Methods for reducing physical dependence on neuropsychiatric treatments

Abstract

Neuropsychiatric treatments, including methods, regimens and interventions for reducing physical dependence on neuropsychiatric treatments based on the administration of urotalonto.

Description

[Technical Field]

[0001] (Priority) This application claims priority to U.S. Provisional Application No. 63 / 379,364, filed October 13, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to methods, regimens and interventions for reducing physical dependence on pharmacological neuropsychiatric treatments and those neuropsychiatric treatments based on urotalonto administration. [Background technology]

[0003] Neuropsychiatric drugs are a heterogeneous group of compounds with wide variations in receptor affinity. The clinical effects of individual compounds vary, and receptor affinity is therefore an important factor not only for efficacy but also for side effect profile, particularly [Correll (2010)].

[0004] Physical dependence, which can develop with the therapeutic use of psychotropic drugs, is the physical symptoms that occur when the drug is suddenly or gradually discontinued. Appropriate withdrawal strategies are complex and depend on the drug's side-effect profile, pharmacodynamics and kinetics, mechanism of action, and the patient's comorbidities and vulnerabilities [Cerovecki et al. (2013)].

[0005] Urotalont (also known as SEP-363856 or SEP-856) is an investigational drug under clinical development by Sunovion Pharmaceuticals Inc. (Marlborough, Massachusetts) for various neurological disorders. In animal studies, urotalont has demonstrated primarily antipsychotic-like properties in addition to anxiolytic and antidepressant properties [Dedic et al. (2019)]. Physical dependence studies in rats are reported in US 2021 / 0315859 A1.

[0006] Abrupt cessation of neuropsychiatric treatment carries a high risk of withdrawal symptoms, including a variety of physical, motor, and psychological symptoms [Chouinard et al. (2017)]. Depending on the drug's target receptor, both first- and second-generation antipsychotics may be associated with the following clinical features upon drug discontinuation or tapering: cholinergic withdrawal symptoms, such as restlessness, insomnia, anxiety or depression, dizziness, unsteadiness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremor, parkinsonism, agitation, muscle pain, muscle rigidity, dysesthesias, fear, hallucinations, confusion or disorientation, hypothermia, and sweating; dopaminergic withdrawal symptoms (nigrostriatal), selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia; and flu-like symptoms, sweating or chills, dizziness, unsteadiness, and choking. or serotonergic withdrawal symptoms selected from tachycardia, abnormal sensations, electric shock sensations, anxiety, restlessness, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and difficulty concentrating; histaminergic withdrawal symptoms selected from irritability, insomnia, restlessness, depressed mood, loss of appetite or nausea, tremors, lack of coordination and lethargy or amnesia; dopaminergic withdrawal symptoms (mesolimbic or striatal) selected from auditory hallucinations, paranoia, and other psychotic symptoms; and adrenergic withdrawal symptoms selected from headache, anxiety or restlessness, high blood pressure, tachycardia, angina, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating [Horowitz et al. (2021)].

[0007] Patients who tolerate increasing doses are more likely to experience withdrawal symptoms [Chouinard et al. (2017)]. Research has also shown that the longer the exposure to drug treatment, the higher the risk of developing withdrawal-related psychosis upon drug cessation [Tiihonen et al. (2018)].

[0008] Relapse is another significant risk associated with withdrawal of antipsychotic medications. One study reported that 48% of relapses occurred in the first 12 months after withdrawal (40% in the first 6 months), and only 2% per year thereafter [Viguera et al. (1997)]. The risk of relapse doubles after 1–2 years, triples after 2–5 years, and increases sevenfold after 8 years of medication. Horowitz et al. (2021) recently published a method for tapering antipsychotic medications to minimize the risk of relapse. This involves gradual tapering over months and years, incorporating hyperbolic tapering, which allows for a more even reduction in D2 blockade.

[0009] There is a need for neuropsychiatric treatment regimens and withdrawal strategies that do not result in the historical problems associated with withdrawal from neuropsychiatric medications.

[0010] (Abstract) Surprisingly, it has been found that urotalont has a favorable side effect profile when human subjects discontinue the drug, allowing urotalont therapy to be discontinued suddenly or gradually without significant risk of many, if not all, clinically significant complications.

[0011] Thus, in one embodiment, the present disclosure provides a method for treating a neuropsychiatric disorder in a human subject in need of treatment without significant physical dependence upon cessation of treatment, comprising selecting a therapeutically effective amount of urotalont, or a pharmaceutically acceptable salt thereof, and administering it to the subject for an effective period of time before cessation of administration, wherein cessation of administration does not result in significant physical dependence compared to placebo.

[0012] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: (a) administering to the subject a therapeutically effective amount of urotalont, or a pharmaceutically acceptable salt thereof, for an effective period of time; and (b) abruptly discontinuing administration of urotalont after the effective period of time.

[0013] In another embodiment, the disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need of treatment, comprising: (a) administering a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof to the subject for an effective period of time; and (b) discontinuing administration of urotalont and any drug therapy for the neuropsychiatric disorder after the effective period of time.

[0014] In another embodiment, the disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need thereof, the method comprising: (a) administering a therapeutically effective amount of urotalont, or a pharmaceutically acceptable salt thereof, to the subject for an effective period of time; and (b) discontinuing administration of urotalont after the effective period of time; wherein the subject is at risk for or has previously experienced one or more symptoms or syndromes associated with neuropsychiatric drug withdrawal, or the method is performed without the appearance of one or more symptoms or syndromes associated with neuropsychiatric drug withdrawal.

[0015] Additional advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the detailed description, or may be learned by practice of the present disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is also to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed.

[0016] (Detailed Description of the Invention) All published documents cited herein are incorporated by reference in their entirety.

[0017] (Terminology) As used herein, the singular articles "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0018] Unless otherwise defined, the term "comprises" (or variations thereof, such as "includes," "including," etc.) is intended to be open-ended. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[0019] As used in this specification and the claims that follow, the word "comprise" and variations of the word, such as "comprises" and "comprises," mean "including, but not limited to," and are not intended to exclude, for example, other additives, ingredients, integers, or steps. Where an element is described as comprising multiple ingredients, steps, or conditions, it will be understood that such element can also be described as including any combination of the multiple, or as "consisting of" or "consisting essentially of" a combination of multiple ingredients, steps, or conditions.

[0020] When a range is expressed by separately specifying a lower and upper limit of the range, or by specifying specific numerical values, it will be understood that the range can be defined by any mathematically possible combination of the lower limit variable, the upper limit variable, and the specific numerical values. When a range is stated as from one endpoint to another, it will be understood that both endpoints are included in the range. However, it will also be understood that a range "from / to" also includes embodiments in which the range is defined as between the two specified endpoints, and that the term "between" can be used in place of the language "from / to" to omit the endpoints from the range.

[0021] This disclosure describes various embodiments. Those skilled in the art who review this disclosure will readily recognize that the various embodiments can be combined in any variation. For example, embodiments of the present disclosure include treatments for various disorders, patient populations, administration of formulations at various dosages, minimization of various adverse events, and improvement of various degrees of efficacy. Any combination of the various embodiments is within the scope of this disclosure.

[0022] When published test methods and diagnostic devices are referred to herein, unless otherwise stated herein, it is understood that the test methods and diagnostic devices are performed based on the version in effect as of October 1, 2022, even if the method or means is defined herein based on a publication reported in an earlier version.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0024] (definition) "MDD combination therapy" or "AMDD therapy" refers to the addition of medications to an antidepressant regimen to improve efficacy when the previously optimized dose and duration of the antidepressant regimen is insufficiently effective.

[0025] As used herein, "administering" or "administration" of urotalont or a pharmaceutically acceptable salt thereof includes delivering urotalont or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein.

[0026] An "AE" or "adverse event" is a medically untoward occurrence associated with the use of a drug in humans, whether or not related to the drug. A medically untoward event occurring after the first dose of a study drug is considered an AE. Thus, an AE is an untoward, unexpected sign (e.g., an abnormal laboratory test), symptom, or illness occurring after administration of a drug (investigational drug), whether or not related to the intended drug (investigational drug). AEs include the onset of new illnesses and the worsening of pre-existing conditions. A "mild" AE, as used herein and throughout this document, refers to a "usually transient symptom that does not affect the subject's activities of daily living." Alternative treatment is usually not indicated. A "moderate" AE, as used herein and throughout this document, refers to a "symptom significant enough to cause discomfort to the subject." The impact on activities of daily living is moderate. Alternative treatment may be necessary. A "severe" AE, as used herein and throughout this document, refers to a "symptom that causes significant discomfort." The impact on activities of daily living is moderate. The study may not continue, and alternative treatment may be necessary.

[0027] As disclosed herein, the methods of the present disclosure can be performed without the occurrence or manifestation of one or more adverse events selected from the neuropsychiatric drug withdrawal symptoms or syndromes generally defined based on the Markush group format of adverse events. "One or more," by which the method can be performed without the occurrence or manifestation of any of the listed adverse events, means that the method can be performed without the occurrence or manifestation of any particular one of the listed adverse events, or the method can be performed without the occurrence or manifestation of any combination of the listed adverse events. It will be understood that, in accordance with Markush group conventions, a Markush group can be limited to only one member of the group.

[0028] When it is said that drug treatment is carried out without inducing physical dependence, or that cessation of drug treatment is carried out without adverse events or drug withdrawal symptoms or syndromes, it will be understood to refer only to significant physical dependence, adverse events, or drug withdrawal symptoms or syndromes that, in the clinical judgment of the treating physician, are attributable to the drug treatment or cessation of drug treatment. In one embodiment, "significant" refers to moderate or severe adverse events.

[0029] The "AIMS" (Abnormal Involuntary Movement Scale) assessment consists of 10 items describing dyskinesia symptoms [Guy 1976]. Facial and oral movements (items 1–4), limb movements (items 5 and 6), and trunk movements (item 7) are discreetly observed while the subject is at rest, and the investigator also provides a global assessment of the subject's dyskinesia (items 8–10). Each item is rated on a 5-point scale, with 0 indicating no symptoms (item 10, "unaware") and 4 indicating severe symptoms (item 10, "aware, severe distress"). In addition, the AIMS includes two yes / no questions regarding the subject's dental condition. The AIMS motor assessment score is defined as the sum of items 1–7 (i.e., items 1–4 for facial and oral movements, items 5 and 6 for limb movements, and item 7 for trunk movements).

[0030] "Antidepressant regimen" or "antidepressant treatment" refers to any pharmacological treatment regimen administered to treat depression, and should be distinguished from augmentation, in which an agent that is not considered an antidepressant itself is added to an antidepressant regimen to improve efficacy. Examples of pharmacological agents for treating depression according to the present disclosure include, but are not limited to, SSRIs, SNRIs, bupropion, and mirtazapine, and pharmaceutically acceptable salts thereof.

[0031] As used herein, " at risk " individual refers to the individual who is at risk of developing the disorder to be treated or the adverse event to be prevented.This can be represented, for example, by one or more risk factors that are measurable parameters that correlate with the development of the disorder and are known in the art.When a method is said to treat a symptom without causing or inducing adverse event, it should be understood that the method can be carried out in the subject who is at risk of the adverse event.

[0032] The "BARS" (Barnes Akathisia Rating Scale) is a global clinical assessment of akathisia [Barnes 1989]. The BARS consists of four items related to akathisia: the investigator's objective observation of akathisia, the subject's subjective feelings of irritability, the subjective distress due to akathisia, and an overall clinical assessment of akathisia. The first three items are rated on a 4-point scale, with 0 representing no symptoms and 3 representing severe symptoms. The overall clinical assessment is on a 6-point scale, with 0 representing no symptoms and 5 representing severe akathisia.

[0033] The "CGI-C" (Clinical Global Impression-Change) rating scale measures the effectiveness of drug treatment by providing a comprehensive assessment of the subject's changes since the start of drug treatment, whether or not they are due to the drug. Response options are: 1 = much better; 2 = much better; 3 = minor better; 4 = no change; 5 = minor worse; 6 = much worse; and 7 = very worse.

[0034] The "CGI-S" (Clinical Global Impression-Severity) rating scale is a standardized, clinician-administered global rating scale that measures the severity of illness on a 7-point Likert scale. Higher scores on the CGI-S indicate greater severity. To make this assessment, the rater or investigator answers the following question: "Considering your clinical experience with this particular population, how mentally ill is this patient at this time?"; response options are: 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mild; 4 = moderate; 5 = markedly ill; 6 = severe; and 7 = very severely ill.

[0035] As used herein, "clinically significant" or "clinically meaningful" improvement can mean both a statistically significant improvement, generally based on a static measure such as the CGI-S or a retrospective assessment of improvement such as the CGI-C, and an improvement that is meaningful from the perspective of the patient, clinician, or caregiver, as generally described in various U.S. Food and Drug Administration publications, including FDA 2018, FDA 2019, and FDA 2020. When a treatment or efficacy is described herein, it will be understood that the treatment or efficacy demonstrates clinically significant efficacy in a patient population, preferably to a statistically significant degree.

[0036] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a tool designed to systematically assess and follow-up suicide-related events (suicidal behaviors and suicidal ideation) throughout the study period. The strength of this suicide classification system is its comprehensive identification of suicidal events while limiting overidentification of suicidal behaviors [Nilsson et al. (2013)]. Administering this scale takes approximately 5 minutes.

[0037] As used herein, "delaying" the onset of a disorder means delaying, preventing, slowing, stabilizing, and / or postponing the onset of the disorder. The length of the delay will vary depending on the individual's medical history and / or treatment.

[0038] "Depression" has its ordinary meaning in the field of psychiatry and may assume the definition set forth in DSM-5. When depression is referred to herein, it will be understood that major depressive disorder ("MDD") is a type of depression, and that the present disclosure is more specifically directed to the treatment of MDD (particularly AMDD) in all its aspects.

[0039] "DSM-5" refers to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Terms used herein may be defined with reference to DSM-5 where necessary to give meaning to the term. When a person is defined herein in accordance with DSM-5, the person need not have been diagnosed using DSM-5 criteria, but if so diagnosed, it is understood that the person meets the criteria set forth in DSM-5.

[0040] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, formulations and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which provides a detailed description of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of urotalonto include those derived from suitable inorganic and organic acids and bases.

[0042] Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid), or formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Counterions include hydroxyl, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. While pharmaceutically acceptable counterions are preferred for the preparation of pharmaceutical formulations, other anions (X) are also fully acceptable as synthetic intermediates. Thus, when such salts are chemical intermediates, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, or trifluoromethanesulfonate.

[0043] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binders, fillers, adjuvants, carriers, fillers, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonicity agents, solvents, emulsifiers, anti-caking agents, flavorings, desiccants, plasticizers, disintegrants, lubricants, polymer matrix systems, and abrasives, which have been approved by or otherwise cleared by the U.S. Food and Drug Administration with appropriate qualifications for human or veterinary use.

[0044] The Physician Withdrawal Checklist (PWC) is a 34-item physician-administered questionnaire developed to assess benzodiazepine withdrawal symptoms. The PWC20 total score includes the 20 items of the PWC, which have been validated for internal consistency, test-retest, inter-rater reliability and factor structure [Rickels (2008)].

[0045] As used herein, "prevention" or "preventing" refers to a regimen that prevents the onset of a disorder, such that clinical symptoms of the disorder do not develop. Thus, "prevention" relates to administering a therapeutic agent to a subject before signs of the disorder can be detected (e.g., administering a therapeutic agent when there are no detectable symptoms of the disorder). A subject may be an individual at risk of developing a disorder.

[0046] The Simpson-Angus Scale (SAS) consists of 10 symptoms of parkinsonism (gait, arm drop, shoulder tremor, elbow rigidity, wrist rigidity, head rotation, eye orbital tapping, tremor, salivation, and akathisia) (Simpson 1970). Each item is rated on a 5-point scale, with 0 representing no symptoms and 4 representing severe symptoms. The SAS total score is the sum of the scores for all 10 items.

[0047] "Selecting" refers to the act of choosing from a number and group by aptitude or preference. In the context of the present disclosure, urotalont is selected from the group of generally accepted psychotropic drugs for the treatment of any of the neuropsychiatric conditions described herein based on the lack of physical dependence induced by urotalont, whether for short-term or long-term treatment, or for mild, moderate, or intensive treatment.

[0048] The term "significantly" as used herein refers to a statistically significant level. The statistical significance level may be p<0.1, p<0.05, p<0.01, p<0.005, or p<0.001. Unless otherwise specified, when "significant," "significantly," or other variations of the term are used, the statistical significance level is p<0.05. When a measurable result or effect is described or identified herein, it is understood that the result or effect is preferably evaluated based on statistical significance compared to a baseline, such as a placebo. Similarly, when a treatment or benefit is described herein, it is understood that the treatment or benefit preferably demonstrates efficacy in a patient population to a statistically significant degree.

[0049] "SNRIs" (Serotonin Norepinephrine Reuptake Inhibitors) include, but are not limited to, desvenlafaxine (Pristiq®), duloxetine (Cymbalta®), levomilnacipran (Fetzima®), and venlafaxine (Effexor® XR), and pharmaceutically acceptable salts thereof.

[0050] "SSRIs" (selective serotonin reuptake inhibitors) include, but are not limited to, citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), paroxetine (Paxil®, Pexeva®), and sertraline (Zoloft®), and pharmaceutically acceptable salts thereof.

[0051] As used herein, a "subject" or "patient" to whom administration is intended includes, but is not limited to, humans, i.e., males or females of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, older adults) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, e.g., cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or commercially relevant birds, e.g., chickens, ducks, geese, quail and / or turkeys.

[0052] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, and includes an amount of a compound sufficient to achieve treatment of such a disorder when administered to a subject for treating the disorder. The effective amount varies depending on the disorder and its severity, the age, weight, etc., of the subject to be treated. An effective amount may be administered in one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount is considered to be administered when a desired or beneficial result can be achieved or is achieved in combination with one or more other agents. The appropriate dose of a co-administered compound may be reduced, if desired, due to the combined, additive, or synergistic effects of the compounds.

[0053] As used herein, the terms "treatment," "treatment," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, including, but not limited to, therapeutic benefit. In some embodiments, treatment occurs after the onset of one or more symptoms, e.g., an acute exacerbation of symptoms. In some embodiments, treatment may occur in the absence of symptoms. For example, a subject can be treated before the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have subsided, e.g., to prevent or delay recurrence.

[0054] In this specification, when describing the treatment of two kinds of drugs, it should be understood that these drugs are co-administered according to the parallel administration regimen, and the number of times or the time of administration can be different.To be co-administered, the two drugs do not necessarily have to be administered at the same time.For example, co-administered includes the drug that is administered three times a day and the drug that is administered once a day.

[0055] Therapeutic benefit includes eradication and / or amelioration of the underlying disease being treated, and also includes eradication and / or amelioration of one or more symptoms associated with the underlying disease, such that improvement is observed in the subject even though the subject is still afflicted with the underlying disease.

[0056] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., alleviating one or more symptoms resulting from the disorder and / or reducing the severity of the disorder); (b) delaying or preventing the onset of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or slowing the deterioration or progression of the disorder); and / or (c) alleviating the disorder (e.g., regression of clinical symptoms, improvement of the disorder, slowing the progression of the disorder, and / or improving quality of life).

[0057] "Urotalont" referred to herein for use in the disclosed methods has the chemical name (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (which may be abbreviated as "(S)-TPMA"). Urotalont has the following structure: [ka]

[0058] Unless otherwise indicated or the context dictates otherwise, in this disclosure, the term "urotalont" independently includes the free form of urotalont, as well as its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms. When the free form is intended, or when other forms or salts are specifically intended, it will be so indicated.

[0059] Urotalont can be used in the methods described herein as a free base or in the form of a pharmaceutically acceptable salt. In a preferred embodiment, the hydrochloride (HCl) salt of urotalont is used in the methods described herein. Urotalont or its pharmaceutically acceptable salt (e.g., its HCl crystalline form) can be obtained according to the preparation methods described in PCT Patent Publication No. WO2011 / 069063 (U.S. Patent No. 8,710,245, published April 29, 2014) or PCT Patent Publication No. WO2019 / 161238 or similar methods, which are incorporated herein by reference in their entirety for all purposes.

[0060] Methods of using urotalonto for the treatment of neuropsychiatric disorders described herein, particularly schizophrenia, depression, and anxiety, are described in PCT Patent Publication No. WO 2020 / 118032 and Dedic et al. (2019).

[0061] Also provided herein are pharmaceutical compositions and preparations comprising urotalont or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.The compositions and preparations provided herein can further comprise one or more additional active ingredients.Urotalont or its pharmaceutically acceptable salt can be administered as part of the pharmaceutical composition as described herein.

[0062] (Consideration) The physical dependence that can develop from therapeutic use of psychotropic drugs carries a high risk of causing withdrawal symptoms, including a variety of physical, motor, and psychological symptoms. This disclosure relates to the act of selecting urotalonto from among available psychotropic drugs and the resulting reduction in physical dependence and withdrawal symptoms upon discontinuation of treatment.

[0063] In one embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need thereof without significant physical dependence upon cessation of treatment, the method comprising selecting a therapeutically effective amount of urotalont, or a pharmaceutically acceptable salt thereof, and administering it to the subject for an effective period of time until cessation of administration, such that no significant physical dependence occurs over placebo. In one embodiment, administration is daily.

[0064] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need of treatment, comprising: (a) administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and (b) abruptly discontinuing administration of urotalont after the effective period of time. In one embodiment, the method is performed without significant physical dependence upon cessation of treatment in the subject in need of treatment, resulting in no significant physical dependence over placebo.

[0065] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need of treatment, comprising: (a) administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and (b) discontinuing administration of urotalont and any medication for the neuropsychiatric disorder after the effective period of time. In one embodiment, the method is carried out without significant physical dependence upon cessation of treatment in the subject in need of treatment, resulting in no significant physical dependence over placebo.

[0066] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need of treatment, comprising: (a) administering a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof to the subject for an effective period of time; and (b) discontinuing administration of urotalont after the effective period of time, wherein the subject is at risk for, or the subject has previously experienced, one or more symptoms or symptoms of psychotropic drug withdrawal, or the method is performed without the onset of one or more symptoms or symptoms of psychotropic drug withdrawal. In one embodiment, the method is performed in a subject in need of treatment without significant physical dependence upon cessation of treatment, resulting in no significant physical dependence over placebo.

[0067] The present methods can be used to treat a number of neuropsychiatric disorders, symptoms of such disorders, or side effects associated with conventional treatments for such disorders. Exemplary disorders include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a common medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson's psychosis, agitated psychosis, Tourette's syndrome, organic or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, dyskinesia, Huntington's disease, dementia, mood disorders, anxiety, affective disorders (e.g., depression, e.g., major depressive disorder), and the like. disorders or dysthymia; bipolar disorders, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, dizziness, epilepsy, pain (e.g., neuropathic pain, sensitization and inflammatory pain associated with neuropathic pain), fibromyalgia, migraine, cognitive impairment, movement disorders, restless legs syndrome (RLS), multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsiness side effect of medications, insomnia, substance abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyhan syndrome, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoric disorder.

[0068] Given urotalont's unique behavioral characteristics (reported by Dedic 2019), human clinical results reported in PCT Patent Publication No. WO 2020 / 118032, and urotalont's novel mechanism of action and receptor binding profile, urotalont is expected to treat neuropsychiatric disorders with high safety and efficacy. Thus, in one embodiment, urotalont is used to improve symptoms in a neuropsychiatric disorder selected from psychosis, depression, pain, cognition, mood disorders, and anxiety.

[0069] In another embodiment, neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizoid personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general illness, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, excited psychosis, organic psychosis or NOS psychosis, dyskinesia, mood disorders, anxiety, affective disorders (e.g., depression (e.g., major depressive disorder and dysthymia); bipolar disorders (e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder), pain (e.g., neuropathic pain, sensitization associated with neuropathic pain and inflammatory pain), cognitive disorders, and movement disorders.

[0070] In another embodiment, the treatment is carried out without inducing clinically significant manifestations of symptoms traditionally associated with neuropsychiatric treatments, such as hyperprolactinemia, abnormal blood prolactin levels, increased blood prolactin levels, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, dyslipidemia, akathisia, extrapyramidal disorders, agitation, increased appetite, chronic pancreatitis, weight gain, and neck stiffness.

[0071] In one embodiment, the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety. In another embodiment, the neuropsychiatric disorder is schizophrenia. In another embodiment, the neuropsychiatric disorder is bipolar depression (particularly MDD as defined in DSM-5, more particularly AMDD). In yet another embodiment, the neuropsychiatric disorder is an anxiety disorder (e.g., generalized anxiety disorder (GAD) as defined in DSM-5).

[0072] An "effective period" refers to a period of time sufficient to determine the effectiveness or ineffectiveness of treatment. Thus, in various embodiments, an effective period can be 2 weeks or more, 4 weeks or more, 8 weeks or more, 12 weeks or more, 26 weeks or more, 1 year or more, or 2 years or more, or optionally, less than 5 years, less than 4 years, or less than 3 years.

[0073] In other embodiments, the effective period is described functionally. Thus, in one embodiment, the effective period is a period sufficient for a clinically significant improvement in the neuropsychiatric disorder. In another embodiment, the effective period is a period sufficient for complete recovery from the neuropsychiatric disorder. In other embodiments, the effective period is a period sufficient for complete recovery from the neuropsychiatric disorder as evidenced by the absence of a diagnosis of the neuropsychiatric disorder according to criteria set forth in DSM-5. In yet other embodiments, the effective period is a period sufficient for complete recovery from the neuropsychiatric disorder of at least 3 months, at least 6 months, at least 1 year, at least 18 months, or at least 2 years.

[0074] The effective period can also be a period for determining the ineffectiveness of urotalont. Thus, in one embodiment, the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder. In other embodiments, the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by a failure to achieve clinically significant improvement from the neuropsychiatric disorder. In other embodiments, the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by a continued diagnosis of the neuropsychiatric disorder according to the criteria set forth in DSM-5. In further embodiments, the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by one or more of the following: (a) inadequate clinical response to acute symptoms despite optimal dosage and adequate duration of treatment; (b) inadequate control of chronic symptoms and persistent functional impairment during maintenance treatment; (c) relapse despite adequate preventive or maintenance treatment of the neuropsychiatric disorder; and (d) persistence of certain symptoms of the neuropsychiatric disorder despite adequate administration of urotalont.

[0075] The method can also be defined by the nature of discontinuation of urotalonto therapy. Discontinuation can be abrupt (i.e., without tapering) or with tapering. "Tapering" refers to a gradual reduction in dosage, regardless of frequency or duration. In some embodiments, the dosage reduction is in 12.5 mg and / or 25 mg increments. In some embodiments, the dosage reduction and eventual discontinuation occur over a period of one week to one year. Gradual does not mean that the magnitude of the dose reduction must be uniform. Thus, for example, gradual dose reduction includes the hyperbolic dose reduction proposed by Horowitz (2021).

[0076] In any embodiment, the subject may be at risk of one or more symptoms or syndromes of psychotropic drug withdrawal. Alternatively, in any embodiment, the subject may have previously experienced one or more symptoms or syndromes of psychotropic drug withdrawal. In a further alternative applicable to any embodiment, the method is performed without the onset of one or more symptoms or syndromes of psychotropic drug withdrawal. In yet another alternative, significant physical dependence is defined as the onset or appearance of one or more symptoms or syndromes of psychotropic drug withdrawal.

[0077] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event comprising a clinically significant increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score, or the subject may have previously experienced, or the method may be performed without the occurrence of, such an event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising a clinically significant increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score.

[0078] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event comprising an increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score of 4.0, 4.25, 4.5, 4.71, 4.75, 5.0, or 5.25 or greater, or the subject may have previously experienced, or the method may be performed without the occurrence of, such an event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising an increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score of 4.0, 4.25, 4.5, 4.71, 4.75, 5.0, or 5.25 or greater.

[0079] In some embodiments, the subject may be at risk for a withdrawal-related adverse event as defined by the Medical Dictionary of Restricted Drugs (MedDRA) standardized query: Drug Withdrawal, or the subject may have previously experienced said event, or the method may be performed without the occurrence of said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event as defined by the Medical Dictionary of Restricted Drugs (MedDRA) standardized query: Drug Withdrawal.

[0080] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, a withdrawal-related adverse event comprising one or more psychotropic drug withdrawal symptoms selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising one or more psychotropic drug withdrawal symptoms selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

[0081] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, a withdrawal-related adverse event comprising one or more physical symptoms of psychotropic drug withdrawal selected from one or more of: (i) insomnia, (ii) sweating, (iii) tremors, (iv) headache, and (v) muscle pain or rigidity. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising one or more physical symptoms of psychotropic drug withdrawal selected from: (i) insomnia, (ii) sweating, (iii) tremors, (iv) headache, and (v) muscle pain or rigidity.

[0082] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the onset of, a withdrawal-related adverse event comprising one or more mood symptoms associated with psychotropic drug withdrawal selected from (i) anxiety-irritability, (ii) irritability, (iii) dysphoric mood-depression, (iv) restlessness-irritability, and (v) difficulty concentrating, memory impairment. In other embodiments, significant physical dependence is defined as the occurrence or onset of a withdrawal-related adverse event comprising one or more mood symptoms associated with psychotropic drug withdrawal selected from (i) anxiety-irritability, (ii) irritability, (iii) dysphoric mood-depression, (iv) restlessness-irritability, and (v) difficulty concentrating, memory impairment.

[0083] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, a withdrawal-related adverse event comprising one or more cognitive symptom(s) of psychotropic drug withdrawal selected from (i) lack of coordination, (ii) dizziness-lightheadedness, (iii) increased sensitivity to sound, smell, touch, and (iv) depersonalization-derealization. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising one or more cognitive symptom(s) of psychotropic drug withdrawal selected from (i) lack of coordination, (ii) dizziness-lightheadedness, (iii) increased sensitivity to sound, smell, touch, and (iv) depersonalization-derealization.

[0084] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, one or more psychotropic medication withdrawal-related adverse events, including fatigue symptoms selected from (i) fatigue-lethargy-lack of energy, (ii) weakness, and (iii) dysesthesias. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of, one or more psychotropic medication withdrawal-related adverse events, including fatigue symptoms selected from (i) fatigue-lethargy-lack of energy, (ii) weakness, and (iii) dysesthesias.

[0085] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, a withdrawal-related adverse event comprising one or more gastrointestinal symptoms associated with psychotropic drug withdrawal selected from (i) anorexia, (ii) nausea-vomiting, and (iii) diarrhea. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising one or more gastrointestinal symptoms associated with psychotropic drug withdrawal selected from (i) anorexia, (ii) nausea-vomiting, and (iii) diarrhea.

[0086] In any of the embodiments of the present disclosure, the subject may be at risk for a withdrawal-related adverse event, including one or more mild, moderate, or severe withdrawal symptoms, or the subject may have previously experienced said event, or the method may be practiced without the occurrence of said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event, including one or more mild, moderate, or severe withdrawal symptoms.

[0087] Similarly, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event, including one or more symptoms associated with neuropsychiatric drug withdrawal selected from the following: (a) cholinergic symptoms evidenced by one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, lethargy, muscle pain, sweating, rhinitis, dysesthesias, and slow bowel movements; (b) dopaminergic symptoms evidenced by one or more of withdrawal dyskinesia, akathisia, dystonia, and tardive dyskinesia; and (c) rebound psychosis evidenced by one or more of psychosis, illusions, hallucinations, and catatonia above pre-treatment levels, or the subject may have previously experienced such an event, or the method may be performed without the occurrence of such an event. In other embodiments, significant physical dependence is defined as the occurrence or emergence of one or more withdrawal-related adverse events, including symptoms associated with neuropsychiatric drug withdrawal, selected from the following: (a) cholinergic symptoms evidenced by one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, lethargy, muscle pain, sweating, rhinitis, dysesthesias, and slow bowel movements; (b) dopaminergic symptoms evidenced by one or more of withdrawal dyskinesia, akathisia, dystonia, and tardive dyskinesia; and (c) rebound psychosis evidenced by one or more of psychosis, illusions, hallucinations, and catatonia above pre-treatment levels.

[0088] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event selected from, cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonin withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms, or the subject may have previously experienced, or the method may be practiced without the occurrence of, said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event selected from, cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonin withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms.

[0089] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the onset of, a withdrawal-related adverse event comprising a cholinergic withdrawal symptom selected from restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, agitation, muscle pain, muscle rigidity, dysesthesias, fear, hallucinations, confusion or disorientation, hypothermia, and sweating. In other embodiments, significant physical dependence is defined as the occurrence or appearance of a withdrawal-related adverse event comprising a cholinergic withdrawal symptom selected from restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, agitation, muscle pain, muscle rigidity, dysesthesias, fear, hallucinations, confusion or disorientation, hypothermia, and sweating.

[0090] In further embodiments, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (nigrostriatal) selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia, or the method may be practiced without the occurrence of said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (nigrostriatal) selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia.

[0091] In some embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the onset of, a withdrawal-related adverse event comprising a serotonin withdrawal symptom selected from flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensation, anxiety, restlessness, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and difficulty concentrating. In other embodiments, significant physical dependence is defined as the occurrence or onset of a withdrawal-related adverse event comprising a serotonin withdrawal symptom selected from flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensation, anxiety, restlessness, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and difficulty concentrating.

[0092] Additionally, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event, including a histaminergic withdrawal symptom selected from irritability, insomnia, restlessness, depressed mood, loss of appetite or nausea, tremors, lack of coordination, and lethargy or amnesia, or the subject may have previously experienced, or the method may be practiced without the occurrence of, said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event, including a histaminergic withdrawal symptom selected from irritability, insomnia, restlessness, depressed mood, loss of appetite or nausea, tremors, lack of coordination, and lethargy or amnesia.

[0093] Additionally, the subject may be at risk for, or the subject may have previously experienced, a withdrawal-related adverse event, including a dopaminergic withdrawal symptom (mesolimbic or striatal) selected from, auditory hallucinations, paranoia, and other psychotic symptoms, or the subject may have previously experienced, or the method may be practiced without the occurrence of, said event. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event, including a dopaminergic withdrawal symptom (mesolimbic or striatal) selected from, auditory hallucinations, paranoia, and other psychotic symptoms.

[0094] In other embodiments, the subject may be at risk for, or the subject may have previously experienced, or the method may be practiced without the occurrence of, a withdrawal-related adverse event, including an adrenergic withdrawal symptom selected from headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremor, and sweating. In other embodiments, significant physical dependence is defined as the occurrence or occurrence of a withdrawal-related adverse event, including an adrenergic withdrawal symptom selected from headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremor, and sweating.

[0095] It will be understood that any of the foregoing embodiments may be limited to subjects at risk of one or more withdrawal-related adverse events. Likewise, it will be understood that any of the foregoing embodiments may be limited to subjects who have previously experienced one or more withdrawal-related adverse events. Furthermore, it will be understood that the method may be performed without the onset of one or more withdrawal-related adverse events. Moreover, the method may be performed without significant physical strain.

[0096] Withdrawal-related adverse events are classified as mild, moderate, or severe. Thus, in any of the foregoing embodiments, the subject may be at risk for a withdrawal-related adverse event of mild, moderate, or severe magnitude, or the subject may have previously experienced said event, or the method may be performed without the occurrence of a withdrawal-related adverse event of mild, moderate, or severe magnitude.

[0097] In one embodiment, when urotalonto therapy is discontinued, the subject discontinues all antipsychotic medication for the neuropsychiatric disorder. Thus, any of the foregoing embodiments may further include discontinuing administration of urotalonto and any medication for the neuropsychiatric disorder for a period of 3 months or more, 6 months or more, 1 year or more, 18 months or more, or 2 years or more after an effective period.

[0098] A therapeutically effective amount of urotalont may be variously described as 25-150 mg / day, 25-100 mg / day, 50-125 mg / day, or 50-100 mg / day by oral administration. Alternatively, a therapeutically effective amount may be described as 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day by oral administration. In any of the embodiments of the present disclosure, a therapeutically effective amount may be administered once daily under fed or fasted conditions. Urotalont may also be administered as the hydrochloride salt.

[0099] The incidence of post-dose AEs was compared between placebo and SEP-363856-treated subjects in subjects with schizophrenia, as shown in Example 1. The withdrawal study in Example 2 compared abrupt withdrawal of SEP-363856 (switching SEP-363856 to placebo) with continued administration of SEP-363856 in subjects with schizophrenia.

[0100] Preferred aspects of the present disclosure can be defined based on the following embodiments AA to CD: [Embodiment AA] 1. A method for treating a neuropsychiatric disorder in a human subject in need of treatment without significant physical dependence upon cessation of treatment, comprising selecting a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof and administering it to the subject for an effective period of time until cessation of administration, such that no significant physical dependence occurs beyond placebo. [Embodiment AB] 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of: a) administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b) abruptly discontinuing administration of urotalonto after an effective period of time; A method comprising:

[0101] [Embodiment AC] 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of: a) administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b) discontinuing administration of urotalonto and any medication for the neuropsychiatric disorder after an effective period of time; A method comprising:

[0102] [Embodiment AD] 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising administering to a subject a therapeutically effective amount of: a) administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b) discontinuing administration of urotalonto after an effective period of time. wherein the subject is at risk for one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced said symptoms or syndromes, or the method is performed without the onset of said symptoms or syndromes. method.

[0103] [Embodiment AE] The method of any one of embodiments AB-AD, which is carried out without significant physical dependence upon cessation of treatment in a subject in need thereof, resulting in no significant physical dependence over placebo.

[0104] [Embodiment AF] The method of any one of embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events comprising a clinically significant increase in the 20-item Physician-Administered Withdrawal Checklist (PWC-20) total score.

[0105] [Embodiment AG] The method of any one of embodiments AA or AE, wherein significant physical dependence is defined as the emergence of withdrawal-related adverse events comprising an increase in the 20-item Physician-Administered Withdrawal Checklist (PWC-20) total score of 4.71 or greater.

[0106] [Embodiment AH] The method of any one of embodiments AA or AE, wherein significant physical dependence is defined as an occurrence of withdrawal-related adverse events as defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) standardized query: drug withdrawal.

[0107] [Embodiment AI] The method of any one of embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events comprising one or more symptoms of psychotropic agent withdrawal selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

[0108] [Embodiment AJ] The method of any one of embodiments AA or AE, wherein significant physical dependence is defined as the development of withdrawal-related adverse events selected from cholinergic withdrawal, dopaminergic withdrawal (nigrostriatal), serotonin withdrawal, histaminergic withdrawal, dopaminergic withdrawal (mesolimbic or striatal), and adrenergic withdrawal.

[0109] [Embodiment AK] The method of any one of embodiments AA-AJ, wherein the effective period is 2 weeks or more, 4 weeks or more, 8 weeks or more, 12 weeks or more, 26 weeks or more, 1 year or more, or 2 years or more in duration.

[0110] [Embodiment AL] The method of any one of embodiments AA-AK, wherein the duration of efficacy is sufficient for a clinically meaningful improvement of the neuropsychiatric disorder.

[0111] [Embodiment AM] The method of any one of embodiments AA-AK, wherein the duration of effectiveness is sufficient to achieve complete recovery from the neuropsychiatric disorder.

[0112] [Embodiment AN] The method of any one of embodiments AA-AK, wherein the effective period is sufficient to achieve complete recovery from the neuropsychiatric disorder as evidenced by the absence of a diagnosis of the neuropsychiatric disorder according to criteria set forth in DSM-5.

[0113] [Embodiment AO] The method of any one of embodiments AA-AN, wherein the duration of efficacy is sufficient to achieve complete recovery from the neuropsychiatric disorder for a period of ≧3 months, ≧6 months, ≧1 year, ≧18 months, or ≧2 years.

[0114] [Embodiment AP] The method of any one of embodiments AA-AK, wherein the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder.

[0115] [Embodiment AQ] The method of any one of embodiments AA-AK, wherein the duration of efficacy is sufficient to determine ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by a failure to achieve clinically meaningful improvement from the neuropsychiatric disorder.

[0116] [Embodiment AR] The method of any one of embodiments AA-AK, wherein the period of efficacy is sufficient to determine ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by a sustained diagnosis of the neuropsychiatric disorder according to criteria set forth in DSM-5.

[0117] [Embodiment AS] The effective period is sufficient to determine the ineffectiveness of urotalonto for the subject's neuropsychiatric disorder, and includes the following: a) Inadequate clinical response to acute symptoms despite optimal dosage and adequate treatment duration; b) inadequate control of chronic symptoms and persistent functional impairment during maintenance treatment; c) recurrence of the neuropsychiatric disorder despite adequate preventive or maintenance treatment; d) persistence of certain neuropsychiatric symptoms despite adequate administration of Urotalonto; The method of any one of embodiments AA-AK, AP, AQ, or AR, as evidenced by one or more of:

[0118] [Embodiment AT] The method of any one of embodiments AA-AS, wherein the discontinuation is sudden.

[0119] [Embodiment AU] The method of any one of embodiments AA or AC-AS, wherein the discontinuation is tapering.

[0120] [Embodiment AV] The method of any one of embodiments AA-AU, wherein the subject is at risk for one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0121] [Embodiment AW] The method of any one of embodiments AA-AU, wherein the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0122] [Embodiment AX] The method of any one of embodiments AA-AU, wherein the method is performed without the appearance of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0123] [Embodiment AY] The method of any one of embodiments AA-AU, wherein the subject is at risk for a withdrawal-related adverse event comprising a clinically significant increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score, the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0124] [Embodiment AZ] The method of any one of embodiments AA-AU, wherein the subject is at risk for a withdrawal-related adverse event comprising an increase in the 20-item Physician's Withdrawal Checklist (PWC-20) total score of 4.71 or greater, the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0125] [Embodiment BA] The method of any one of embodiments AA-AU, wherein the subject is at risk for a withdrawal-related adverse event as defined by the Standardized Medical Dictionary of Relevant Terms (MedDRA) standard query: drug withdrawal, the subject has previously experienced said event, or the method is performed without the occurrence of said withdrawal-related adverse event.

[0126] [Embodiment BB] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising one or more psychotropic medication withdrawal symptoms selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms, or the method is performed without the occurrence of said event.

[0127] [Embodiment BC] The method of any one of embodiments AA-AU, wherein the subject is at risk for, has previously experienced, or the method is performed without the occurrence of a withdrawal-related adverse event comprising one or more physical symptoms associated with neuropsychiatric medication withdrawal selected from: (i) insomnia, (ii) sweating, (iii) tremor-shaking, (iv) headache, and (v) muscle pain or rigidity.

[0128] [Embodiment BD] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising one or more mood symptoms associated with psychotropic medication withdrawal selected from: (i) anxiety-irritability, (ii) irritability, (iii) dysphoric mood-depression, (iv) agitation-restlessness, and (v) difficulty concentrating, memory impairment.

[0129] [Embodiment BE] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising one or more cognitive symptoms of psychotropic medication withdrawal selected from: (i) lack of coordination; (ii) dizziness-lightheadedness; (iii) increased sensitivity to sound, smell, touch; and (iv) depersonalization-derealization; or the method is performed without the occurrence of said event.

[0130] [Embodiment BF] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, one or more withdrawal-related adverse events, including fatigue symptoms, associated with psychotropic drug withdrawal selected from (i) fatigue-lethargy-lack of energy, (ii) weakness, and (iii) sensory disturbances, or the method is performed without the occurrence of, said events.

[0131] [Embodiment BG] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or the subject has previously experienced, a withdrawal-related adverse event comprising a gastrointestinal symptom associated with psychotropic agent withdrawal selected from (i) anorexia, (ii) nausea-vomiting, and (iii) diarrhea, or the method is performed without the occurrence of, the event.

[0132] [Embodiment BH] The method of any one of embodiments AA-AU, wherein the subject is at risk for a withdrawal-related adverse event comprising one or more mild, moderate, or severe withdrawal symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0133] [Embodiment BI] Subject to the following: a) Cholinergic syndrome evidenced by one or more of the following: nausea, vomiting, headache, agitation, anxiety, insomnia, fatigue, malaise, muscle pain, sweating, rhinitis, paresthesia, and diarrhea; b) dopaminergic syndrome evidenced by one or more of the following: withdrawal dyskinesia, akathisia, dystonia, tardive dyskinesia; and c) rebound psychosis evidenced by one or more of the following: psychosis, illusions, hallucinations, and catatonia above pretreatment levels; The method of any one of embodiments AA-AU, wherein the subject is at risk for, or the subject has previously experienced, a withdrawal-related adverse event comprising one or more syndromes of neuropsychiatric drug withdrawal selected from, or the method is performed without the occurrence of, said event.

[0134] [Embodiment BJ] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or the subject has previously experienced, a withdrawal-related adverse event selected from, cholinergic withdrawal, dopaminergic withdrawal (nigrostriatal), serotonin withdrawal, histaminergic withdrawal, dopaminergic withdrawal (mesolimbic or striatal), and adrenergic withdrawal, or the method is performed without the occurrence of, said event.

[0135] [Embodiment BK] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or the subject has previously experienced, a withdrawal-related adverse event comprising a cholinergic withdrawal symptom selected from restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremor, parkinsonism, agitation, muscle pain, muscle rigidity, dysesthesias, fear, hallucinations, confusion or disorientation, hypothermia, and sweating, or the method is performed without the occurrence of said event.

[0136] [Embodiment BL] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (nigrostriatal) selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia, or the method is performed without the occurrence of, said event.

[0137] [Embodiment BM] The method of any one of embodiments AA-AU, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising a serotonin withdrawal symptom selected from flu-like symptoms, sweating or chills, dizziness, unsteadiness or rapid heart rate, abnormal sensations, electric shock sensations, anxiety, agitation, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and difficulty concentrating, or the method is performed without the occurrence of said event.

[0138] [Embodiment BN] The method of any one of embodiments AA-AU, wherein the subject is at risk of developing a withdrawal-related adverse event, comprising a histaminergic withdrawal symptom selected from irritability, insomnia, restlessness, depressed mood, loss of appetite or nausea, tremor, lack of coordination, and lethargy or amnesia, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0139] [Embodiment BO] The method of any one of embodiments AA-AU, wherein the subject is at risk of developing a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (mesolimbic or striatal) selected from auditory hallucinations, delusions of persecution and other psychotic symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0140] [Embodiment BP] The method of any one of embodiments AA-AU, wherein the subject is at risk for a withdrawal-related adverse event comprising an adrenergic withdrawal symptom selected from headache, anxiety or restlessness, hypertension, tachycardia, angina, palpitations, risk of myocardial infarction, presyncope, tremor, and sweating, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0141] [Embodiment BQ] The method of any one of embodiments AY-BP, wherein the subject is at risk for one or more withdrawal-related adverse events.

[0142] [Embodiment BR] The method of any one of embodiments AY-BP, wherein the subject has previously experienced one or more withdrawal-related adverse events.

[0143] [Embodiment BS] The method of any one of embodiments AY-BP, wherein the method is performed without the occurrence of one or more withdrawal-related adverse events.

[0144] [Embodiment BT] The method of any one of embodiments AY-BP, wherein the subject is at risk for a withdrawal-related adverse event comprising one or more mild, moderate, or severe withdrawal symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

[0145] [Embodiment BU] The method of any one of embodiments AA-BT, comprising discontinuing administration of urotalonto and any medication for the neuropsychiatric disorder for a period of 3 months or more, 6 months or more, 1 year or more, 18 months or more, or 2 years or more after the effective period.

[0146] [Embodiment BV] The method of any one of embodiments AA-BU, wherein the therapeutically effective amount is an amount of 25-150 mg / day, 25-100 mg / day, 50-125 mg / day, or 50-100 mg / day by oral administration.

[0147] [Embodiment BW] The method of any one of embodiments AA-BU, wherein the therapeutically effective amount is an amount of 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day or 150 mg / day by oral administration.

[0148] [Embodiment BX] The method of any one of embodiments AA-BW, wherein the therapeutically effective amount is administered once daily in the fed or fasted state.

[0149] [Embodiment BY] The method of any one of embodiments AA-BX, wherein urotalont is administered as the hydrochloride salt.

[0150] [Embodiment BZ] Neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizotypal personality disorder, schizophrenic personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a common medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson's psychosis, agitated psychosis, Tourette's syndrome, organic or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorders, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dyskinesia, Huntington's disease, dementia, mood disorders, anxiety, affective disorders (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar disorder, The method of any one of embodiments AA-BY, wherein the treatment is selected from, for example, bipolar depressive disorder, manic disorder, seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, dizziness, epilepsy, pain (e.g., neuropathic pain, sensitization and inflammatory pain associated with neuropathic pain), fibromyalgia, migraine, cognitive impairment, movement disorder, restless legs syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, medication sleepiness side effect, insomnia, medication abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyhan syndrome, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoric disorder.

[0151] [Embodiment CA] The method of any one of embodiments AA-BY, wherein the neuropsychiatric disorder is selected from schizophrenia, depression and anxiety.

[0152] [Embodiment CB] The method of any one of embodiments AA-BY, wherein the neuropsychiatric disorder is schizophrenia.

[0153] [Embodiment CC] The method of any one of embodiments AA-BY, wherein the neuropsychiatric disorder is selected from bipolar depression and major depression.

[0154] [Embodiment CD] The method of any one of embodiments AA-BY, wherein the neuropsychiatric disorder is anxiety. [Example]

[0155] In the following examples, efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures), but some errors and deviations should be accounted for. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the methods of the present invention are performed and evaluated, and are intended to be purely exemplary of the present application and are not intended to limit the scope of what the inventors regard as the present disclosure.

[0156] Example 1 A review of post-treatment adverse events (AEs) in completed and ongoing studies of SEP-363856 in patients with schizophrenia

[0157] A study was conducted to examine post-treatment adverse events (AEs) with a start date after the last treatment exposure date in one completed double-blind, placebo-controlled study, one completed open-label study, and one ongoing (as of the date of this evaluation) open-label study of SEP-363856.

[0158] Post-dose AEs were defined as AEs with an onset date after the last treatment exposure date, and post-dose AEs were examined in the treatment-withdrawn cohort. However, because the study drug was administered at bedtime during the study period, AEs that began more than one day after the last dose were also examined for patients in the treatment-withdrawn cohort who had a follow-up period of two or more days. The results of these analyses are shown in Tables 1 and 2.

[0159] In the completed double-blind, placebo-controlled trial, the incidence of post-dose AEs was similar in the placebo and SEP-363856 groups (9 patients [23.7%] placebo; 8 patients [23.5%] SEP-363856; Table 1). The only post-dose AE occurring in more than one patient in the SEP-363856 group was schizophrenia, and the incidence of this AE was similar between groups (4 patients [10.5%] placebo; 4 patients [11.8%] SEP-363856). [Table 1]

[0160] A total of 36 (18.8%) patients experienced post-treatment AEs in the completed and ongoing open-label studies at the time of this evaluation (Table 2). The only post-treatment AEs occurring in ≥2% of patients were schizophrenia (22 [11.5%]) and suicidal ideation (4 [2.1%]).

[0161] A total of 12 (6.5%) patients had post-infusion AEs with a start date >1 day after the last dose. No post-infusion AEs with a start date >1 day after the last dose occurred in ≥2% of patients.

[0162] [Table 2]

[0163] Post-dose AEs were also searched using a predefined list of preferred terms using MedDRA version 22.0 SMQ: Drug withdrawal [20000102]. Preferred terms were compiled using the MedDRA version used in each study (i.e., coding for studies not using MedDRA version 22.0 was not updated). No post-dose withdrawal-related AEs defined in SMQ: Drug withdrawal were identified in any of the completed phase 2 or ongoing phase 3 studies.

[0164] In conclusion, analysis of post-administration AEs at this evaluation time point did not reveal any signals of withdrawal effects.

[0165] Example 2: A double-blind, placebo-controlled and randomized withdrawal study evaluating the physical dependence of SEP-363856 in adult subjects with schizophrenia The primary objective of this study is to confirm the absence of physical dependence associated with SEP-363856, as indicated by the presence or absence of signs and / or symptoms of drug withdrawal following abrupt discontinuation of SEP-363856 (i.e., switching to placebo) in subjects with schizophrenia compared to subjects with schizophrenia who continue treatment with SEP-363856. A secondary objective is to evaluate the safety and tolerability of SEP-363856 in adult patients with schizophrenia. The overall study design, including a 4-week open-label treatment period, is consistent with published physical dependence studies (Stauffer 2014, Lerner 2015, Lerner 2019).

[0166] This is a double-blind, placebo-controlled, randomized withdrawal study comparing abrupt withdrawal of SEP-363856 (switching SEP-363856 to placebo) with continued SEP-363856 treatment in adult men and women with schizophrenia. The study consists of four periods: a screening / washout period (up to 21 days), an open-label period (Days 1-35, SEP-363856), a double-blind randomized withdrawal period (Days 36-43), and a follow-up period (7+2 days after the last dose). Study medication will be taken at approximately the same time each night at bedtime, with or without food.

[0167] Approximately 40 subjects will be enrolled in the open-label period, and at least 34 subjects (17 per group) will be randomized for the randomized washout period. Every effort will be made to enroll at least 30% of each gender. Subjects will have the option of outpatient visits for most days of the screening / washout period, up to 7 days prior to the first day, if the investigator deems clinically necessary. Subjects will receive inpatient or outpatient treatment for the first 7 days of the open-label period for dose escalation, if the investigator deems clinically necessary. Subjects will be admitted again on day 29 (day -3) and will remain in the clinic until the end of the randomized washout period. Subjects will be discharged at the end of the randomized washout period or will remain in the clinic for part or all of the follow-up period, at the investigator's discretion.

[0168] Subjects will be assessed for eligibility during a screening / washout period of up to 21 days, during which time they will be tapered off all psychiatric medications (excluding permitted concomitant medications) in a manner consistent with package insert recommendations and conventional medical practice. If the investigator determines it is clinically necessary, subjects will be admitted to the clinic up to one week prior to the first day. If the investigator determines it is clinically necessary, subjects will be outpatients for most of the screening / washout period, with the option of continuing as outpatients or inpatients one week prior to entering the open-label period. Preferably, all psychiatric medications will be discontinued within three days or five half-lives (whichever is longer) prior to the first dose of study medication.

[0169] After completing the pre-treatment washout period, subjects who meet the eligibility criteria will enter the open-label period where they will receive SEP-363856 orally once daily (QD) for 35 days (Days 1-35) to establish a steady-state baseline. Open-label SEP-363856 administration will begin on the evening of Visit 2 (Day 1) and continue once daily at bedtime for the remainder of the open-label period. During this 7-day titration period, subjects will be either inpatients or outpatients at the investigator's discretion. Inpatient subjects will be discharged on Day 8.

[0170] All subjects will receive SEP-363856 at 50 mg / day on days 1-3 and 75 mg / day on days 4-7. For the remainder of the open-label period, from day 8 through day 35, subjects will receive 100 mg / day. Subjects who are unable to tolerate 100 mg / day of study drug will be discontinued and replaced. Subjects will be outpatients for three weeks of this period (days 8-28), then hospitalized at the clinical trial unit (CRU) for the final week of the open-label period (days 29-35).

[0171] After the final dose in the open-label period on Day 35 (evening), subjects will enter a 7-day double-blind randomized washout period and continue to be admitted to the clinic. On Day 36 of the randomized washout period, subjects will be randomized 1:1 to the SEP-363856 continuation group or placebo group. Subjects may be discharged or terminated early (ET) from Day 43 onward at the investigator's discretion.

[0172] All subjects will undergo safety follow-up assessments 7 days (+2 days) after the last dose of study medication. Subjects who discontinue early from the study will have an early discontinuation visit within 24 hours of the last dose of study medication. Subjects will remain hospitalized from day one until the end of the randomized washout period. Subjects will be discharged at the end of the randomized washout period if they meet the discharge criteria, but may remain hospitalized in the clinic during the follow-up period at the investigator's discretion.

[0173] To be eligible to participate, subjects must meet the following main eligibility criteria: · Male or female between 18 and 65 years of age (inclusive). Subjects meet Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for a primary diagnosis of schizophrenia established by clinical interview. Subjects must have a Clinical Global Impression-Severity (CGI-S) score ≤ 4 (normal to moderate). Subjects must have a total score of ≤80 on the Positive and Negative Symptom Scale (PANSS). Subjects must have a PANSS P7 (hostility) and G8 (uncooperativeness) score of ≦4. Subjects must have a BMI of at least 18.0 kg / m at screening. 2 but 40.0 kg / m 2 The following is the result. Subjects must have normal or mild symptoms at screening and on day 1 on all items of the Simpson Angus Scale (SAS) (<2), Abnormal Involuntary Movements Scale (<3), and Barnes Akathisia Rating Scale (BARS) (<3).

[0174] The primary endpoint was the maximum change from steady-state baseline (CSSB) in the 20-item Physician-Administered Withdrawal Checklist (PWC-20) total score during a 7-day randomized washout period. max The primary analysis was the mean CSSB score on the PWC-20 total score during the 7-day randomized washout period in the Physical Dependence Analysis (PDA) population. max A non-inferiority trial will be conducted assuming a non-inferiority margin of 4.71 between the placebo and SEP-363856 groups.

[0175] The following safety endpoints will also be assessed: incidence, frequency, and severity of all AEs; incidence of withdrawal-related AEs (e.g., MedDRA (International Medical Dictionary) Standardized Query: including, but not limited to, drug withdrawal), vital signs (heart rate, blood pressure, respiratory rate, oral temperature), weight and body mass index (BMI), Columbia-Suicide Severity Rating Scale (C-SSRS), Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Symptom Assessment Scale (SAS).

[0176] Other evaluation items were as follows: During the 7-day randomized washout period, the PWC-20 total score and CSSBmax The emergence of clinically significant withdrawal syndrome was defined as a mean mean of at least 4.71 points (i.e., an increase of ≥ 4.71). Mean change in PWC-20 total score from baseline at steady state over a 7-day randomized washout period. Time to maximum PWC-20 total score during the 7-day randomized washout period. Change from Day 36 in PANSS total score and positive, negative and general psychopathological symptom subscores during a 7-day randomized washout period. Change from Day 36 in CGI-S total score during the 7-day randomized washout period.

[0177] The original language used by the investigator or their designee to identify AEs in the case report form (CRF) will be coded using the Medical Dictionary for Reproductive Healthcare Applications (MedDRA; version 22.0 or higher). All AE summaries will include all AEs observed in subjects during SEP-363856 treatment and up to 9 days after the last dose of SEP-363856. For the randomized washout period, AEs from the first dose of study drug on or after the randomized washout period through 9 days after the last dose of study drug (SEP-363856 or placebo) will be summarized by randomized treatment group. AEs occurring before the open-label period will be considered "pre-treatment events" and will be reported separately.

[0178] AEs are assigned to treatment groups based on timing of onset in relation to the last treatment administered before the AE occurred. AEs are summarized by treatment, MedDRA SOC, and MedDRA PT. A list of AEs is provided, as well as a list of TEAEs that led to death, SAE, or discontinuation of study drug.

[0179] References Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672 676. Cerovecki A, Musil R, Klimke A, Seemueller F, Haen E, Schennach R, et al. Withdrawal Symptoms and Rebound Syndromes Associated with Switching and Discontinuing Atypical Antipsychotics:Theoretical Background and Practical Recommendations. CNS Drugs (2013)27:545-72. Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N, Takase M, Iyo M. Antipsychotic-Induced Dopamine Supersensitivity Psychosis:Pharmacology, Criteria, and Therapy. Psychother Psychosom. 2017;86(4):189-219. Correll CU. From receptor pharmacology to improved outcomes:individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry (2010)25:12-21. Food and Drug Administration (U.S.). Discussion Document for Patient-Focused Drug Development Public Workshop on Guidance 3:SELECT, DEVELOP OR MODIFY FIT-FOR-PURPOSE CLINICAL OUTCOME ASSESSMENTS (including Appendices)(Published at Patient-Focused Drug Development Guidance:Methods to Identify What is Important to Patients and Select, Develop or Modify Fit-for-Purpose Clinical Outcome Assessments, Meeting October 15-16, 2018)(“FDA 2018”) Food and Drug Administration (U.S.). Patient-Focused Drug Development:Methods to Identify What Is Important to Patients Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (October 2019)("FDA 2019") Food and Drug Administration (U.S.). Patient-Focused Drug Development:Collecting Comprehensive and Representative Input; Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (June 2020)("FDA 2020"). Guy W. ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW Publication No. ADM 76-338). Rockville, MD, US Department of Health, Education, and Welfare, 1976:218-22. Horowitz MA, Jauhar S, Natesan S, Murray RM, Taylor D. A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse. Schizophr Bull. 2021 Jul 8;47(4):1116-1129. Lerner A and Klein M. Dependence, withdrawal and rebound of CNS drugs:an update and regulatory considerations for new drugs development. BRAIN COMMUNICATIONS 2019:23 pages, Oxford University Press on behalf of the Guarantors of Brain. Lerner A. Evaluation of Dependence and Withdrawal in Clinical Trials and Human Dependence Study-Design and Considerations. Session 2B:Regulatory Guidelines and Methodological Approaches to Assess Prescription Drug Abuse and Misuse During CNS Drug Development. 11th Annual International Society for CNS Clinical Trials and Methodology (ISCTM)Scientific Meeting Washington, DC February 18, 2015. https: / / isctm.org / public_access / Feb2015 / Presentations / Lerner.pdf Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389. Nilsson ME, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K. Columbia Suicide Severity Rating Scale Scoring and Data Analysis Guide. Feb 2013. Available from http: / / cssrs.columbia.edu / wp-content / uploads / ScoringandDataAnalysisGuide-for-Clinical-Trials-1.pdf. PCT Patent Publication No. WO 2020 / 118032 Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol 2008;28(4):447-451. Simpson GN, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand. 1970;212(Suppl 44):S11-S19. Stauffer V, Baygani S, Kinon B and Krikke-Workel J. A Short-Term, Multicenter, Placebo-Controlled, Randomized Withdrawal Study of a Metabotropic Glutamate 2 / 3 Receptor Agonist Using an Electronic Patient-Reported Outcome Device in Patients with Schizophrenia. J Clin Psychopharmacol 2014;34:552-558. Tiihonen J, Tanskanen A, Taipale H. 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia. Am J Psychiatry. 2018 Aug 1;175(8):765-773. US 2020 / 0179336 A1 (June 11, 2020) US 2021 / 0315859 A1 (October 14, 2021). Viguera AC, Baldessarini RJ, Hegarty JD, van Kammen DP, Tohen M. Clinical Risk Following Abrupt and Gradual Withdrawal of Maintenance Neuroleptic Treatment. Arch Gen Psychiatry. 1997;54(1):49-55. Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988;45:742-747. Williams JBW. Structured interview guide for the Hamilton Anxiety Scale (SIGH-A). Biometrics Research Department, New York State Psychiatric Institute, New York, New York; Revision 15 Jan 2008. * * * * * * * *

[0180] Throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this disclosure pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and embodiments of the present disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the present disclosure being indicated by the following claims.

Claims

1. 1. A method for treating a neuropsychiatric disorder in a human subject in need of such treatment without significant physical dependence upon cessation of treatment, comprising selecting a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof and administering it to the subject for an effective period of time until cessation of administration, such that no significant physical dependence occurs beyond placebo.

2. 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a. administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b. abruptly discontinuing administration of urotalonto after an effective period of time; A method comprising:

3. 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a. administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b. discontinuing administration of urotalonto and any medication for the neuropsychiatric disorder after an effective period of time; A method comprising:

4. 1. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a. administering to a subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof for an effective period of time; and b. Discontinuing administration of urotalonto after an effective period of time. wherein the subject is at risk for one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced said symptoms or syndromes, or the method is performed without the onset of said symptoms or syndromes.

5. 5. The method of any one of claims 2 to 4, which is carried out without significant physical dependence upon cessation of treatment in a human subject in need thereof, resulting in no significant physical dependence over placebo.

6. 5. The method of any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events including a clinically significant increase in the total score on the Physician-Compensated Withdrawal Checklist 20 (PWC-20).

7. 5. The method of any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events comprising an increase in the 20-item Physician-Administered Withdrawal Checklist (PWC-20) total score of 4.71 or greater.

8. 5. The method of any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events as defined by the Medical Dictionary of Clinical Terms for Adverse Reactions (MedDRA) standardized query: Drug Withdrawal.

9. 5. The method of any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events comprising one or more psychotropic drug withdrawal symptoms selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

10. 5. The method of any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonin withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal) and adrenergic withdrawal symptoms.

11. 5. The method of any one of claims 1 to 4, wherein the effective period is 2 weeks or more, 4 weeks or more, 8 weeks or more, 12 weeks or more, 26 weeks or more, 1 year or more, or 2 years or more.

12. 5. The method of any one of claims 1 to 4, wherein the duration of efficacy is sufficient for a clinically significant improvement in the neuropsychiatric disorder.

13. 5. The method of any one of claims 1 to 4, wherein the duration of effectiveness is sufficient to achieve complete recovery from the neuropsychiatric disorder.

14. 5. The method of any one of claims 1 to 4, wherein the duration of efficacy is sufficient to achieve complete recovery from the neuropsychiatric disorder as evidenced by the absence of a diagnosis of the neuropsychiatric disorder according to criteria set forth in DSM-5.

15. 5. The method of any one of claims 1 to 4, wherein the duration of efficacy is sufficient to achieve complete recovery from the neuropsychiatric disorder for a period of 3 months or more, 6 months or more, 1 year or more, 18 months or more, or 2 years or more.

16. The method of any one of claims 1 to 4, wherein the effective period is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder.

17. 5. The method of any one of claims 1 to 4, wherein the duration of efficacy is sufficient to determine ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by a failure to achieve clinically meaningful improvement from the neuropsychiatric disorder.

18. 5. The method of any one of claims 1 to 4, wherein the effective period is sufficient to determine the ineffectiveness of urotalonto for the subject's neuropsychiatric disorder, as evidenced by a sustained diagnosis of the neuropsychiatric disorder according to criteria set forth in DSM-5.

19. The valid period is as follows: a. Inadequate clinical response to acute symptoms despite optimal dosage and adequate duration of treatment; b. Inadequate control of chronic symptoms resulting in persistent functional impairment during maintenance treatment; c. Recurrence of a neuropsychiatric disorder despite appropriate preventive or maintenance treatment; and d. Persistence of certain neuropsychiatric symptoms despite adequate administration of urotalonto; The method of any one of claims 1 to 4, wherein the method is sufficient to determine the ineffectiveness of urotalont for the subject's neuropsychiatric disorder, as evidenced by one or more of the following:

20. 5. The method of any one of claims 1 to 4, wherein the discontinuation is sudden.

21. 5. The method of any one of claims 1 or 3-4, wherein the discontinuation is tapering.

22. 5. The method of any one of claims 1 to 4, wherein the subject is at risk for one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

23. 5. The method of any one of claims 1 to 4, wherein the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

24. 5. The method of any one of claims 1 to 4, wherein the method is performed without the appearance of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

25. 5. The method of any one of claims 1-4, wherein the subject is at risk for a withdrawal-related adverse event comprising a clinically significant increase in the Physician's Withdrawal Checklist 20-Item (PWC-20) total score, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

26. 5. The method of any one of claims 1-4, wherein the subject is at risk for a withdrawal-related adverse event comprising an increase in the Physician's Withdrawal Checklist 20-item (PWC-20) total score of 4.71 or greater, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

27. 5. The method of any one of claims 1 to 4, wherein the subject is at risk for a withdrawal-related adverse event as defined by the Medical Dictionary of Clinical Terms for Advanced Diseases (MedDRA) standardized query: drug withdrawal, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

28. 5. The method of any one of claims 1 to 4, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising one or more psychotropic medication withdrawal symptoms selected from somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms, or the method is performed without the occurrence of said event.

29. 5. The method of any one of claims 1-4, wherein the subject is at risk of, or has previously experienced, a withdrawal-related adverse event comprising one or more physical symptoms associated with neuropsychiatric medication withdrawal selected from (i) insomnia, (ii) sweating, (iii) tremor-shaking, (iv) headache, and (v) muscle pain or rigidity, or the method is performed without the occurrence of said event.

30. 5. The method of any one of claims 1-4, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising mood symptoms associated with psychotropic medication withdrawal selected from one or more of: (i) anxiety-irritability, (ii) irritability, (iii) dysphoric mood-depression, (iv) agitation-irritability, and (v) difficulty concentrating, memory, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

31. 5. The method of any one of claims 1-4, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising one or more cognitive symptoms of psychotropic medication withdrawal selected from: (i) lack of coordination; (ii) dizziness-lightheadedness; (iii) increased sensitivity to sound, smell, touch; and (iv) depersonalization-derealization; or the method is performed without the occurrence of said event.

32. 5. The method of any one of claims 1 to 4, wherein the subject is at risk for, or has previously experienced, one or more withdrawal-related adverse events comprising fatigue symptoms associated with psychotropic drug withdrawal selected from (i) fatigue-lethargy-lack of energy, (ii) weakness, and (iii) paresthesia, or the method is performed without the occurrence of said events.

33. 5. The method of any one of claims 1 to 4, wherein the subject is at risk for, or has previously experienced, a withdrawal-related adverse event comprising a gastrointestinal symptom associated with psychotropic medication withdrawal selected from one or more of: (i) anorexia; (ii) nausea-vomiting; (iii) diarrhea; or the subject has previously experienced said event; or the method is performed without the occurrence of said event.

34. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of a withdrawal-related adverse event comprising one or more mild, moderate or severe withdrawal symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

35. The target is the following: a. Cholinergic syndrome evidenced by one or more of the following: nausea, vomiting, headache, agitation, anxiety, insomnia, fatigue, malaise, muscle pain, sweating, rhinitis, paresthesia, and diarrhea; b. Dopaminergic syndrome evidenced by one or more of the following: withdrawal dyskinesia, akathisia, dystonia, and tardive dyskinesia; and c. Rebound psychosis evidenced by one or more of the following: psychosis, delusions, hallucinations, and catatonia above pretreatment levels 5. The method of any one of claims 1 to 4, wherein the subject is at risk for, or the subject has previously experienced, a withdrawal-related adverse event comprising one or more neuropsychiatric drug withdrawal syndromes selected from, or the method is performed without the occurrence of, the event.

36. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of, or the subject has previously experienced, a withdrawal-related adverse event selected from cholinergic withdrawal, dopaminergic withdrawal (nigrostriatal), serotonin withdrawal, histaminergic withdrawal, dopaminergic withdrawal (mesolimbic or striatal) and adrenergic withdrawal, or the method is performed without the occurrence of said event.

37. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of, or has previously experienced, a withdrawal-related adverse event comprising a cholinergic withdrawal symptom selected from restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, agitation, muscle pain, muscle rigidity, dysesthesias, fear, hallucinations, confusion or disorientation, hypothermia, and sweating, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

38. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (nigrostriatal) selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome and akathisia, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

39. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of, or has previously experienced, a withdrawal-related adverse event comprising a serotonin withdrawal symptom selected from flu-like symptoms, sweating or chills, dizziness, unsteadiness or tachycardia, abnormal sensations, electric shock sensations, anxiety, agitation, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and difficulty concentrating, or the method is performed without the occurrence of said event.

40. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of, or has previously experienced, a withdrawal-related adverse event comprising a histaminergic withdrawal symptom selected from irritability, insomnia, restlessness, depressed mood, loss of appetite or nausea, tremors, lack of coordination, and lethargy or amnesia, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

41. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of a withdrawal-related adverse event comprising a dopaminergic withdrawal symptom (mesolimbic or striatal) selected from auditory hallucinations, delusions of persecution and other psychotic symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

42. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of a withdrawal-related adverse event comprising an adrenergic withdrawal symptom selected from headache, anxiety or restlessness, hypertension, tachycardia, angina, palpitations, risk of myocardial infarction, presyncope, tremor, and sweating, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

43. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of one or more withdrawal-related adverse events.

44. 5. The method of any one of claims 1 to 4, wherein the subject has previously experienced one or more withdrawal-related adverse events.

45. 5. The method of any one of claims 1 to 4, wherein the method is performed without the occurrence of one or more withdrawal-related adverse events.

46. 5. The method of any one of claims 1 to 4, wherein the subject is at risk of a withdrawal-related adverse event comprising one or more mild, moderate or severe withdrawal symptoms, or the subject has previously experienced said event, or the method is performed without the occurrence of said event.

47. 5. The method of any one of claims 1 to 4, comprising discontinuing administration of urotalonto and any medication for the neuropsychiatric disorder for a period of 3 months or more, 6 months or more, 1 year or more, 18 months or more, or 2 years or more after the effective period.

48. 5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount is 25 to 150 mg / day, 25 to 100 mg / day, 50 to 125 mg / day, or 50 to 100 mg / day by oral administration.

49. 5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount is 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day by oral administration.

50. 5. The method of any one of claims 1 to 4, wherein the therapeutically effective amount is administered once daily in a fed or fasted state.

51. 5. The method of any one of claims 1 to 4, wherein urotalont is administered as the hydrochloride salt.

52. The neuropsychiatric disorder may be schizophrenia, schizophrenia spectrum disorder, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, schizotypal personality disorder, schizophreniform personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a common medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoaffective disorder, aggression, delirium, Parkinson's disease psychosis, agitated psychosis, Tourette's syndrome, organic or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, dyskinesia, Huntington's disease, dementia, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar disorder).

5. The method of any one of claims 1 to 4, wherein the treatment is selected from the group consisting of: bipolar depressive disorder, manic disorder, seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, dizziness, epilepsy, pain (e.g., neuropathic pain, sensitization associated with neuropathic pain and inflammatory pain), fibromyalgia, migraine, cognitive impairment, movement disorders, restless legs syndrome (RLS), multiple sclerosis, sleep disorders, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, a drowsiness side effect of medication, insomnia, substance abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorders, sexual dysfunction, hypertension, vomiting, Lesch-Nyhan disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoric disorder.

53. 5. The method of any one of claims 1 to 4, wherein the neuropsychiatric disorder is selected from schizophrenia, depression and anxiety.

54. The method according to any one of claims 1 to 4, wherein the neuropsychiatric disorder is schizophrenia.

55. 5. The method of any one of claims 1 to 4, wherein the neuropsychiatric disorder is selected from bipolar depression and major depression.

56. The method according to any one of claims 1 to 4, wherein the neuropsychiatric disorder is anxiety.

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