Method of reducing physical dependence on neuropsychiatric treatment

Abstract

Neuropsychiatric treatments, including methods, regimens and interventions to reduce physical dependencies on those neuropsychiatric treatments based on ulotarone administration.

Description

[0001] Priority

[0002] This application claims priority to U.S. Provisional Application No. 63 / 379,364, filed October 13, 2022, the content of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to pharmacological neuropsychiatric treatments, as well as methods, regimens, and interventions for reducing physical dependence on those neuropsychiatric treatments administered based on ulotaront. Background Art

[0004] Neuropsychiatric drugs are a heterogeneous group of compounds with high variability in receptor affinity. The clinical effects of individual compounds vary, as receptor affinity is an important factor in efficacy, but especially in the side effect profile. Correll (2010).

[0005] Physical dependence (which may arise from the therapeutic use of neuropsychiatric drugs) is a physical condition in which sudden or gradual drug withdrawal results in adverse side effects. Appropriate discontinuation strategies are complex issues and depend on the drug's side effect profile, its pharmacodynamics and kinetics, and behavioral mechanisms, as well as the patient's comorbidities and vulnerabilities. Cerovecki et al. (2013).

[0006] Ulotaront (also known as SEP-363856, SEP-856) is an investigational drug being clinically developed by Sunovion Pharmaceuticals Inc. (Marlborough, Massachusetts) for various neurological disorders. In animal studies, in addition to anxiolytic and antidepressant components, ulotaront also exhibited major antipsychotic-like characteristics. Dedic et al. (2019). US2021 / 0315859 A1 reports a physical dependence study in rats.

[0007] Suddenly stopping neuropsychiatric therapy carries a risk of high withdrawal symptoms (including various somatic, motor, and psychological symptoms). Chouinard et al. (2017). Depending on the target receptor of the drug, both first-generation and second-generation antipsychotics can be associated with the following clinical features when the drug is discontinued or reduced: cholinergic withdrawal symptoms such as agitation, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion or disorientation, hypothermia, and sweating; dopaminergic withdrawal symptoms (nigrostriatal), which are selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia; serotonergic withdrawal symptoms, which are selected from flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric chock sensations, anxiety, agitation, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and decreased concentration; histaminergic withdrawal symptoms, which are selected from irritability, insomnia, agitation, depressed affect, anorexia or nausea, shakiness, ataxia, and drowsiness or amnesia; dopaminergic withdrawal symptoms (mesolimbic or striatal), which are selected from auditory hallucinations, persecutory delusions, and other psychotic symptoms; and adrenergic withdrawal symptoms, which are selected from headache, anxiety or agitation, hypertension, tachycardia, angina, palpitations, risk of myocardial infarction, presyncope, shakiness, and sweating. Horowitz et al. (2021).

[0008] Patients who show tolerance to dose increases are more likely to have withdrawal symptoms. Chouinard et al. (2017). Studies have also shown that the longer the exposure to the drug, the higher the risk of withdrawal-related psychosis upon discontinuation. Tiihonen et al. (2018).

[0009] Relapse is another major risk of neuropsychiatric drug discontinuation. One study reported that 48% of relapses occurred within the first 12 months after discontinuation (40% within the first 6 months), and only 2% per year after this period. Viguera et al. (1997). The risk of relapse doubles after 1 - 2 years of drug exposure, triples after 2 - 5 years of drug exposure, and increases 7-fold after 8 years of drug exposure. Horowitz et al. (2021) recently published a method of tapering neuropsychiatric drugs to minimize the risk of relapse, which is done gradually over months or even years, combined with hyperbolic dose reduction to provide a more uniform reduction in D2 blockade.

[0010] What we need are neuropsychiatric regimens and withdrawal strategies that do not cause the problems historically associated with withdrawal from neuropsychiatric treatment. SUMMARY OF THE INVENTION

[0011] We have unexpectedly found that ulotaront has an excellent side effect profile when human subjects discontinue the drug, and that the subject can discontinue ulotaront therapy either abruptly or gradually without significant risk of many (if not all) clinically significant complications.

[0012] Accordingly, 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, comprising selecting a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for a period of time effective until administration is discontinued, whereby no significant physical dependence greater than placebo occurs.

[0013] 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 ulotaront or a pharmaceutically acceptable salt thereof for a period of time effective, and (b) abruptly discontinuing ulotaront administration after the effective period.

[0014] 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 ulotaront or a pharmaceutically acceptable salt thereof for a period of time effective, and (b) after the effective period, discontinuing ulotaront administration and any drug therapy for the neuropsychiatric disorder.

[0015] 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 ulotaront or a pharmaceutically acceptable salt thereof for a period of time effective, and (b) discontinuing ulotaront administration after the effective period; wherein the subject is at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the method occurs without the presence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0016] 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 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 to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure as claimed. Detailed Description of the Invention

[0018] All published documents cited herein are hereby incorporated by reference in their entirety.

[0019] Use of Terms

[0020] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0021] Unless otherwise noted, the word "includes" (or any variant thereof, such as "include", "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.

[0022] As used in this specification and in the following claims, the word "comprise" and variations of the word, such as "comprising" and "comprises", mean "including but not limited to", and are not intended to exclude, for example, other additives, ingredients, integers, or steps. When an element is described as comprising a plurality of components, steps, or conditions, it should be understood that the element may also be described as comprising any combination of such plurality of components, steps, or conditions, or "consisting of" or "consisting essentially of": a plurality of components, steps, or conditions or a combination of components, steps, or conditions.

[0023] When a range is given by separately specifying the lower end and the upper end of the range, or by specifying a particular numerical value, it should be understood that the range may be defined by selectively combining any lower end variable, upper end variable, and particular numerical value that are mathematically possible. When a range is expressed as extending from one endpoint to another endpoint, it should be understood that both endpoints are included within the range. However, it should also be understood that a range from / to also includes embodiments in which the range is defined as being between two specified endpoints, and the term "between" may be substituted for the "from / to" language to omit the endpoints from the range.

[0024] The present disclosure describes various embodiments. Those skilled in the art will readily recognize that the various embodiments can be combined in any variation. For example, embodiments of the present disclosure include treating various disorders, patient populations, dosage forms administered, various doses, minimizing various adverse events, and improving various efficacy measurements, etc. Any combination of the various embodiments is within the scope of the present disclosure.

[0025] When reference is made herein to published test methods and diagnostic tools, it should be understood that the test method or diagnostic tool is based on the version in effect as of October 1, 2022, unless otherwise stated to the contrary herein. This is true even when the method or tool is defined herein based on a publication reporting an earlier version.

[0026] 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 pertains.

[0027] Definitions

[0028] “Adjunctive MDD therapy” or “AMDD therapy” refers to adding an agent to an antidepressant regimen to improve efficacy because the subject has experienced an insufficient response to an antidepressant regimen that has been optimized in terms of dose and duration.

[0029] As used herein, “administering” or “administration” of ulotaront or a pharmaceutically acceptable salt thereof includes delivering ulotaront 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).

[0030] "AE" or "adverse event" means any untoward medical event that is associated with the use of a drug in humans, whether or not it is considered drug-related. Those untoward medical events that occur after the first administration of the investigational drug are considered AEs. Thus, an AE can be any adverse and unexpected sign (including abnormal laboratory findings), symptom, or disease that occurs after the administration of a medicinal (investigational) product, whether or not it is considered related to the medicinal (investigational) product. An AE may include the onset of a new disease and the exacerbation of a pre-existing condition. As used herein and throughout the document, a "mild" AE means "usually brief symptoms that do not affect the performance of the subject's daily activities. Usually do not indicate the need for additional treatment." As used herein and throughout the document, a "moderate" AE means "obvious symptoms that are sufficient to make the subject uncomfortable. Have a moderate impact on the performance of the subject's daily activities. May require additional treatment." As used herein and throughout the document, a "severe" AE means "symptoms that cause considerable discomfort. Have a substantial impact on the subject's daily activities. May not be able to continue the study and may require additional treatment."

[0031] As disclosed herein, the methods of the present disclosure can be carried out without the occurrence or appearance of one or more adverse events selected from the symptoms or syndromes of neuropsychiatric drug withdrawal, which are generally defined based on the Markush grouping of adverse events. "One or more" means that the method can be practiced without the occurrence or appearance of any of the listed adverse events, can be practiced without the occurrence or appearance of any particular one of the listed adverse events, or can be practiced without the occurrence or appearance of any combination of the listed adverse events. Consistent with Markush grouping practice, it should be understood that the Markush grouping can be limited to one species within the group.

[0032] When drug treatment is said to occur without inducing physical dependence, or when the discontinuation of drug treatment is said to occur without adverse events or symptoms or syndromes of drug withdrawal, it should be understood to refer only to physical dependence, adverse events, or symptoms or syndromes of drug withdrawal that are significant in the clinical judgment of the treating physician and are caused by the drug treatment or its discontinuation. In one embodiment, "significant" means moderate or severe adverse events.

[0033] The "AIMS" (Abnormal Involuntary Movement Scale) assessment consists of 10 items that describe symptoms of movement dysfunction. Guy 1976. Facial and oral movements (items 1 to 4), limb movements (items 5 and 6), and trunk movements (item 7) are unobtrusively observed while the subject is at rest; the investigator also makes an overall judgment of the subject's movement dysfunction (items 8 to 10). Each item is rated on a 5-point scale, with a score of 0 indicating no symptoms (unconscious for item 10), and a score of 4 indicating a severe condition (conscious, severe distress for item 10). In addition, the AIMS includes 2 yes / no questions that address the subject's dental status. The AIMS motor rating score is defined as the sum of items 1 to 7 (i.e., items 1 to 4, facial and oral movements; items 5 and 6, limb movements; item 7, trunk movements).

[0034] "Antidepressant regimen" or "antidepressant therapy" refers to any pharmacological treatment regimen administered as a therapy for treating depression and should be distinguished from augmentation, which is the addition of an agent - not considered an antidepressant itself - 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 their pharmaceutically acceptable salts.

[0035] As used herein, an "at-risk" individual is an individual at risk of developing a disorder to be treated or an adverse event to be prevented. This can be demonstrated, for example, by one or more risk factors, which are measurable parameters known in the art and associated with the development of the disorder. When a method is said to treat a condition without causing or triggering an adverse event, it should be understood that the method can be performed in a subject at risk of an adverse event.

[0036] The "BARS" (Barnes Akathisia Rating Scale) is an overall clinical assessment of akathisia. Barnes 1989. The BARS consists of 4 items related to akathisia: the investigator's objective observation of akathisia, the subject's subjective feeling of restlessness, the subjective distress caused by akathisia, and the overall clinical assessment of akathisia. The first 3 items are rated on a 4-point scale, with a score of 0 representing no symptoms and a score of 3 representing a severe condition. The overall clinical assessment is made on a 6-point scale, with a score of 0 representing no symptoms and a score of 5 representing severe akathisia.

[0037] The "CGI-C" (Clinical Global Impression - Change) scale measures the efficacy of pharmacotherapy by rating the total change in the subject since the start of pharmacotherapy (regardless of whether this change is entirely attributable to pharmacotherapy). Response options include: 1 = very much improved, 2 = much improved, 3 = minimal improvement, 4 = slightly improved, 5 = slightly worse, 6 = much worse, 7 = very much worse.

[0038] The "CGI-S" (Clinical Global Impression - Severity) scale is a standardized, clinician-administered global rating scale that measures the severity of a disease on a 7-point Likert scale. The higher the CGI-S score, the higher the severity of the disease. For this assessment, the rater or investigator answers the following question: "Considering your overall clinical experience with this specific group, how ill is the patient at this time with respect to their mental illness?" Response options include: 1 = normal, not ill at all; 2 = borderline mental illness; 3 = mild illness; 4 = moderate illness; 5 = marked illness; 6 = severe illness; and 7 = among the most severely ill patients.

[0039] As used herein, a "clinically significant" or "clinically meaningful" improvement may refer to an improvement that is statistically significant and meaningful from the perspective of the patient, clinician, or caregiver, typically based on a static measurement (e.g., CGI-S) or a retrospective assessment of improvement (e.g., CGI-C), as generally described in various publications of the U.S. Food and Drug Administration (including FDA 2018, FDA 2019, and FDA 2020). When a treatment or benefit is described herein, it should be understood that the treatment or benefit preferably shows clinically significant efficacy to a statistically significant degree in a patient population.

[0040] The Columbia Suicide Severity Rating Scale (C-SSRS) is a tool designed to systematically assess and track suicidal AEs (suicidal behavior and suicidal ideation) throughout a trial. The strength of this suicide classification system is its ability to comprehensively identify suicide events while limiting over-identification of suicidal behavior. Nilsson et al. (2013). The scale takes approximately 5 minutes to administer.

[0041] As used herein, the development of a "delayed" disorder refers to postponing, hindering, slowing, stabilizing, and / or delaying the development of the disorder. The delay can have different time lengths, depending on the disease history and / or the individual being treated.

[0042] "Depression" has the meaning commonly ascribed to the term in the field of psychiatric medications and may be assumed to have the definition set forth in the DSM-5. When depression is mentioned herein, it should be understood that major depressive disorder ("MDD") is one type of depression, and the present disclosure is more specifically directed to MDD in all aspects, particularly the treatment of AMDD.

[0043] "DSM-5" refers to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Terms used herein may be defined with reference to DSM-5 as necessary to give life and meaning to the term. When a person is defined based on DSM-5 in this document, it should be understood that the person does not need to have been diagnosed using the criteria in DSM-5, but rather the person who meets the criteria set forth in DSM-5 is so diagnosed.

[0044] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of ulotaront include those salts derived from suitable inorganic and organic acids and bases.

[0046] Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed from the amino group and inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts formed from the amino group and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecyl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Although pharmaceutically acceptable counterions are preferred for the preparation of pharmaceutical formulations, other anions (X) are also fully acceptable as synthetic intermediates. Thus, when these salts are chemical intermediates, X may be an anion not desired pharmaceutically, such as iodide, oxalate, trifluoromethanesulfonate, etc.

[0047] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, anti-caking agent, flavoring agent, desiccant, plasticizer, disintegrant, lubricant, polymeric matrix system, and polish that has been approved by or otherwise accepted by the U.S. Food and Drug Administration for use in humans or livestock in an appropriate qualification.

[0048] The Physician Withdrawal Checklist (PWC) is a 34-item physician-administered questionnaire that was developed to assess benzodiazepine withdrawal symptoms. The PWC 20 total score includes 20 items from the PWC that have been validated for internal consistency, test-retest, and inter-rater reliability, as well as factor structure. Rickels (2008).

[0049] As used herein, "prevention" or "preventing" refers to a regimen that prevents the onset of a disorder such that the clinical symptoms of the disorder do not develop. Thus, "prevention" involves administering a therapy to a subject before signs of the disease are detectable in the subject (e.g., treating in the absence of detectable disease symptoms). The subject may be an individual at risk of developing the disorder.

[0050] The "SAS" (Simpson Angus Scale) consists of a list of 10 symptoms of parkinsonism (gait, arm hanging, shoulder tremor, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia). Simpson 1970. Each item is rated on a 5-point scale, with a score of 0 indicating no symptoms and a score of 4 indicating severe disease. The total SAS score is the sum of the scores for all 10 items.

[0051] The term "select" refers to the act of choosing from a number or group by fitness or preference. In the context of the present disclosure, ulotaront is selected from a group of generally recognized neuropsychiatric drugs for the treatment of any of the neuropsychiatric disorders described herein, based on the fact that ulotaront does not cause physical dependence, whether for short-term or long-term treatment, or for mild, moderate, or intensive treatment.

[0052] As used herein, the term "significantly" refers to a level of statistical significance. The level of statistical significance can be p < 0.1, p < 0.05, p < 0.01, p < 0.005, or p < 0.001. Unless otherwise stated, when the term "significant", "significantly", or other variants of the term are used, the level of statistical significance is p < 0.05. When a measurable result or effect is expressed or identified herein, it should be understood that the result or effect is preferably evaluated based on its statistical significance relative to a baseline (e.g., placebo). In a similar manner, when a treatment or benefit is described herein, it should be understood that the treatment or benefit preferably shows efficacy to a statistically significant degree in a patient population.

[0053] "SNRI" (serotonin-norepinephrine reuptake inhibitor) includes, but is not limited to, desvenlafaxine duloxetine levomilnacipran and venlafaxine and pharmaceutically acceptable salts thereof.

[0054] "SSRI" (selective serotonin reuptake inhibitor) includes, but is not limited to, citalopram escitalopram fluoxetine paroxetine and sertraline and pharmaceutically acceptable salts thereof.

[0055] As used herein, a “subject” or “patient” (the terms are used interchangeably) to whom administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged or elderly individuals)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys.

[0056] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount effective to elicit a desired biological or medical response, including, when administered to a subject for treating a disorder, an amount of a compound sufficient to effect treatment of such disorder. The effective amount will vary depending on the disorder and its severity and the age, weight, etc., of the subject to be treated. The effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to reach the desired treatment endpoint). An effective amount is considered to be administered in an effective amount if a desired or beneficial result can be achieved or effected in combination with one or more other agents. Due to the combined action (additive or synergistic) of the compounds, the appropriate dose of any co-administered compound may optionally be reduced.

[0057] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, including, but not limited to, therapeutic benefits. In some embodiments, treatment is administered after the occurrence of one or more symptoms (e.g., symptoms of an acute exacerbation). In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, e.g., to prevent or delay their recurrence.

[0058] When two separate agents are described herein for treatment, it is understood that the agents will be administered concomitantly based on a co-running dosing regimen, which may differ in dosing frequency or time of administration. The two agents do not necessarily have to be administered simultaneously to be administered concomitantly. For example, concomitant administration may include one agent that is administered three times daily and one agent that is administered once daily.

[0059] Therapeutic benefits include eradicating and / or ameliorating the underlying disorder being treated; it also includes eradicating and / or ameliorating one or more symptoms associated with the underlying disorder such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder.

[0060] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting a disorder (e.g., reducing one or more symptoms caused by the disorder, and / or alleviating the severity of the disorder); (b) slowing or preventing the development of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or delaying the worsening or progression of the disorder); and / or (c) alleviating the disorder (e.g., resulting in the resolution of clinical symptoms, improvement of the disorder, delaying the progression of the disorder, and / or improving quality of life).

[0061] As used herein in the methods of the present disclosure, "Ulotaront" 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"). Ulotaront has the following structure:

[0062]

[0063] Unless otherwise specified, or unless the context otherwise requires, for the purposes of the present disclosure, the term "ulotaront" standing alone includes the free form of ulotaront and also includes its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms. When the free form is intended or any other form or salt is specifically intended, it will be stated so explicitly.

[0064] Ulotaront can be used in the methods described herein as the free base or in the form of a pharmaceutically acceptable salt. In a preferred embodiment, the hydrochloride (HCl) salt of ulotaront is used in the methods described herein. Ulotaront or its pharmaceutically acceptable salts (including its HCl crystalline form) can be obtained according to the production methods described in PCT Patent Publication No. WO2011 / 069063 (U.S. Patent No. 8,710,245 issued on April 29, 2014) or PCT Patent Publication No. WO2019 / 161238 or methods similar thereto, which patents are incorporated herein by reference in their entirety and for all purposes.

[0065] Methods of using ulotaront to treat the neuropsychiatric disorders described herein (particularly schizophrenia, depression, and anxiety) are described in PCT Patent Publication No. WO 2020 / 118032 and Dedic et al. (2019).

[0066] The present disclosure also provides pharmaceutical compositions and dosage forms that comprise ulotaront or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The compositions and dosage forms provided herein may further comprise one or more additional active ingredients. Ulotaront or a pharmaceutically acceptable salt thereof may be administered as part of a pharmaceutical composition as described herein.

[0067] Discussion

[0068] Physical dependence (which can develop from the therapeutic use of neuropsychiatric drugs) poses a high risk of withdrawal symptoms that include a variety of somatic, motor, and psychological symptoms. The present disclosure pertains to the selection of ulotaront from available neuropsychiatric drugs, and the reduction of physical dependence and withdrawal symptoms upon cessation of therapy.

[0069] 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, which comprises selecting a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time until administration is discontinued, whereby no significant physical dependence greater than placebo occurs. In one embodiment, the administration is carried out daily.

[0070] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need thereof, which comprises: (a) administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and (b) abruptly discontinuing ulotaront administration after the effective period of time. In one embodiment, the method is carried out without significant physical dependence upon cessation of treatment of the subject in need thereof, whereby no significant physical dependence greater than placebo occurs.

[0071] In another embodiment, the present disclosure provides a method of treating a neuropsychiatric disorder in a human subject in need thereof, which comprises: (a) administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and (b) after the effective period of time, discontinuing ulotaront administration and any drug therapy for the neuropsychiatric disorder. In one embodiment, the method is carried out without significant physical dependence upon cessation of treatment of the subject in need thereof, whereby no significant physical dependence greater than placebo occurs.

[0072] 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 ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and (b) discontinuing the administration of ulotaront after the effective period; wherein the subject is at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the method occurs in the absence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal. In one embodiment, the method is carried out in the absence of significant physical dependence after treatment cessation in a subject in need, whereby no significant physical dependence greater than placebo occurs.

[0073] The method can be used to treat a variety of neuropsychiatric disorders, symptoms of these disorders, or side effects associated with the conventional treatment of these disorders. Representative disorders include schizophrenia, schizophrenic spectrum disorders, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoemotional disorder, aggression, delirium, Parkinson's psychosis, excitatory psychosis, Tourette syndrome, organic or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar affective disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), fibromyalgia, migraine, cognitive disorder, movement disorder, restless legs syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, sedating side effects of drugs, insomnia, substance abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorder, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson disease, autism, Huntington's chorea, and premenstrual dysphoria.

[0074] Given the unique behavioral characteristics of ulotaront (as reported in Dedic 2019), the human clinical results reported in PCT patent publication number WO2020 / 118032, and the novel mechanism of action and receptor binding characteristics of ulotaront, it can be expected that ulotaront treats neuropsychiatric disorders with a high degree of safety and efficacy. Accordingly, in one embodiment, ulotaront is used to improve the symptoms of neuropsychiatric disorders selected from psychosis, depression, pain, cognition, mood disorders, and anxiety disorders.

[0075] In another embodiment, the neuropsychiatric disorders include schizophrenia, schizophrenic spectrum disorders, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoemotional disorder, excitatory psychosis, organic or NOS psychosis, movement dysfunction, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar affective disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder), pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), cognitive disorder, movement disorder.

[0076] In another embodiment, the treatment is carried out without clinically significant occurrence of conditions traditionally associated with neuropsychiatric treatment, including treating such conditions as hyperprolactinemia, abnormal blood prolactin, elevated blood prolactin, galactorrhea, cogwheel rigidity, obesity, metabolic syndrome, dyslipidemia, akathisia, extrapyramidal disorder, restlessness, increased appetite, chronic pancreatitis, weight gain, and nuchal rigidity.

[0077] In one embodiment, the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety disorder. In another embodiment, the neuropsychiatric disorder is schizophrenia. In another embodiment, the neuropsychiatric disorder is bipolar depression (specifically MDD as defined by DSM-5, and more specifically AMDD). In yet another embodiment, the neuropsychiatric disorder is an anxiety disorder (e.g., generalized anxiety disorder (GAD) as defined by DSM-5).

[0078] "Effective time period" is a period of time sufficient to determine the efficacy or ineffectiveness of the treatment. Thus, in various embodiments, the effective time period is ≥2 weeks, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥26 weeks, ≥1 year, or ≥2 years, or optionally a period of less than 5 years, 4 years, or 3 years.

[0079] In other embodiments, the effective time period is described functionally. Thus, in one embodiment, the effective time period is sufficient to achieve a clinically significant improvement in the neuropsychiatric disorder. In another embodiment, the effective time period is sufficient for the complete recovery of the neuropsychiatric disorder. In other embodiments, the effective time period is sufficient for the complete recovery of the neuropsychiatric disorder, as evidenced by no diagnosis of the neuropsychiatric disorder under the criteria set forth in DSM-5. In still other embodiments, the effective time period is sufficient for the complete recovery of the neuropsychiatric disorder for a period of ≥3 months, ≥6 months, ≥1 year, ≥18 months, or ≥2 years.

[0080] The effective time period can also be a period of time to determine the ineffectiveness of ulotaront. Thus, in one embodiment, the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject. In other embodiments, the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by the failure of a clinically significant improvement in the neuropsychiatric disorder. In other embodiments, the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by the continued diagnosis of the neuropsychiatric disorder under the criteria set forth in DSM-5. In further embodiments, the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by one or more of the following: (a) insufficient clinical response to acute symptoms despite dose optimization and sufficient treatment trial duration; (b) poor control of chronic symptoms and persistence of dysfunction during maintenance therapy; (c) recurrence despite adequate preventive or maintenance treatment of the neuropsychiatric disorder; and (d) persistence of certain symptoms of the neuropsychiatric disorder despite the use of a sufficient dose of ulotaront.

[0081] The method can also be defined by the nature of the discontinuation of ulotaront therapy. The discontinuation will be either abrupt (i.e., without any tapering) or tapered. "Tapering" means any gradual reduction in the dose at any frequency over any period of time. In some embodiments, the dose reduction occurs in increments of 12.5 and / or 25 mg. In some embodiments, the dose reduction and ultimate discontinuation occur over a period of one week to one year. Gradual does not mean that the degree of reduction must be equal. Thus, for example, a gradual reduction will include the hyperbolic dose reduction proposed by Horowitz (2021).

[0082] In any embodiment, the subject may be at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal. Alternatively, in any embodiment, the subject may have previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal. In a further alternative applicable to any embodiment, the method occurs in the absence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal. In a further alternative, significant physical dependence is defined as the occurrence or appearance of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0083] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur in the absence of withdrawal-related adverse events, which include a clinically significant increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20). In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which include a clinically significant increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20).

[0084] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur in the absence of withdrawal-related adverse events, which include an increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20) of more than 4.0, 4.25, 4.5, 4.71, 4.75, 5.0, or 5.25. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which include an increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20) of more than 4.0, 4.25, 4.5, 4.71, 4.75, 5.0, or 5.25.

[0085] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, which are defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query: Drug withdrawal. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which are defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query: Drug withdrawal.

[0086] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, which include one or more symptoms of neuropsychiatric drug withdrawal selected from the following: somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which include one or more symptoms of neuropsychiatric drug withdrawal selected from the following: somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

[0087] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, which include one or more somatic symptoms of neuropsychiatric drug withdrawal selected from the following: (i) insomnia, (ii) sweating, (iii) tremor-shaking, (iv) headache, and (v) muscle pain or stiffness. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which include one or more somatic symptoms of neuropsychiatric drug withdrawal selected from the following: (i) insomnia, (ii) sweating, (iii) tremor-shaking, (iv) headache, and (v) muscle pain or stiffness.

[0088] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more emotional symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anxiety-neuroticism, (ii) irritability, (iii) dysphoric mood-depression, (iv) restlessness-agitation, and (v) inattention, difficulty with memory. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including one or more emotional symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anxiety-neuroticism, (ii) irritability, (iii) dysphoric mood-depression, (iv) restlessness-agitation, and (v) inattention, difficulty with memory.

[0089] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more cognitive symptoms of neuropsychiatric drug withdrawal selected from the following: (i) poor 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 appearance of withdrawal-related adverse events, the withdrawal-related adverse events including one or more cognitive symptoms of neuropsychiatric drug withdrawal selected from the following: (i) poor coordination, (ii) dizziness-lightheadedness, (iii) increased sensitivity to sound, smell, touch, and (iv) depersonalization-derealization.

[0090] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more fatigue symptoms of neuropsychiatric drug withdrawal selected from the following: (i) fatigue-somnolence-asthenia, (ii) weakness, and (iii) paresthesia. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including one or more fatigue symptoms of neuropsychiatric drug withdrawal selected from the following: (i) fatigue-somnolence-asthenia, (ii) weakness, and (iii) paresthesia.

[0091] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more gastrointestinal symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anorexia, (ii) nausea-vomiting, and (iii) diarrhea. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including one or more gastrointestinal symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anorexia, (ii) nausea-vomiting, and (iii) diarrhea.

[0092] In any embodiment of the present disclosure, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more withdrawal symptoms of mild, moderate, or severe magnitude. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including one or more withdrawal symptoms of mild, moderate, or severe magnitude.

[0093] In a similar manner, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more syndromes of neuropsychiatric drug withdrawal selected from the following: (a) cholinergic syndrome, which is manifested as one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, malaise, myalgia, diaphoresis, rhinitis, paresthesia, and diarrhea; (b) dopaminergic syndrome, which is manifested as one or more of withdrawal dyskinesia, akathisia, dystonia, tardive dyskinesia; and (c) rebound psychosis, which is manifested as one or more of psychosis, delusion, hallucination, and catatonia at levels higher than pre-treatment levels. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, which include one or more syndromes of neuropsychiatric drug withdrawal selected from the following: (a) cholinergic syndrome, which is manifested as one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, malaise, myalgia, diaphoresis, rhinitis, paresthesia, and diarrhea; (b) dopaminergic syndrome, which is manifested as one or more of withdrawal dyskinesia, akathisia, dystonia, tardive dyskinesia; and (c) rebound psychosis, which is manifested as one or more of psychosis, delusion, hallucination, and catatonia at levels higher than pre-treatment levels.

[0094] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events being selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonergic withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events being selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonergic withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms.

[0095] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including cholinergic withdrawal symptoms selected from: restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion or disorientation, hypothermia, and sweating. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including cholinergic withdrawal symptoms selected from: restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal cramps, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion or disorientation, hypothermia, and sweating.

[0096] In further embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including dopaminergic withdrawal symptoms (nigrostriatal) selected from: withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including dopaminergic withdrawal symptoms (nigrostriatal) selected from: withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia.

[0097] In some embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including serotonin withdrawal symptoms selected from: flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensations, anxiety, restlessness, depressed mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and decreased concentration. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including serotonin withdrawal symptoms selected from: flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensations, anxiety, restlessness, depressed mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and decreased concentration.

[0098] Furthermore, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including histaminergic withdrawal symptoms selected from: irritability, insomnia, restlessness, depressive affect, anorexia or nausea, tremors, ataxia, and drowsiness or amnesia. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including histaminergic withdrawal symptoms selected from: irritability, insomnia, restlessness, depressive affect, anorexia or nausea, tremors, ataxia, and drowsiness or amnesia.

[0099] In addition, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including dopaminergic withdrawal symptoms (mesolimbic or striatal) selected from: auditory hallucinations, delusions of persecution, and other psychotic symptoms. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including dopaminergic withdrawal symptoms (mesolimbic or striatal) selected from: auditory hallucinations, delusions of persecution, and other psychotic symptoms.

[0100] In other embodiments, the subject may be at risk of withdrawal-related adverse events, or the subject may have previously experienced withdrawal-related adverse events, or the method may occur without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including adrenergic withdrawal symptoms selected from: headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating. In other embodiments, significant physical dependence is defined as the occurrence or appearance of withdrawal-related adverse events, the withdrawal-related adverse events including adrenergic withdrawal symptoms selected from: headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating.

[0101] It should be understood that any of the foregoing embodiments may be limited to subjects at risk of one or more withdrawal-related adverse events. In a similar manner, it should be understood that any of the foregoing embodiments may be limited to subjects who have previously experienced one or more withdrawal-related adverse events. Further, it should be understood that the method may occur without the occurrence of one or more withdrawal-related adverse events. Further, the method may be carried out without significant physical dependence.

[0102] Withdrawal-related adverse events may be characterized as being of mild, moderate, or severe magnitude. Thus, in any of the foregoing embodiments, the subject may be at risk of withdrawal-related adverse events of mild, moderate, or severe magnitude, or the subject may have previously experienced withdrawal-related adverse events of mild, moderate, or severe magnitude, or the method may be carried out without the occurrence of withdrawal-related adverse events of mild, moderate, or severe magnitude.

[0103] In one embodiment, the subject discontinues all antipsychotic therapy for the neuropsychiatric disorder when stopping ulotaront therapy. Thus, any of the foregoing embodiments may further include stopping ulotaront administration and any drug therapy for the neuropsychiatric disorder after the effective period for a period of ≥3 months, ≥6 months, ≥1 year, ≥18 months, or ≥2 years.

[0104] An effective therapeutic amount of ulotaront can alternatively be described as 25 - 150 mg / day or 25 - 100 mg / day or 50 - 125 mg / day or 50 - 100 mg / day administered orally. Alternatively, the effective therapeutic amount can be described as 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day or 150 mg / day administered orally. In any embodiment of the present disclosure, the effective therapeutic amount can be administered once daily in the fed or fasted state. The ulotaront can also be administered as a hydrochloride salt.

[0105] As shown in Example 1, the incidence of AEs after dosing was compared between a placebo group and a SEP-363856 treatment group in patients with schizophrenia. Example 2 Withdrawal study compared abrupt discontinuation of SEP-363856 (SEP-363856 switched to placebo) versus continued SEP-363856 treatment in patients with schizophrenia.

[0106] Preferred aspects of the present disclosure can be defined based on the following embodiments AA to CD:

[0107] [Embodiment AA] A method for treating a neuropsychiatric disorder in a human subject in need thereof without significant physical dependence after discontinuation of treatment, comprising selecting an effective therapeutic amount of ulotaront or a pharmaceutically acceptable salt thereof and administering to the subject the effective therapeutic amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time until administration is discontinued, whereby no significant physical dependence greater than placebo occurs.

[0108] [Embodiment AB] A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising:

[0109] a) administering to the subject an effective therapeutic amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and

[0110] b) abruptly stopping ulotaront administration after the effective period of time.

[0111] [Embodiment AC] A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising:

[0112] a) administering to the subject an effective therapeutic amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and

[0113] b) after the effective period of time, stopping ulotaront administration and any drug therapy for the neuropsychiatric disorder.

[0114] [Embodiment AD]A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising:

[0115] a) administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and

[0116] b) stopping the administration of ulotaront after said effective period of time;

[0117] wherein the subject is at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the method occurs in the absence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0118] [Embodiment AE]The method according to any one of Embodiments AB - AD, which is carried out in a subject in need thereof without significant physical dependence after treatment cessation, whereby no significant physical dependence greater than that of a placebo occurs.

[0119] [Embodiment AF]The method according to any one of Embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include a clinically significant increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20).

[0120] [Embodiment AG]The method according to any one of Embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include an increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20) by more than 4.71.

[0121] [Embodiment AH]The method according to any one of Embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events are defined by querying the Standardized MedDRA Query (SMQ): Drug Withdrawal in the Medical Dictionary for Regulatory Activities (MedDRA).

[0122] [Embodiment AI]The method according to any one of Embodiments AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include one or more symptoms of neuropsychiatric drug withdrawal selected from the following: somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

[0123] [Embodiment AJ] The method according to any one of Embodiment AA or AE, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events are selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonergic withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms.

[0124] [Embodiment AK] The method according to any one of Embodiments AA - AJ, wherein the effective time period is a duration of ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 12 weeks, ≥ 26 weeks, ≥ 1 year, or ≥ 2 years.

[0125] [Embodiment AL] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient to achieve a clinically significant improvement in the neuropsychiatric disorder.

[0126] [Embodiment AM] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder.

[0127] [Embodiment AN] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder, as evidenced by not being diagnosed with the neuropsychiatric disorder under the criteria set forth in DSM - 5.

[0128] [Embodiment AO] The method according to any one of Embodiments AA - AN, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder, lasting for a duration of ≥ 3 months, ≥ 6 months, ≥ 1 year, ≥ 18 months, or ≥ 2 years.

[0129] [Embodiment AP] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject.

[0130] [Embodiment AQ] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by the failure of a clinically significant improvement in the neuropsychiatric disorder.

[0131] [Embodiment AR] The method according to any one of Embodiments AA - AK, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by continuing to be diagnosed with the neuropsychiatric disorder under the criteria set forth in DSM - 5.

[0132] The method according to any one of embodiments AA - AK, AP, AQ or AR, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the neuropsychiatric disorder of the subject, as evidenced by one or more of the following:

[0133] a) Inadequate clinical response to acute symptoms despite dose optimization and sufficient duration of the treatment trial;

[0134] b) Poor control of chronic symptoms and persistent dysfunction during maintenance therapy;

[0135] c) Recurrence despite adequate preventive or maintenance treatment for the neuropsychiatric disorder; and

[0136] d) Persistence of certain symptoms of the neuropsychiatric disorder despite the use of an adequate dose of ulotaront.

[0137] [Embodiment AT] The method according to any one of embodiments AA - AS, wherein the discontinuation is sudden.

[0138] [Embodiment AU] The method according to any one of embodiments AA or AC - AS, wherein the discontinuation is a gradual reduction.

[0139] [Embodiment AV] The method according to any one of embodiments AA - AU, wherein the subject is at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0140] [Embodiment AW] The method according to any one of embodiments AA - AU, wherein the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0141] [Embodiment AX] The method according to any one of embodiments AA - AU, wherein the method occurs without the occurrence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

[0142] [Embodiment AY] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include a clinically significant increase in the total score of the 20 - item Physician's Withdrawal Checklist (PWC - 20).

[0143] [Embodiment AZ] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include an increase in the total score of the 20 - item Physician Withdrawal Checklist (PWC - 20) by more than 4.71.

[0144] [Embodiment BA] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events are defined by querying the Standardized MedDRA for Regulatory Activities (MedDRA): Drug Withdrawal.

[0145] [Embodiment BB] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more symptoms of neuropsychiatric drug withdrawal selected from the following: somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

[0146] [Embodiment BC] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more somatic symptoms of neuropsychiatric drug withdrawal selected from the following: (i) insomnia, (ii) sweating, (iii) tremor - shakiness, (iv) headache, and (v) muscle pain or stiffness.

[0147] [Embodiment BD] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more mood symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anxiety - nervousness, (ii) irritability, (iii) restlessness - depression, (iv) restlessness - agitation, and (v) inattention, difficulty in memory.

[0148] [Embodiment BE] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more cognitive symptoms of neuropsychiatric drug withdrawal, selected from the following: (i) poor coordination, (ii) dizziness - light - headedness, (iii) increased sensitivity to sound, smell, touch, and (iv) depersonalization - derealization.

[0149] [Embodiment BF] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more fatigue symptoms of neuropsychiatric drug withdrawal, selected from the following: (i) fatigue - drowsiness - lack of energy, (ii) weakness, and (iii) paresthesia.

[0150] [Embodiment BG] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more gastrointestinal symptoms of neuropsychiatric drug withdrawal, selected from the following: (i) loss of appetite, (ii) nausea - vomiting, and (iii) diarrhea.

[0151] [Embodiment BH] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more withdrawal symptoms of mild, moderate, or severe magnitude.

[0152] [Embodiment BI] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more syndromes of neuropsychiatric drug withdrawal, selected from the following:

[0153] a) cholinergic syndrome, manifested as one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, discomfort, myalgia, sweating, rhinitis, paresthesia, and diarrhea;

[0154] b) Dopaminergic syndrome, manifested as one or more of withdrawal movement dysfunction, akathisia, dystonia, tardive movement dysfunction; and

[0155] c) Rebound psychosis, manifested as one or more of psychosis, delusions, hallucinations, and catatonia at a level higher than before treatment.

[0156] [Embodiment BJ] The method according to any one of Embodiments AA - AU, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events are selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonergic withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms.

[0157] [Embodiment BK] The method according to any one of Embodiments AA - AU, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include cholinergic withdrawal symptoms selected from the following: restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal colic, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion or disorientation, hypothermia, and sweating.

[0158] [Embodiment BL] The method according to any one of Embodiments AA - AU, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include dopaminergic withdrawal symptoms (nigrostriatal) selected from the following: withdrawal movement dysfunction, parkinsonism, neuroleptic malignant syndrome, and akathisia.

[0159] [Embodiment BM] The method according to any one of Embodiments AA - AU, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include serotonergic withdrawal symptoms selected from the following: flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensations, anxiety, restlessness, mood lability, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and decreased concentration.

[0160] [Embodiment BN] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include histaminergic withdrawal symptoms selected from the following: irritability, insomnia, restlessness, depressive affect, anorexia or nausea, tremors, ataxia, and drowsiness or amnesia.

[0161] [Embodiment BO] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include dopaminergic withdrawal symptoms (mesolimbic or striatal) selected from the following: auditory hallucinations, delusions of persecution, and other psychotic symptoms.

[0162] [Embodiment BP] The method according to any one of embodiments AA - AU, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include adrenergic withdrawal symptoms selected from the following: headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating.

[0163] [Embodiment BQ] The method according to any one of embodiments AY - BP, wherein the subject is at risk of one or more withdrawal - related adverse events.

[0164] [Embodiment BR] The method according to any one of embodiments AY - BP, wherein the subject has previously experienced one or more withdrawal - related adverse events.

[0165] [Embodiment BS] The method according to any one of embodiments AY - BP, wherein the method occurs without the occurrence of withdrawal - related adverse events.

[0166] [Embodiment BT] The method according to any one of embodiments AY - BP, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs without the occurrence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more withdrawal symptoms of mild, moderate, or severe magnitude.

[0167] [Embodiment BU] The method according to any one of Embodiments AA - BT, which comprises stopping the administration of ulotaront and any drug therapy for the neuropsychiatric disorder after the effective time period, for a time period of ≥ 3 months, ≥ 6 months, ≥ 1 year, ≥ 18 months or ≥ 2 years.

[0168] [Embodiment BV] The method according to any one of Embodiments AA - BU, wherein the therapeutically effective amount is administered orally at 25 - 150 mg / day, or 25 - 100 mg / day, or 50 - 125 mg / day, or 50 - 100 mg / day.

[0169] [Embodiment BW] The method according to any one of Embodiments AA - BU, wherein the therapeutically effective amount is administered orally at 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day or 150 mg / day.

[0170] [Embodiment BX] The method according to any one of Embodiments AA - BW, wherein the therapeutically effective amount is administered once daily in the fed or fasted state.

[0171] [Embodiment BY] The method according to any one of Embodiments AA - BX, wherein the ulotaront is administered as the hydrochloride salt.

[0172] [Embodiment BZ]The method according to any one of embodiments AA - BY, wherein the neuropsychiatric disorder is selected from schizophrenia, schizophrenic spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoemotional disorder, aggression, delirium, Parkinson's psychosis, excitatory psychosis, Tourette syndrome, organic or NOS psychosis, seizure, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar affective disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g., neuropathic pain, sensitization associated with neuropathic pain, and inflammatory pain), fibromyalgia, migraine, cognitive disorder, movement disorder, restless legs syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effect of drugs, insomnia, substance abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorder, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoria.

[0173] [Embodiment CA]The method according to any one of embodiments AA - BY, wherein the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety disorder.

[0174] [Embodiment CB]The method according to any one of embodiments AA - BY, wherein the neuropsychiatric disorder is schizophrenia.

[0175] [Embodiment CC]The method according to any one of embodiments AA - BY, wherein the neuropsychiatric disorder is selected from bipolar depression and major depression.

[0176] [Embodiment CD]The method according to any one of embodiments AA - BY, wherein the neuropsychiatric disorder is anxiety disorder. Example

[0177] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be taken into account. The following examples are presented to provide a complete disclosure and description to those skilled in the art of how the methods claimed herein are carried out and evaluated, and are intended solely as examples of the present disclosure and are not intended to limit the scope that the inventors regard as their disclosure.

[0178] Example 1. Examination of Adverse Events (AEs) after Administration in Completed and Ongoing Studies of SEP-363856 in Patients with Schizophrenia

[0179] Analyses were conducted in a completed double-blind placebo-controlled study, a completed open-label study, and an ongoing (as of the date of this evaluation) open-label study of SEP-363856 to examine adverse events (AEs) after administration with start dates after the last treatment exposure date.

[0180] Adverse events after administration (defined as AEs with start dates after the last treatment exposure date) were examined in the withdrawal population. However, since the study drug was administered at bedtime in the study, AEs with start dates >1 day after the last dose were also examined in patients in the withdrawal population with ≥2 follow-up days. The results of these analyses are presented in Tables 1 and 2.

[0181] In the completed double-blind placebo-controlled study, the incidence of adverse events after administration was similar between the placebo group and the SEP-363856 treatment group (9 [23.7%] placebo; 8 [23.5%] SEP-363856; Table 1). The only adverse event after administration that occurred in ≥2 patients in the SEP-363856 group was schizophrenia; the incidence of this AE was similar between the treatment groups (4 [10.5%] placebo; 4 [11.8%] SEP-363856).

[0182] Table 1: Adverse Events after Administration in the Completed Double-Blind Placebo-Controlled Study: Withdrawal Population

[0183]

[0184] Abbreviations: d = day, mg = milligram

[0185] Note: The withdrawal population includes patients who took at least one dose of the study drug and had at least one day of follow-up after administration. Rollover patients in the double-blind study and ongoing subjects are not included in the withdrawal population.

[0186] Note: n is the number of patients with the event. Percentages are based on the total number of patients in the treatment groups in the withdrawal population. Each preferred term and system organ class is counted once per patient.

[0187] Note: Post - administration adverse events (AEs) are AEs with start dates after the last treatment exposure date.

[0188] * Among patients in the withdrawal population with ≥ 2 follow - up days, weight gain in one placebo patient was the only AE identified using the definition of post - administration AE with a start date > 1 day after the last dosing date.

[0189] In completed and ongoing open - label studies, as of the date of this assessment, a total of 36 (18.8%) patients had post - administration AEs (Table 2). The only post - administration AEs occurring in ≥ 2% of patients were schizophrenia (22 [11.5%]) and suicidal ideation (4 [2.1%]).

[0190] A total of 12 (6.5%) patients had post - administration AEs with start dates > 1 day after the last dosing date. There were no post - administration AEs that occurred in ≥ 2% of patients and had start dates > 1 day after the last dosing date.

[0191] Table 2: Post - administration adverse events in completed and ongoing open - label studies: Withdrawal population

[0192]

[0193]

[0194] Abbreviations: d = day, mg = milligram

[0195] a Subjects in the withdrawal population with ≥ 2 follow - up days.

[0196] Note: The withdrawal population includes patients who took at least one dose of the study drug and had at least one day of post - administration follow - up time. Patients in the extension trials of double - blind studies and ongoing subjects are not included in the withdrawal population.

[0197] Note: n is the number of patients with the event. Percentages are based on the total number of patients in the treatment groups in the withdrawal population. Each preferred term and system organ class is counted once per patient.

[0198] Note: Post - administration adverse events (AEs) are AEs with start dates after the last treatment exposure date.

[0199] The MedDRA version 22.0 SMQ: Drug Withdrawal [20000102] was also used to search for post - dosing AEs using a predefined list of preferred terms. The preferred terms were tabulated using the MedDRA version for each study (i.e., for studies not using MedDRA version 22.0, the coding was not updated). No withdrawal - related post - dosing AEs as defined by the SMQ: Drug Withdrawal were identified in any completed Phase 2 study or ongoing Phase 3 study.

[0200] In summary, the analysis of post - dosing AEs as of the date of this assessment did not reveal any signal of a withdrawal effect.

[0201] Example 2. Double - Blind, Placebo - Controlled, Randomized Withdrawal Study to Evaluate the Physical Dependence of SEP - 363856 in Adult Subjects with Schizophrenia

[0202] The primary objective of this study was to confirm the lack of physical dependence associated with SEP - 363856, as indicated by the presence or absence of signs and / or symptoms of drug withdrawal when SEP - 363856 was abruptly discontinued (i.e., switched to placebo) in subjects with schizophrenia compared to subjects with schizophrenia receiving continuous SEP - 363856 treatment. The secondary objectives were to evaluate the safety and tolerability of SEP - 363856 when used in adults with schizophrenia. The overall study design (including the duration of the 4 - week open - label treatment period) was consistent with published physical dependence studies (Stauffer 2014, Lerner 2015, Lerner 2019).

[0203] This was a double - blind, placebo - controlled, randomized withdrawal study comparing abruptly discontinued SEP - 363856 (SEP - 363856 switched to placebo) with continuous SEP - 363856 treatment in adult male and female subjects with schizophrenia. The study consisted of 4 periods: a screening / washout period (up to 21 days), an open - label period (SEP - 363856 on Days 1 - 35), a double - blind, randomized withdrawal period (Days 36 - 43), and a follow - up period (7 [+2] days after the last dose). The study drug was taken daily in the evening at approximately the same time before bedtime, with or without food.

[0204] Approximately 40 subjects were enrolled during the open-label period in order to randomize at least 34 subjects (17 per group) during the randomized withdrawal period. Every effort was made to enroll at least 30% of subjects of each sex. Subjects were outpatients for most of the screening / washout period and could be elected to be hospitalized for up to 7 days prior to Day 1 if the investigator deemed it clinically necessary. During the first 7 days of the open-label period, subjects were hospitalized or outpatients as the subjects' doses were titrated up based on what the investigator deemed to be clinically necessary. Subjects were readmitted on Day 29 (-3 days) and remained hospitalized until the end of the randomized withdrawal period. Subjects were discharged at the end of the randomized withdrawal period or remained hospitalized at the discretion of the investigator for part or all of the follow-up period.

[0205] During the up to 21-day screening / washout period, subject eligibility was evaluated, during which subjects tapered all neuropsychiatric medications (except permitted concomitant medications) in a manner consistent with label recommendations and routine medical practice. If the investigator deemed it clinically necessary, subjects could be hospitalized for up to one week prior to Day 1. Subjects were outpatients for most of the screening / washout period and could be elected to continue as outpatients or be hospitalized for 1 week prior to entering the open-label period if the investigator deemed it clinically necessary. Preferably, all neuropsychiatric medications were washed out within 3 days or 5 half-lives (whichever was longer) prior to the first dose of the study drug.

[0206] Subjects who successfully completed the washout of the prior medication and met the eligibility criteria entered the open-label period, during which they received oral, open-label SEP-363856 once daily (QD) for 35 days (Day 1 to Day 35) to establish a steady-state baseline. Administration of open-label SEP-363856 began in the evening of Visit 2 (Day 1) and continued once daily (in the evening, before bedtime) for the remainder of the open-label period. During this 7-day titration period, subjects were hospitalized or outpatients at the discretion of the investigator. Hospitalized subjects were discharged on Day 8.

[0207] All subjects received 50 mg / day of SEP-363856 for Days 1 to 3, then 75 mg / day of SEP-363856 for Days 4 to 7. Beginning on Day 8 through Day 35, subjects received 100 mg / day for the remainder of the open-label period. Subjects who could not tolerate 100 mg / day of the study drug stopped the study and were replaced. Subjects were outpatients for 3 weeks during this period (Days 8 - 28), then were admitted to the Clinical Research Unit (CRU) for the last week of the open-label period (Days 29 - 35).

[0208] After the final dose in the open-label period on Day 35 (evening), subjects entered a 7-day double-blind randomized withdrawal period and remained hospitalized. On Day 36 of the randomized withdrawal period, subjects were randomized 1:1 to continue SEP-363856 treatment or placebo. Subjects were eligible to be discharged starting on Day 43 or to be prematurely terminated (ET) at the discretion of the investigator.

[0209] All subjects had safety follow-up assessments 7 days (+2 days) after the last dose of the study drug. Subjects who discontinued prematurely from the study completed the premature termination visit within 24 hours of the last dose of the study drug. Subjects were hospitalized from Day 1 until the end of the randomized withdrawal period. If a subject met the discharge criteria, the subject was discharged at the end of the randomized withdrawal period or remained hospitalized during the follow-up period at the discretion of the investigator.

[0210] To be eligible to participate, subjects must meet the following major inclusion criteria:

[0211] · Male or female subjects aged 18 to 65 years (inclusive).

[0212] · Subjects met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for a primary diagnosis of schizophrenia as determined by clinical interview.

[0213] · Subjects must have had a Clinical Global Impression - Severity Scale (CGI-S) score ≤4 (normal to moderate illness).

[0214] · Subjects must have had a total score on the Positive and Negative Syndrome Scale (PANSS) ≤80.

[0215] · Subjects must have had a score ≤4 on PANSS P7 (hostility) and G8 (uncooperativeness).

[0216] · At screening, the subject's body mass index (BMI) was at least 18.0 kg / m 2 , but not more than 40.0 kg / m 2。

[0217] · At screening and on Day 1, subjects must have had normal to mild symptoms on all individual items of the Simpson Angus Scale (SAS) (<2), Abnormal Involuntary Movement Scale (AIMS) (<3), and Barnes Akathisia Rating Scale (BARS) (<3).

[0218] The primary endpoint was the maximum change from steady-state baseline in the total score on the 20-item Physician Withdrawal Checklist (PWC-20) during the 7-day randomized withdrawal period (CSSB max)。The primary analysis was the non-inferiority test of the mean CSSB in the total PWC-20 score between the placebo group and the SEP-363856 group during the 7-day randomized withdrawal period in the physical dependence assessment ("PDA") population, assuming a non-inferiority margin of 4.71. max The following safety endpoints were also evaluated: the overall incidence, frequency, and severity of AEs; the incidence of withdrawal-related AEs, including but not limited to MedDRA queries: 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); and Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson-Angus Scale (SAS).

[0219] Other endpoints to be evaluated included:

[0220] · The occurrence of a clinically significant withdrawal syndrome during the 7-day randomized withdrawal period, defined as a CSSB in the total PWC-20 score

[0221] reaching at least 4.71 points (i.e., an increase of ≥4.71) max · The mean change in the total PWC-20 score relative to the steady-state baseline during the 7-day randomized withdrawal period

[0222] · The time to reach the maximum total PWC-20 score during the 7-day randomized withdrawal period

[0223] · The change in the total PANSS score and the scores of the positive, negative, and general psychopathology subscales relative to Day 36 during the 7-day randomized withdrawal period

[0224] · The change in the total CGI-S score relative to Day 36 during the 7-day randomized withdrawal period

[0225]

[0226] The original terms used by the investigator or designee to identify AEs in the case report form (CRF) were coded using the Medical Dictionary for Regulatory Activities (MedDRA; version 22.0 or higher). The overall summary of AEs included all AEs in subjects from receipt of SEP-363856 until 9 days after the last dose of SEP-363856. For the randomized withdrawal period, AEs were summarized by randomized treatment group from the start of the first dose of the study drug during the randomized withdrawal period or from the first dose of the study drug during the randomized withdrawal period until 9 days after the last dose of the study drug (SEP-363856 or placebo). AEs that occurred prior to the open-label period were considered "pre-treatment events" and reported separately.

[0227] ​Adverse events (AEs) were assigned to the treatment based on the time of occurrence relative to the last treatment administered before the onset of the AE. AEs were summarized by treatment and by MedDRA System Organ Class (SOC) and Preferred Term (PT). Lists of AEs and of deaths, serious adverse events (SAEs), or treatment-emergent adverse events (TEAEs) leading to discontinuation of the study drug were presented.

[0228] References

[0229] Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–676.

[0230] Cerovecki A, Musil R, Klimke A, Seemüller 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.

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[0232] Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry (2010) 25:12–21.

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[0234] Food and Drug Administration(U.S.).Patient-Focused Drug Development:Methods to Identify What Is Important to Patients Guidance for Industry,Foodand Drug Administration Staff,and Other Stakeholders(October 2019)(“FDA2019”)

[0235] Food and Drug Administration(U.S.).Patient-Focused Drug Development:Collecting Comprehensive and Representative Input;Guidance for Industry,Foodand Drug Administration Staff,and Other Stakeholders(June 2020)(“FDA2020”).

[0236] 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.

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[0238] 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.

[0239] Lerner A.Evaluation of Dependence and Withdrawal in Clinical TrialsandHuman Dependence Study-Design and Considerations.Session 2B:RegulatoryGuidelines and Methodological Approaches to Assess PrescriptionDrug Abuseand Misuse During CNS Drug Development.11th Annual InternationalSocietyfor CNS Clinical Trials and Methodology(ISCTM)ScientificMeetingWashington,DC February 18,2015.https: / / isctm.org / public_access / Feb2015 / Presentations / Lerner.pdf

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[0252] ********

[0253] Throughout this application, various publications are cited. The disclosures of these publications are hereby incorporated by reference in their entirety into this application to more fully describe the prior 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. By considering the specification and practicing the disclosure herein, other embodiments of the disclosure will be apparent to those skilled in the art. The specification and examples are to be considered as exemplary only, and the true scope and spirit of the disclosure are indicated by the following claims.

Claims

1. A method for treating neuropsychiatric disorders in human subjects in need thereof without significant physical dependence after cessation of treatment, comprising selecting a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof and administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time until administration is discontinued, whereby no significant physical dependence greater than that of a placebo occurs.

2. A method for treating neuropsychiatric disorders in human subjects in need thereof, which comprises: a. administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and b. abruptly discontinuing ulotaront administration after said effective period of time.

3. A method for treating neuropsychiatric disorders in human subjects in need thereof, which comprises: a. administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and b. after said effective period of time, discontinuing ulotaront administration and any drug therapy for said neuropsychiatric disorder.

4. A method for treating neuropsychiatric disorders in human subjects in need thereof, which comprises: a. administering to the subject a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof for an effective period of time, and b. discontinuing ulotaront administration after said effective period of time; wherein the subject is at risk of one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the subject has previously experienced one or more symptoms or syndromes of neuropsychiatric drug withdrawal, or the method occurs without the presence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

5. The method according to any one of claims 2-4, which is carried out in a human subject in need thereof without significant physical dependence upon cessation of treatment, whereby no significant physical dependence greater than that of a placebo occurs.

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

7. The method according to any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, said withdrawal-related adverse events including an increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20) of more than 4.

71.

8. The method according to any one of claims 1 to 4, wherein significant physical dependence is defined as the occurrence of withdrawal-related adverse events, said withdrawal-related adverse events being defined by the Regulatory Activities Dictionary of Medicine (MedDRA) query: drug withdrawal.

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

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

11. The method according to any one of claims 1 - 4, wherein the effective time period is a duration of ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, ≥ 12 weeks, ≥ 26 weeks, ≥ 1 year, or ≥ 2 years.

12. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient for the neuropsychiatric disorder to achieve a clinically significant improvement.

13. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder.

14. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder, as evidenced by not being diagnosed with the neuropsychiatric disorder under the criteria set forth in DSM-5.

15. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient for complete recovery from the neuropsychiatric disorder for a duration of ≥ 3 months, ≥ 6 months, ≥ 1 year, ≥ 18 months, or ≥ 2 years.

16. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the subject's neuropsychiatric disorder.

17. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the subject's neuropsychiatric disorder, as evidenced by the failure of a clinically significant improvement of the neuropsychiatric disorder.

18. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the subject's neuropsychiatric disorder, as evidenced by continued diagnosis of the neuropsychiatric disorder under the criteria set forth in DSM-5.

19. The method according to any one of claims 1 - 4, wherein the effective time period is sufficient to determine that ulotaront is ineffective for the subject's neuropsychiatric disorder, as evidenced by one or more of the following: a. Inadequate clinical response to acute symptoms despite dose optimization and sufficient treatment trial duration; b. Poor control of chronic symptoms and persistent dysfunction during maintenance therapy; c. Relapse despite adequate preventive or maintenance treatment for the neuropsychiatric disorder; and d. Certain symptoms of the neuropsychiatric disorder persist despite the use of an adequate dose of ulotaront.

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

21. The method according to claim 1 or any one of claims 3-4, wherein the discontinuation is a gradual reduction.

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

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

24. The method according to any one of claims 1-4, wherein the method occurs without the occurrence of one or more symptoms or syndromes of neuropsychiatric drug withdrawal.

25. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including a clinically significant increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20).

26. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including an increase in the total score of the 20-item Physician Withdrawal Checklist (PWC-20) of more than 4.

71.

27. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events being defined by querying the Standardized MedDRA Query (SMQ): Drug Withdrawal in the Medical Dictionary for Regulatory Activities (MedDRA).

28. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more symptoms of neuropsychiatric drug withdrawal selected from the following: somatic symptoms, mood symptoms, cognitive symptoms, fatigue symptoms, and gastrointestinal symptoms.

29. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more somatic symptoms of neuropsychiatric drug withdrawal selected from the following: (i) insomnia, (ii) sweating, (iii) tremor-shaking, (iv) headache, and (v) muscle pain or stiffness.

30. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more emotional symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anxiety - nervousness, (ii) irritability, (iii) dysphoric mood - depression, (iv) restlessness - agitation, and (v) inattention, memory difficulties.

31. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more cognitive symptoms of neuropsychiatric drug withdrawal selected from the following: (i) poor coordination, (ii) dizziness - light - headedness, (iii) increased acuity of sound, smell, touch, and (iv) depersonalization - derealization.

32. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more fatigue symptoms of neuropsychiatric drug withdrawal selected from the following: (i) fatigue - drowsiness - lack of energy, (ii) weakness, and (iii) paresthesia.

33. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more gastrointestinal symptoms of neuropsychiatric drug withdrawal selected from the following: (i) anorexia, (ii) nausea and vomiting, and (iii) diarrhea.

34. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more withdrawal symptoms of mild, moderate, or severe magnitude.

35. The method according to any one of claims 1 - 4, wherein the subject is at risk of withdrawal - related adverse events, or the subject has previously experienced withdrawal - related adverse events, or the method occurs in the absence of withdrawal - related adverse events, and the withdrawal - related adverse events include one or more syndromes of neuropsychiatric drug withdrawal selected from the following: a. Cholinergic syndrome, manifested as one or more of nausea, vomiting, headache, restlessness, anxiety, insomnia, fatigue, discomfort, myalgia, sweating, rhinitis, paresthesia, and diarrhea; b. Dopaminergic syndrome, manifested as one or more of withdrawal movement dysfunction, akathisia, dystonia, tardive movement dysfunction; and c. Rebound psychosis, manifested as one or more of psychosis, delusions, hallucinations, and catatonia at a level higher than before treatment.

36. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events are selected from cholinergic withdrawal symptoms, dopaminergic withdrawal symptoms (nigrostriatal), serotonergic withdrawal symptoms, histaminergic withdrawal symptoms, dopaminergic withdrawal symptoms (mesolimbic or striatal), and adrenergic withdrawal symptoms.

37. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include cholinergic withdrawal symptoms selected from the following: restlessness, insomnia, anxiety or depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal colic, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion or disorientation, hypothermia, and sweating.

38. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include dopaminergic withdrawal symptoms (nigrostriatal) selected from the following: withdrawal movement dysfunction, parkinsonism, neuroleptic malignant syndrome, and akathisia.

39. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include serotonergic withdrawal symptoms selected from the following: flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensations, anxiety, restlessness, low mood, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and decreased concentration.

40. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs without the occurrence of withdrawal-related adverse events, and the withdrawal-related adverse events include histaminergic withdrawal symptoms selected from the following: irritability, insomnia, restlessness, depressive affect, anorexia or nausea, tremors, ataxia, and drowsiness or amnesia.

41. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs in the absence of withdrawal-related adverse events, the withdrawal-related adverse events including dopaminergic withdrawal symptoms (mesolimbic or striatal) selected from the following: auditory hallucinations, persecutory delusions, and other psychotic symptoms.

42. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs in the absence of withdrawal-related adverse events, the withdrawal-related adverse events including adrenergic withdrawal symptoms selected from the following: headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating.

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

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

45. The method according to any one of claims 1-4, wherein the method occurs in the absence of withdrawal-related adverse events.

46. The method according to any one of claims 1-4, wherein the subject is at risk of withdrawal-related adverse events, or the subject has previously experienced withdrawal-related adverse events, or the method occurs in the absence of withdrawal-related adverse events, the withdrawal-related adverse events including one or more withdrawal symptoms of mild, moderate, or severe magnitude.

47. The method according to any one of claims 1-4, which comprises stopping the administration of ulotaront and any drug therapy for the neuropsychiatric disorder after the effective period, for a period of ≥ 3 months, ≥ 6 months, ≥ 1 year, ≥ 18 months, or ≥ 2 years.

48. The method according to any one of claims 1-4, wherein the therapeutically effective amount is 25-150 mg / day, or 25-100 mg / day, or 50-125 mg / day, or 50-100 mg / day, administered orally.

49. The method according to any one of claims 1-4, 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, administered orally.

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

51. The method according to any one of claims 1-4, wherein the ulotaront is administered as the hydrochloride salt.

52. The method according to any one of claims 1-4, wherein the neuropsychiatric disorder is selected from schizophrenia, schizophrenic spectrum disorder, acute schizophrenia, chronic schizophrenia, schizophrenia NOS, schizotypal personality disorder, schizoid personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), psychoemotional disorder, aggression, delirium, Parkinson's psychosis, excitatory psychosis, Tourette syndrome, organic or NOS psychosis, seizures, agitation, post-traumatic stress disorder, behavioral disorder, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, movement disorder, Huntington's disease, dementia, mood disorder, anxiety, affective disorder (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar affective disorder, e.g., bipolar depressive disorder; manic disorder; seasonal affective disorder; and attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)), obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g., neuropathic pain, sensitization accompanying neuropathic pain, and inflammatory pain), fibromyalgia, migraine, cognitive disorder, movement disorder, restless legs syndrome (RLS), multiple sclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jet lag, drowsy side effects of drugs, insomnia, substance abuse or dependence (e.g., nicotine, cocaine), addiction, eating disorder, sexual dysfunction, hypertension, vomiting, Lesche-Nyhane disease, Wilson's disease, autism, Huntington's chorea, and premenstrual dysphoria.

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

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

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

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

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