenous formulation.

77. The method of any one of claims 39 to 48, 54 to 62, 68 to 73, or 76, wherein the administering of apimostinel or a pharmaceutically acceptable salt thereof is intravenous administering.

78. The method of any one of claims 39 to 77, wherein monitoring the electrical brain activity of the subject comprises monitoring prior to the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

79. The method of any one of claims 39 to 78, wherein monitoring the electrical brain activity of the subject comprises monitoring during the administering of zelquistinel or a pharmaceutically acceptable salt thereof.

80. A method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of at least four weeks.

81. The method of claim 80, wherein the at least four weeks is from about 4 weeks to about 208 weeks.

82. The method of claim 81, wherein the at least four weeks is from about 4 weeks to about 104 weeks.

83. The method of claim 82, wherein the at least four week is from above 4 weeks to about 104 weeks.

84. A method of treating a disease or disorder in a subject in need thereof, comprising chronically administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt over the course of more than four weeks.

85. The method of any one of claims 80 or 84, wherein the chronic administration comprises administering each dose of zelquistinel or a pharmaceutically acceptable salt weekly, biweekly, every three weeks, monthly, or bimonthly.

86. The method of claim 85, wherein the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt weekly.

87. The method of claim 85, wherein the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt biweekly.

88. The method of claim 85, wherein the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt monthly.

89. The method of claim 85, wherein the chronic administration comprises administering the dose of zelquistinel or a pharmaceutically acceptable salt bimonthly.

90. The method of any one of claims 80 to 89, wherein each dose is selected from about 1 mg to about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

91. The method of claim 90, wherein each dose is selected from about 1 mg, about 3 mg, about 6 mg, and about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

92. The method of claim 91, wherein each dose is about 3 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

93. The method of claim 91, wherein each dose is about 6 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

94. The method of claim 91, wherein each dose is about 10 mg of zelquistinel or a pharmaceutically acceptable salt thereof.

95. The method of any one of claims 80 to 94, wherein zelquistinel or a pharmaceutically acceptable salt thereof is formulated as a capsule or a tablet.

96. The method of any one of claims 80 to 95, wherein the administering is orally administering.

97. The method of any one of claims 1 to 96, wherein the disease or disorder is selected from autism, anxiety, depression, major depressive disorder, refractory depression, post-partum depression, suicidality, suicidal ideation, bipolar disorder, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, a psychotic disorder, a psychotic symptom, social withdrawal, obsessive-compulsive disorder (OCD), phobia, post-traumatic stress syndrome, a behavior disorder, an impulse control disorder, a substance abuse disorder, a sleep disorder, a memory disorder, a learning disorder, urinary incontinence, multiple system atrophy, progressive supra-nuclear palsy, Friedrich's ataxia, Down's syndrome, fragile X syndrome, tuberous sclerosis, olivio-ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, dementia, AIDS dementia, Alzheimer's disease, Huntington's chorea, spasticity, myoclonus, muscle spasm, Tourette's syndrome, epilepsy, cerebral ischemia, stroke, a brain tumor, traumatic brain injury, cardiac arrest, myelopathy, spinal cord injury, peripheral neuropathy, acute neuropathic pain, chronic neuropathic pain, Parkinson’s disease, Huntington’s disease, Mild Cognitive Impairment, social phobias, panic disorder, eating disorders, tic disorders, and delirium.

98. The method of claim 97, wherein the disease or disorder is major depressive disorder.

99. The method of claim 97, wherein the disease or disorder is autism.

100. The method of claim 97, wherein the disease or disorder is schizophrenia.

101. The method of claim 100, wherein the schizophrenia is selected from CognitiveImpairment associated with Schizophrenia and Cognitive Impairment associated with Schizophrenia Negative Symptoms.

102. The method of claim 97, wherein the disease or disorder is Mild Cognitive Impairment.

103. A method of improving metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

104. A method of improving metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

105. A method of enhancing metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

106. A method of enhancing metaplasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

107. A method of improving synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

108. A method of improving synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

109. A method of enhancing synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

110. A method of enhancing synaptic strength in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

111. A method of improving synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

112. A method of improving synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

113. A method of enhancing synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at least once a week over the course of at least four weeks.

114. A method of enhancing synaptic plasticity in a subject in need thereof, comprising administering a dose of about 1 mg to about 25 mg of zelquistinel or a pharmaceutically acceptable salt for at most once a week over the course of at least four weeks.

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