Methods of transforming neuropsychiatric drugs using ulotaront

Abstract

Neuropsychiatric treatments that include methods and regimens for the administration of a transition neuropsychiatric drug based on ulotaront.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 383,774, filed on November 15, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present disclosure relates to neuropsychiatric drugs, as well as methods and regimens for switching drugs based on ulotaront administration. Background art

[0004] Neuropsychiatric drugs (especially antipsychotics) are first - line drugs for managing schizophrenia and related disorders. As with other chronic diseases, clinicians often must decide whether to switch a patient's current medication to attempt to improve treatment response, or reduce intolerable side effects and improve quality of life and function. Antipsychotic agents are generally classified into typical antipsychotics and atypical antipsychotics. Atypical antipsychotics differ from typical antipsychotics in that atypical antipsychotics have an increased binding effect on the 5 - HT2a receptor and the degree and reversibility of binding to the D2 receptor.

[0005] In the treatment of schizophrenia, switching between antipsychotic drugs is common when doctors seek a satisfactory treatment, but such switching has been shown to be associated with poorer clinical and economic outcomes (Faries 2009). There can be many reasons for switching antipsychotic treatment, including dissatisfaction with the current treatment, harmful side effects, co - morbid physical and psychiatric conditions, and patient requests. Clinically reasonable switching can provide benefits by enhancing treatment effectiveness, tolerance, and overall patient acceptance (Weiden 2003). Studies have shown that up to one - third of outpatient patients with schizophrenia in the United States switch antipsychotic therapy within a year (Weiden 2006, Buckley 2007). According to most evidence - based criteria (Kinon 2000), a successful switching paradigm involves gradually discontinuing the original antipsychotic drug when starting a new treatment. Individual patient characteristics, as well as the binding curve and dose level of the original antipsychotic, can affect the appropriate duration for successful discontinuation (Buckley 2007; Cerovecki 2013; Takeuchi 2018).

[0006] During conversion, patients often experience adverse events. These events are typically due to the complex pharmacology of neuropsychiatric drugs and their targeting of various receptor subtypes with different degrees of affinity (e.g., D2, 5-HT2A, M1, α1, H1). For example, conversion from a low-affinity D2 antagonist to a high-affinity D2 antagonist (e.g., from quetiapine to haloperidol) can result in movement disorders, parkinsonism, akathisia, and acute dystonia. Conversely, when converting from a high-affinity D2 antagonist to a low-affinity D2 antagonist, patients may experience breakthrough psychosis, withdrawal movement disorders, and akathisia. Other examples can be cited. See, e.g., Ostuzzi 2022, Ayyagari 2020, Fulone 2021.

[0007] Several techniques are used to switch between different conventional antipsychotics. One conversion method involves cross-titration, in which the dose of an atypical or typical antipsychotic is gradually reduced while the dose of the replacement antipsychotic is gradually increased to the therapeutic dose. A second method is to continue administering the dose of the typical or typical antipsychotic while slowly titrating the dose of the replacement antipsychotic to near the therapeutic dose, then gradually reducing and finally stopping the administration of the first antipsychotic agent, and then titrating the final dose of the replacement antipsychotic to the therapeutic dose. Both of these techniques have been used to switch between different conventional antipsychotics. For cross-titration, conversion between different conventional antipsychotic selections for cross-titration is difficult due to the different pharmacokinetics between antipsychotic agents. For the second method, there will be significant overlap between the two antipsychotics, and there may be adverse reactions during conversion. In addition, there is a risk that the planned discontinuation of the first antipsychotic may not occur or that the second antipsychotic does not reach the therapeutic dose. One technique is to switch directly from one conventional antipsychotic to another, but this can result in drug interactions and withdrawal symptoms. This technique can be used when both antipsychotics have a long half-life and no anticholinergic effects. In the case of the first two techniques, the conversion may take several months, which can lead to compliance problems in patients, and the compliance problems can lead to inadequate psychiatric treatment or adverse reactions. (Stahl 2020)

[0008] A new neuropsychiatric drug (ulotaront) that has been shown to improve psychotic symptoms in schizophrenia has a mode of action different from that of conventional antipsychotics of current classes, as it does not involve binding at the D2 receptor, but its mode of action relies primarily on its trace amine-associated receptor 1 (TAAR1) agonist activity. Unlike conventional antipsychotics of current classes, ulotaront does not significantly interact with receptors known to confer side effects of atypical antipsychotics (such as D2, α1, M1, H1, 5-HT2c). Each conventional antipsychotic binds to other receptors in addition to binding to the D2 receptor, and each receptor has its own unique binding curve.

[0009] There is a need for methods of converting patients from conventional antipsychotics to a new class of drugs including ulotaront and its pharmaceutically acceptable salts to provide more effective and / or tolerable long-term treatment, where adverse events from the conversion are minimized or potentially eliminated.

[0010] There is also a strong need for more clinical research on this subject and for additional resources and drugs to assist clinicians in implementing optimal conversion strategies that are both safe and efficacious. Summary of the Invention

[0011] In one embodiment, the present disclosure provides a method of converting a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or its pharmaceutically acceptable salt (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or its pharmaceutically acceptable salt (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0012] In another embodiment, the present disclosure provides a method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising: (a) administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0013] In another embodiment, the present disclosure provides a method for switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose, and wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0014] In another embodiment, the present disclosure provides a method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising: (a) administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the first ulotaront transition dose is optionally less than the final ulotaront dose, and (ii) the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0015] In another embodiment, the present disclosure provides a method for switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first NM transition dose is the same as the therapeutic NM dose and the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0016] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein: (i) the first NM transition dose is the same as the therapeutic NM dose, and (ii) the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0017] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein: (i) the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; (ii) the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0018] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; (ii) the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period).

[0019] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug affects a target receptor of the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period).

[0020] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug affects a target receptor of the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0021] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug produces one or more adverse events in the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0022] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug produces one or more adverse events in the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0023] Additional advantages of the present disclosure are set forth in part in the description below, 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 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 claimed disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a schematic timeline illustrating the study design reported in Example 2.

[0025] Figure 2 is a schematic timeline illustrating the study design reported in Example 3. DETAILED DESCRIPTION

[0026] All published literature cited herein is hereby incorporated by reference in its entirety.

[0027] USE OF TERMS

[0028] 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.

[0029] 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.

[0030] As used in this specification and in the claims that follow, 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 is 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.

[0031] When ranges are given by separately specifying a lower end and an upper end of the range, or by specifying a particular numerical value, it is understood that ranges can 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 is understood that both endpoints are included within the range. However, it should also be understood that a from / to range also includes embodiments in which the range is defined as being between two specified endpoints, and the term "between" can be substituted for the from / to language to omit the endpoints from the range.

[0032] This 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 this disclosure include treating various disorders, patient populations, dosage forms administered, various doses, minimization of various adverse events, and improvement of various efficacy measurements, etc. Any combination of the various embodiments is within the scope of this disclosure.

[0033] When reference is made herein to published test methods and diagnostic tools, it is 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.

[0034] 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.

[0035] Definitions

[0036] 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).

[0037] "AE" or "adverse event" means any untoward medical event associated with the use of a drug in humans, whether or not 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 administration of a medicinal (investigational) product, whether or not 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, "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, "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, "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."

[0038] 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 typically 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.

[0039] When drug treatment is said to occur without causing adverse events or symptoms or syndromes of drug withdrawal, it is understood to refer only to physical dependence, adverse events, or symptoms or syndromes of drug withdrawal that are considered 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.

[0040] The "AIMS" (Abnormal Involuntary Movement Scale) assessment consists of 10 items that describe symptoms of movement dysfunction. 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). (Guy 1976; Munetz 1988)

[0041] As used herein, an "at-risk" individual is one who is at risk of developing a disorder to be treated or an adverse event to be prevented. This can be shown, 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 carried out in patients at risk of an adverse event.

[0042] 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, where a score of 0 represents no symptoms, and a score of 3 represents 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. (Barnes 1989; Barnes 2003).

[0043] The "BNSS" (Brief Negative Symptom Scale) is a rating scale used to measure the current level of severity of negative symptoms in schizophrenia and schizoaffective disorder (Kirkpatrick 2011). The measurement consists of 13 individual items and 6 subscale scores (affective flattening, alogia, avolition, anhedonia, asociality, and distress). The 6 subscale scores provide a total score, and the 13 individual items provide a composite total score (ranging from 0 to 78). Each item is rated on a Likert-type 7-point scale on a 0-6 scale, where a value of 0 indicates no symptoms, and a value of 6 indicates the symptom in severe form. The number of items in each subscale varies.

[0044] "CGI-I" (Clinical Global Impression - Improvement Scale) is a standard 7-point scale (Guy - 1976) that requires clinicians to assess how much the overall symptoms of a subject have improved or worsened relative to their baseline state.

[0045] "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 severe is the patient's mental illness at this time?" Response options include: 1 = Normal, no illness 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.

[0046] As used herein, a "clinically significant" or "clinically meaningful" improvement can refer to a statistically significant improvement and an improvement that is 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-I), 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.

[0047] "C-SSRS" (Columbia Suicide Severity Rating Scale) is a tool designed to systematically assess and track adverse suicide events (suicidal behavior and suicidal ideation). The strength of this suicide classification system is its ability to comprehensively identify suicide events while limiting over-identification of suicidal behavior. The scale takes approximately 5 minutes to administer (Posner - 2007).

[0048] As used herein, the "development" of a "delayed" disorder refers to delaying, hindering, slowing, stabilizing, and / or retarding the development of the disorder. The delay can have different time lengths, depending on the disease history and / or the individual being treated.

[0049] "DSM-5" refers to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Terms used herein may be defined by reference to DSM-5 as necessary to give life and meaning to the term. When a person is defined or diagnosed 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 that if so diagnosed, the person would meet the criteria set forth in DSM-5.

[0050] Healthcare resource utilization (HCRU) is the quantification or description of the use of services by people for the purpose of preventing and treating health problems, promoting the maintenance of health and well-being, or obtaining information about an individual's health status and prognosis. HCRU includes questions about the number of physician office visits, emergency room (ER) visits, hospitalizations, and the length of hospitalization during the past 1-month period for any reason and due to care.

[0051] The Medication Satisfaction Questionnaire (MSQ) is a single-item, patient-rated questionnaire that asks subjects to rate their satisfaction with their current antipsychotic medication (taking an antipsychotic at screening or within 30 days of screening) using a 7-point Likert-type scale (Vernon 2010). Subjects are asked the following question: "Overall, how satisfied are you with your current medication?" Subjects select 1 of 7 potential responses based on their level of satisfaction (ranging from (1) very dissatisfied to (7) very satisfied).

[0052] The term "neuropsychiatric drug" refers to any drug with neuropsychiatric activity. One class of neuropsychiatric drugs is typical and atypical antipsychotics. Thus, whenever the term "neuropsychiatric drug" is used in this document, it may be replaced with the term "typical or atypical antipsychotic".

[0053] "PANSS" (Positive and Negative Syndrome Scale) is an interview-based measure of the severity of psychopathology in adults with psychotic disorders. The measure consists of 30 items and 3 subscales as follows: The positive subscale assesses hallucinations, delusions, and related symptoms; the negative subscale assesses emotional withdrawal, lack of motivation, and similar symptoms; and the general psychopathology subscale addresses other symptoms such as anxiety, somatic concerns, and disorientation. Each item is scored using a 1-7 anchored Likert scale, where values of 2 and above indicate the presence of increasingly severe symptoms. (Kay-1994, Opler-1992; Perkins-2000).

[0054] "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.

[0055] 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.

[0056] Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed by the amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed by the amino group with 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, gluconates, 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 that is not pharmaceutically desirable, such as iodide, oxalate, trifluoromethanesulfonate, etc.

[0057] 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, polymer matrix system, and polishing agent that has been approved by or otherwise accepted by the U.S. Food and Drug Administration for use in humans or livestock under appropriate qualifications.

[0058] The "PSP" (Personal and Social Performance) scale is a 100-point single-item scale for the assessment of personal and social functioning (Morosini 2000). This assessment is based on the evaluation of the patient's functioning in four domains: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disruptive and aggressive behavior. Higher scores indicate better functioning. Scores of 0 - 30 indicate poor functioning; scores of 31 - 70 indicate varying degrees of difficulty; and scores of 71 - 100 reflect at most only mild difficulties.

[0059] The "PSQI" (Pittsburgh Sleep Quality Index) consists of 19 self-rated questions and 5 questions rated by a bed partner or roommate (if one is present). Only the self-rated questions are included in the scoring. The 19 self-rated items are combined to form 7 "component" scores, each ranging from 0 to 3. In all cases, a score of "0" indicates no difficulty, while a score of "3" indicates severe difficulty. The scores of the 7 components are then added together to obtain an overall score ranging from 0 to 21, with a score of "0" indicating no difficulty and a score of "21" indicating severe difficulty in all domains.

[0060] As used herein, "prevention" or "preventing" or "prevents" refers to a program 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.

[0061] As used herein, the term "a reduced risk of" (or "reduces the risk of") refers to a decrease in the incidence and / or severity of an adverse event or disorder symptoms in a subject.

[0062] 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 of all 10 items.

[0063] The term "selection" refers to the act of choosing from numbers or groups based on fitness or preference. In the context of the present disclosure, ulotaront is selected from a group of commonly recognized neuropsychiatric drugs for the treatment of any neuropsychiatric disorder described herein.

[0064] "SF 12" (12-Item Short Form Survey) is a 12-item self-reported questionnaire that is a subset of the SF 36 Health Survey. This survey covers physical and mental health. There are 8 subscales, including: physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health. Responses are reported on a 3- or 5-point Likert scale depending on the question. SF-12 uses 2 items each to assess the scores of 4 out of 8 health concepts (physical function, role physical, role emotional, and mental health). The scores of the remaining 4 health concepts (bodily pain, general health, vitality, and social function) are each assessed using 1 item. The Physical Component Summary (PCS-12) and Mental Component Summary (MCS-12) are calculated using the scores of the 12 questions and range from 0 to 100, where a score of zero represents the lowest level of health measured by the scale and 100 represents the highest level of health.

[0065] "SF-36" (36-Item Short Form Questionnaire) is a self-reported questionnaire with a standard recall period of 4 weeks that measures 2 broad domains (physical and mental composites) across 8 health domain scales of general health-related quality of life: physical function, pain, role physical, general health, vitality / fatigue, social function, role emotional, and mental health. SF-36 uses norm-based scoring to generate scores on a scale of 0 to 100, where lower scores for the Physical Component Summary and Mental Component Summary represent a lower health-related quality of life, and a score of 50 refers to norm data derived from surveys of a representative sample of the general population in the United States.

[0066] As used herein, the term "significantly" refers to the 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 specified, when the terms "significant", "significantly", or other variants of the term are used, the level of statistical significance is p < 0.05. When measurable results or effects are expressed or identified herein, it should be understood that the results or effects are preferably evaluated based on their statistical significance relative to a baseline (e.g., placebo). In a similar manner, when treatments or benefits are described herein, it should be understood that the treatments or benefits preferably demonstrate efficacy to a statistically significant degree in a patient population.

[0067] The Structured Clinical Interview for DSM-5 Axis I Disorders - Clinical Trials Version (SCID-5-CT) is a modified version of the SCID developed for use in clinical trials. This is a semi-structured interview aimed at making DSM-5 diagnoses (First 2015).

[0068] As used herein, "subject" or "patient" 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)), 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.

[0069] As used herein, "tapering" refers to the period in the methods of the present disclosure during which a subject transitions from a neuropsychiatric medication to ulotaront, and is coextensive with the period of coadministration of the neuropsychiatric medication and ulotaront. This term is also used when referring to the administration of an ulotaront dose (i.e., the first ulotaront dose) during the tapering period, as well as the administration of a neuropsychiatric medication dose (i.e., the first NM dose) during the tapering period. When used to describe doses, the use of the term tapering should not imply whether the ulotaront dose increases or decreases or remains constant during the tapering period, or whether the neuropsychiatric medication dose increases or decreases or remains constant. Additionally, when it is claimed that two medications are administered at specified doses during the tapering period, it should not be implied whether the two medications are administered simultaneously at their specified doses or in what order. The tapering period immediately follows the "first treatment period" (i.e., the period during which only the neuropsychiatric medication is administered).

[0070] 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, as well as 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 realized in combination with one or more other agents. Due to the combined action (additive or synergistic) of the compounds, the appropriate dose of any coadministered compound may optionally be reduced. By definition, a dose administered during the "therapeutic validity period" is a "therapeutically effective amount".

[0071] 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, a therapeutic benefit. In some embodiments, treatment is administered after the appearance 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 predisposing factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0072] A therapeutic benefit includes 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, even though the subject may still be afflicted with the underlying disorder.

[0073] 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 reducing the severity of the disorder); (b) slowing or arresting 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., causing clinical symptoms to resolve, improving the disorder, delaying the progression of the disorder, and / or improving quality of life).

[0074] As mentioned herein, "Ulotaront" (also known as SEP-363856, SEP-363856, SEP-856) for use in the methods of the present disclosure 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:

[0075]

[0076] 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 specifically intended to be any other form or salt, this will be stated explicitly.

[0077] 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.

[0078] Also provided herein are pharmaceutical compositions and dosage forms that comprise ulotaront or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt can be administered as part of a pharmaceutical composition as described herein.

[0079] Discussion

[0080] In one embodiment, the present disclosure provides a method of switching a human subject being treated with a dose of a neuropsychiatric drug (treatment NM dose) for a neuropsychiatric disorder during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or its pharmaceutically acceptable salt (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or its pharmaceutically acceptable salt (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0081] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0082] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose, and wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0083] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the first ulotaront transition dose is optionally less than the final ulotaront dose, and (ii) the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0084] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first NM transition dose is the same as the therapeutic NM dose and the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0085] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the first NM transition dose is the same as the therapeutic NM dose, and (ii) the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0086] In another embodiment, the present disclosure provides a method of switching a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0087] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein: (i) the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0088] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein: (i) the neuropsychiatric drug affects a target receptor of the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuing a drug that affects the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuing a drug that affects the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0089] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug affects a target receptor of the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0090] In another embodiment, the present disclosure provides a method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: (a) administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (b) after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug produces one or more adverse events in the subject; and (ii) the ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0091] 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 therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) during a first treatment period; (b) after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and (c) after the transition period, administering a final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: (i) the neuropsychiatric drug produces one or more adverse events in the subject; and (ii) ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0092] In some embodiments of the present disclosure, (a) the neuropsychiatric disorder is schizophrenia; (b) the neuropsychiatric drug fails to improve the PANSS score of the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject.

[0093] In other embodiments: (a) the neuropsychiatric drug fails to improve the PANSS score of the subject to a clinically significant extent; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject to a clinically significant extent.

[0094] In various embodiments, prior to the initiation of ulotaront administration, the subject has a PANSS score ≤80, and optionally ≥30, 34, 38, 42, 46, 50, 54, 58, 62, 66, or 70. In a further embodiment, the neuropsychiatric drug fails to improve the PANSS score of the subject by ≥10, 14, 18, 22, 26, or 30 points (constituting a lack of clinically significant improvement). In yet a further embodiment, after the initiation of ulotaront administration, the subject's PANSS score improves by ≥14, 18, 22, 26, 30, 34, 38, 42, 46, or 50 points on an absolute basis (constituting a clinically significant improvement). Alternatively, "clinically significant improvement" may refer to an improvement in the PANSS score of at least 20% or at least 30%.

[0095] In some embodiments, (a) during administration of a neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in a subject; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0096] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms selected from negative symptoms, positive symptoms, disorganized symptoms, hostile symptoms, and depressive / anxiety symptoms; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0097] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, negative symptoms persist or worsen in the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0098] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, positive symptoms persist or worsen in the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0099] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, disorganized symptoms persist or worsen in the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0100] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, hostile symptoms persist or worsen in the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0101] In other embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, depressive / anxiety symptoms persist or worsen in the subject; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0102] In some embodiments, (a) the neuropsychiatric disorder is schizophrenia; (b) during administration of a neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms selected from: delusions, suspiciousness / persecution, hallucinatory behavior, grandiosity, conceptual disorganization, poor attention, volitional disturbances, lack of judgment and insight, peculiar habits and postures, stereotyped thinking, unusual thought content, preoccupations, difficulty with abstract thinking, disorientation, anxiety, tension, guilt feelings, depression, somatic concerns, hostility, noncooperativeness, poor impulse control, excitability, affective withdrawal, negative / apathetic social withdrawal, active social avoidance, lack of spontaneity and conversational flow, poor rapport, blunted affect, and psychomotor retardation; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0103] In some embodiments, (a) the neuropsychiatric disorder is depression; (b) during administration of a neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms selected from: apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, anhedonia, pessimistic thoughts, and suicidal thoughts; and (c) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

[0104] In some embodiments, ulotaront is used to treat anxiety, the anxiety including panic disorder, generalized anxiety disorder, social anxiety disorder, agoraphobia, and specific phobia, and the symptoms of anxiety selected from the following: anxious mood, tension, fear, insomnia, intellectual, depressive mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and anxious behavior. If these symptoms in the subject persist or worsen during administration of a neuropsychiatric drug, then it is translated that ulotaront improves one or more of the persistent or worsening symptoms in the subject.

[0105] In some embodiments, ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in a subject.

[0106] In some embodiments, (a) nicotine use increases during administration of a neuropsychiatric drug; and (b) ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in a subject.

[0107] In some embodiments, (a) during administration of a neuropsychiatric drug, the functional level of a subject deteriorates; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of the subject.

[0108] In some embodiments, ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of a subject to a clinically significant degree.

[0109] In some embodiments of the present disclosure, (a) one or more adverse events occur in a subject during administration of a neuropsychiatric drug; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the adverse events in the subject. In some embodiments, the adverse events are selected from: (a) abnormal involuntary movements, as measured by the AIMS (Abnormal Involuntary Movement Scale); or (b) akathisia, preferably as measured by the BARS (Barnes Akathisia Rating Scale); or (c) suicidal tendency, preferably as measured by the C-SSRS (Columbia Suicide Severity Rating Scale); or (d) parkinsonism, preferably as measured by the SAS (Simpson-Angus Scale); or (e) sleep quality, preferably as measured by the PSQI (Pittsburgh Sleep Quality Index).

[0110] In still further embodiments, the adverse events are selected from akathisia, abnormal blood prolactin, elevated blood prolactin, elevated blood triglycerides, elevated body mass index, bradykinesia, bruxism, cogwheel rigidity, dermatillomania, diabetes, drooling, dyskinesia, dyslipidemia, sleep disorder, dystonia, electrocardiogram QT prolongation, enuresis, excessive blinking, extrapyramidal disorder, galactorrhea, impaired glucose tolerance, glycosuria, hyperkinesia, hyperprolactinemia, impaired fasting glucose, increased appetite, metabolic syndrome, muscle rigidity, neck rigidity, obesity, obsessive-compulsive disorder, oculogyric crisis, oromandibular dystonia, orthostatic hypertension, overweight, chronic pancreatitis, parkinsonian gait, parkinsonism, psychomotor retardation, restless legs syndrome, restlessness, excessive salivation, sedation, sexual dysfunction, tardive dyskinesia, tic, tongue biting, tongue spasm, torticollis, type 2 diabetes, and weight gain.

[0111] In some embodiments, during and / or after a transition period, the subject experiences a reduced risk of clinically significant withdrawal adverse events or does not experience clinically significant withdrawal adverse events, the withdrawal adverse events being selected from: cholinergic withdrawal adverse events, dopaminergic withdrawal adverse events (nigrostriatal), dopaminergic withdrawal adverse events (mesolimbic or striatal), serotonergic withdrawal adverse events, histaminergic withdrawal adverse events, and adrenergic withdrawal adverse events.

[0112] In some embodiments, the neuropsychiatric drug is a cholinergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing cholinergic withdrawal adverse events or does not experience cholinergic withdrawal adverse events. In other words, ulotaront reduces the risk of one or more cholinergic withdrawal adverse events or prevents one or more cholinergic withdrawal adverse events. Cholinergic withdrawal adverse events can be selected from 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, among others.

[0113] In some embodiments, the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (nigrostriatal) or does not experience dopaminergic withdrawal adverse events (nigrostriatal). In other words, ulotaront reduces the risk of one or more dopaminergic withdrawal adverse events (nigrostriatal) or prevents one or more dopaminergic withdrawal adverse events (nigrostriatal). Dopaminergic withdrawal adverse events (nigrostriatal) can be selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia, among others.

[0114] In some embodiments, the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (mesolimbic or striatal) or does not experience dopaminergic withdrawal adverse events (mesolimbic or striatal). In other words, ulotaront reduces the risk of one or more dopaminergic withdrawal adverse events (mesolimbic or striatal) or prevents one or more dopaminergic withdrawal adverse events (mesolimbic or striatal). Dopaminergic withdrawal adverse events (mesolimbic or striatal) can be selected from auditory hallucinations, persecutory delusions, and other psychotic symptoms, among others.

[0115] In some embodiments, the neuropsychiatric drug is a serotonergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing serotonergic withdrawal adverse events or does not experience serotonergic withdrawal adverse events. In other words, ulotaront reduces the risk of one or more serotonergic withdrawal adverse events or prevents one or more serotonergic withdrawal adverse events. Serotonergic withdrawal adverse events can be selected from flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, electric shock sensations, anxiety, agitation, depression, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and reduced concentration, among others.

[0116] In some embodiments, the neuropsychiatric drug is a histaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing histaminergic withdrawal adverse events or does not experience histaminergic withdrawal adverse events. In other words, ulotaront reduces the risk of one or more histaminergic withdrawal adverse events or prevents one or more histaminergic withdrawal adverse events. Histaminergic withdrawal adverse events can be selected from irritability, insomnia, restlessness, dysphoria, anorexia or nausea, tremors, ataxia, and drowsiness or amnesia, etc.

[0117] In some embodiments, the neuropsychiatric drug is an adrenergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing adrenergic withdrawal adverse events or does not experience adrenergic withdrawal adverse events. In other words, ulotaront reduces the risk of one or more adrenergic withdrawal adverse events or prevents one or more adrenergic withdrawal adverse events. Adrenergic withdrawal adverse events can be selected from headache, anxiety or restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremors, and sweating, etc.

[0118] In any embodiment of the present disclosure, ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the disorder. In a further embodiment of the present disclosure, (a) the neuropsychiatric drug fails to produce a clinically significant improvement in the neuropsychiatric disorder; and (b) ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the neuropsychiatric disorder.

[0119] In any embodiment of the present disclosure, ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in one or more symptoms of the disorder. In a further embodiment, (a) the neuropsychiatric drug fails to produce a clinically significant improvement in the symptoms; and (b) ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the symptoms.

[0120] In any embodiment of the present disclosure in which a subject experiences one or more adverse events in response to a neuropsychiatric drug, ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the adverse event. In a further embodiment, (a) the neuropsychiatric drug produces a clinically significant adverse event profile; and (b) ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the adverse event profile. In a further embodiment, (a) the neuropsychiatric drug produces one or more moderate or severe adverse events; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves one or more moderate or severe adverse events. In yet a further embodiment, (a) the neuropsychiatric drug produces one or more severe adverse events; and (b) ulotaront or a pharmaceutically acceptable salt thereof improves one or more severe adverse events.

[0121] A variety of drugs can be used as neuropsychiatric drugs. In one embodiment, the neuropsychiatric drug is a D2 receptor antagonist (i.e., a conventional antipsychotic). In one embodiment, the neuropsychiatric drug is selected from cholinergic drugs, dopaminergic drugs, serotonergic drugs, histaminergic drugs, and adrenergic drugs. In another embodiment, the neuropsychiatric drug is a typical antipsychotic selected from the following: acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyanopromazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, loxapine, mesoridazine, metitepine, molindone, mopidone, oxyphenbutazone, oxyprothepine, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, pizotifen, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulfadiazine, thiopropazate, thioridazine, tiotixene, timiperone, trifluoperazine, trifluoroperidol, triflupromazine, and zuclopenthixol. In yet a further embodiment, the neuropsychiatric drug is an atypical antipsychotic selected from the following: amoxapine, amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, carpipramine, clocapramine, clothiapine, clozapine, iloperidone, levosulpiride, lumateperone, lurasidone, mepiprazole, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine.

[0122] The transition period (i.e., the period during the concurrent administration of ulotaront and a neuropsychiatric drug) can last for any period of time that the attending physician deems appropriate for reducing adverse reactions or enhancing efficacy when switching between drugs. The transition period will typically last 2 to 26 weeks, 2 to 8 weeks, 2 to 6 weeks, 2 to 5 weeks, 2 to 4 weeks, 2 to 3 weeks, or 1 week. In some embodiments, the transition period lasts no more than 6 weeks.

[0123] Various transition regimens can also be employed. In one embodiment, the dose of the neuropsychiatric drug can be decreased suddenly or gradually by one or more stepwise dose reductions. In another embodiment, the dose of ulotaront or a pharmaceutically acceptable salt thereof can be suddenly increased by one or more stepwise dose increases.

[0124] Preferably, ulotaront or a pharmaceutically acceptable salt is titrated as follows: administer 50 mg / day for days 1 - 3 of the first week of the transition period, and administer 75 mg / day for days 4 - 7 of the first week of the transition period, then administer an adjusted dose of 50 - 100 mg / day (e.g., 50 mg / day, 75 mg / day, or 100 mg / day) for the remainder of the transition period, which preferably lasts for a length of 2 - 6 weeks. The adjusted dose may or may not be equal to the final ulotaront dose administered during the treatment effective period. The first NM transition dose is preferably maintained at the treatment NM dose during the first week of the transition period, and is decreased starting from day 1 of the second week, and is eliminated at the end of the transition period (which is also preferably 2 - 6 weeks after the start of the transition period).

[0125] In some embodiments, the first NM transition dose is the same as the treatment NM dose.

[0126] In some embodiments, the transition period is 2 to 6 weeks, during at least the first week of the transition period, the first NM transition dose is the same as the treatment NM dose, and a second transition dose (second NM transition dose) of the neuropsychiatric drug that is less than the first NM transition dose is administered during the remainder of the transition period.

[0127] In other embodiments, the transition period is 2 - 6 weeks, during the first week of the transition period, the first NM transition dose is the same as the treatment NM dose, and a second transition dose (second NM transition dose) of the neuropsychiatric drug that is less than the first NM transition dose is administered starting from week 2 and continuing for the remaining 2 - 6 weeks of the transition period.

[0128] In some embodiments, the neuropsychiatric drug has a strong binding affinity for muscarinic-cholinergic (M1) and / or histaminergic (H1) receptors, wherein the transition period lasts 4 - 6 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for the remaining 3 - 5 weeks of the transition period.

[0129] In some embodiments, the neuropsychiatric drug is selected from asenapine, olanzapine, and quetiapine, wherein the transition period is 4 - 6 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for the remaining 3 - 5 weeks.

[0130] In some embodiments, the neuropsychiatric drug has a strong binding affinity for dopaminergic receptors, wherein the transition period lasts 3 - 5 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 2 - 4 weeks.

[0131] In some embodiments, the neuropsychiatric drug is selected from lurasidone, paliperidone, risperidone, ziprasidone, haloperidol, and other typical antipsychotics, wherein the transition period lasts 3 - 5 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 2 - 4 weeks.

[0132] In some embodiments, the neuropsychiatric drug has a long half-life, wherein the transition period lasts 2 - 4 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 1 - 3 weeks.

[0133] In some embodiments, the neuropsychiatric drug is selected from aripiprazole, brexpiprazole, and cariprazine, wherein the transition period lasts 2 - 4 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 1 - 3 weeks.

[0134] In some embodiments, the therapeutic NM dose is at the upper limit of the recommended daily dose range, the transition period lasts 4 - 6 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 3 - 5 weeks.

[0135] In some embodiments, the neuropsychiatric drug is a D2 antagonist, and the first treatment period exceeds 6 months, 1 year, 2 years, 3 years, or 5 years, the transition period lasts 4 - 6 weeks, a first NM transition dose is administered for 1 week, and a second NM transition dose is administered for 3 - 5 weeks.

[0136] In one embodiment, the first ulotaront transition dose is less than the final ulotaront dose.

[0137] In some embodiments, the first ulotaront transition dose is less than the final ulotaront dose and further comprises administering a second dose of ulotaront or a pharmaceutically acceptable salt thereof (second ulotaront transition dose) during the transition period, the second dose being greater than the first ulotaront transition dose and optionally the same as the final ulotaront dose.

[0138] In other embodiments, the transition period is 2 - 6 weeks, the first ulotaront transition dose is administered during days 1 - 3 of the transition period, the second ulotaront transition dose is administered during days 4 - 7 of the transition period, and optionally a third ulotaront transition dose equal to the final ulotaront dose is administered during the remainder of the transition period.

[0139] In further embodiments, the first ulotaront transition dose is 50 mg / day, the second ulotaront transition dose is 75 mg / day, and the final ulotaront dose is 50 - 100 mg / day.

[0140] In one embodiment, the treatment NM dose is greater than the first NM transition dose. In other embodiments, the treatment NM dose is the same as the first NM transition dose. In other embodiments, the treatment NM dose is the same as the first NM transition dose and further comprises administering a second transition dose of a neuropsychiatric drug during the transition period, the second transition dose being less than the treatment NM dose and the first NM transition dose. In another embodiment, the first ulotaront transition dose is the same as the final ulotaront dose. In other embodiments, the first ulotaront transition dose is less than the final ulotaront dose. In other embodiments, the first ulotaront transition dose is less than the final ulotaront dose and further comprises administering a second dose of ulotaront or a pharmaceutically acceptable salt thereof during the transition period, the second dose being greater than the first ulotaront transition dose and optionally the same as the final ulotaront dose.

[0141] 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 that are treatable by first-generation or second-generation antipsychotics. 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, 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 disease, autism, Huntington's chorea, and premenstrual dysphoria.

[0142] Given the unique behavioral profile of ulotaront (as reported by Dedic 2019), the human clinical outcomes reported in PCT patent publication No. WO2020 / 118032, and the novel mechanism of action and receptor binding profile of ulotaront, it is expected that ulotaront will treat 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 disorder, and anxiety disorder.

[0143] In another embodiment, the neuropsychiatric disorder includes 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, excitatory psychosis, organic or NOS psychosis, movement disorder, 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.

[0144] In another embodiment, the treatment is carried out without inducing a clinically significant occurrence of a condition 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.

[0145] 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 still another embodiment, the neuropsychiatric disorder is an anxiety disorder (e.g., generalized anxiety disorder (GAD) as defined by DSM-5).

[0146] The first ulotaront transition dose or the second ulotaront transition dose or the final ulotaront dose may alternatively be described as 10 - 150 mg / day or 25 - 150 mg / day or 25 - 100 mg / day or 50 - 125 mg / day or 50 - 100 mg / day, administered orally. Alternatively, the first ulotaront transition dose or the second ulotaront transition dose or the final ulotaront dose may be described as 10 mg / day, 15 mg / day, 20 mg / day, 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 first ulotaront transition dose or the second ulotaront transition dose or the final ulotaront dose may be administered once daily in the fed or fasted state. Ulotaront may also be administered as the hydrochloride salt.

[0147] Preferred aspects of the present disclosure may be defined based on the following embodiments 1 to 74:

[0148] [Embodiment 1] A method of switching a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: administering to the subject during a transition period a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after said transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0149] [Embodiment 2] A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising: during a first treatment period, administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose); after the first treatment period, during a transition period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0150] [Embodiment 3] A method for switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (therapeutic NM dose) during a first treatment period to ulotaront, comprising: during a transition period, administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose, and wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0151] [Embodiment 4] A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising: during a first treatment period, administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose); after the first treatment period, during a transition period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose, and the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0152] [Embodiment 5] A method of switching a human subject who has been treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: administering to the subject during a transition period a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein the first NM transition dose is the same as the treatment NM dose, and the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0153] [Embodiment 6] A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: during a first treatment period, administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (treatment NM dose); after the first treatment period, during a transition period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the first NM transition dose is the same as the treatment NM dose, and the first ulotaront transition dose is optionally less than the final ulotaront dose.

[0154] [Embodiment 7] A method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; and the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0155] [Embodiment 8] A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (treatment NM dose) during a first treatment period; after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; and the ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0156] [Embodiment 9] A method of switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug affects a target receptor of the subject; and the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0157] [Embodiment 10] A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: during a first treatment period, administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (treatment NM dose); after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug affects a target receptor of the subject; and the ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of the drug affecting the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0158] [Embodiment 11] A method for switching a human subject treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: administering to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug produces one or more adverse events in the subject; and the ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0159] [Embodiment 12] A method for treating a neuropsychiatric disorder in a human subject in need thereof, comprising: administering to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (treatment NM dose) during a first treatment period; after the first treatment period, administering a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) during a transition period; and after the transition period, administering a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: the neuropsychiatric drug produces one or more adverse events in the subject; and the ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

[0160] [Embodiment 13] The method according to Embodiment 11 or 12, wherein the ulotaront or a pharmaceutically acceptable salt thereof alleviates the one or more adverse events.

[0161] [Embodiment 14] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is schizophrenia; the neuropsychiatric drug fails to improve the PANSS score of the subject; and the ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject.

[0162] [Embodiment 15] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is schizophrenia; the neuropsychiatric drug fails to improve the PANSS score of the subject to a clinically significant extent; and the ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject to a clinically significant extent.

[0163] [Embodiment 16] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is schizophrenia; before the start of ulotaront administration, the PANSS score of the subject is ≤80, and optionally ≥ 30, 34, 38, 42, 46, 50, 54, 58, 62, 66 or 70; and the PANSS score of the subject improves by ≥10, 12, 14, 16 or 18 points on an absolute basis.

[0164] [Embodiment 17] The method according to any one of Embodiments 1-12, wherein: during the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more persistent or worsening symptoms of the subject.

[0165] [Embodiment 18] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is schizophrenia; during the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, and the symptoms are selected from: negative symptoms, positive symptoms, disorganized symptoms, hostile symptoms and depressive / anxiety symptoms; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more persistent or worsening symptoms of the subject.

[0166] [Embodiment 19] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is schizophrenia; during the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or deteriorate in the subject, and the symptoms are selected from: delusions, suspicion / persecution, hallucinatory behavior, megalomania, conceptual confusion, poor attention, volitional disorder, lack of judgment and insight, special habits and postures, stereotyped thinking, unusual thinking content, preoccupation, difficulty in abstract thinking, disorientation, anxiety, tension, guilt, depression, somatic concerns, hostility, non-cooperation, poor impulse control, excitement, emotional withdrawal, passive / apathetic social withdrawal, active social avoidance, lack of spontaneity and conversational fluency, poor rapport, blunted affect, and bradykinesia; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or deteriorating symptoms in the subject.

[0167] [Embodiment 20] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is depression; during the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or deteriorate in the subject, and the symptoms are selected from: marked sadness, reported sadness, inner tension, reduced sleep, decreased appetite, difficulty in concentrating, fatigue, anhedonia, pessimistic thoughts, and suicidal thoughts; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or deteriorating symptoms in the subject.

[0168] [Embodiment 21] The method according to any one of Embodiments 1-12, wherein: the neuropsychiatric disorder is an anxiety disorder; during the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or deteriorate in the subject, and the symptoms are selected from: anxious mood, tension, fear, insomnia, intellectual, depressive mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and anxious behavior; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or deteriorating symptoms in the subject.

[0169] [Embodiment 22] The method according to any one of Embodiments 1-21, wherein the ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in the subject.

[0170] [Embodiment 23] The method according to any one of Embodiments 1-22, wherein: during the administration of the neuropsychiatric drug, nicotine use increases; and the ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in the subject.

[0171] [Embodiment 24] The method according to any one of Embodiments 1-23, wherein: during the administration of the neuropsychiatric drug, the functional level of the subject deteriorates; and the ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of the subject.

[0172] [Embodiment 25] The method according to any one of Embodiments 1-24, wherein: during the administration of the neuropsychiatric drug, the functional level of the subject deteriorates; and the ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of the subject to a clinically significant degree.

[0173] [Embodiment 26] The method according to any one of Embodiments 1-25, wherein: during the administration of the neuropsychiatric drug, one or more adverse events occur in the subject; and the ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the adverse events of the subject.

[0174] [Embodiment 27] The method according to any one of Embodiments 1-26, wherein: during the administration of the neuropsychiatric drug, one or more adverse events occur in the subject; the ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the adverse events in the subject; and the adverse events are selected from: (a) abnormal involuntary movements, as measured by AIMS (Abnormal Involuntary Movement Scale); (b) akathisia, preferably as measured by BARS (Barnes Akathisia Rating Scale); (c) suicidal tendency, preferably as measured by C-SSRS (Columbia Suicide Severity Rating Scale); (d) parkinsonism, preferably as measured by SAS (Simpson Angus Scale); and (e) sleep quality, preferably as measured by PSQI (Pittsburgh Sleep Quality Index).

[0175] [Embodiment 28] The method according to any one of Embodiments 1-27, wherein: during the administration of the neuropsychiatric drug, one or more adverse events occur in the subject; the ulotaront or a pharmaceutically acceptable salt thereof improves one or more adverse events in the subject; and the adverse events are selected from akathisia, abnormal blood prolactin, elevated blood prolactin, elevated blood triglycerides, elevated body mass index, bradykinesia, bruxism, cogwheel rigidity, skin scratching, diabetes, drooling, dyskinesia, dyslipidemia, sleep disorder, dystonia, electrocardiogram QT prolongation, enuresis, excessive blinking, extrapyramidal disorder, galactorrhea, impaired glucose tolerance, glycosuria, hyperkinesia, hyperprolactinemia, impaired fasting glucose, increased appetite, metabolic syndrome, muscle rigidity, neck rigidity, obesity, obsessive-compulsive disorder, oculogyric crisis, oromandibular dystonia, orthostatic hypertension, overweight, chronic pancreatitis, parkinsonian gait, parkinsonism, psychomotor retardation, restless legs syndrome, restlessness, excessive salivation, sedation, sexual dysfunction, tardive dyskinesia, convulsion, tongue biting, tongue spasm, torticollis, type 2 diabetes, and weight gain.

[0176] [Embodiment 29] The method according to any one of Embodiments 1-28, wherein during and / or after the transition period, the subject has a reduced risk of experiencing clinically significant withdrawal adverse events or does not experience clinically significant withdrawal adverse events, and the withdrawal adverse events are selected from: cholinergic withdrawal adverse events, dopaminergic withdrawal adverse events (nigrostriatal), dopaminergic withdrawal adverse events (mesolimbic or striatal), serotonergic withdrawal adverse events, histaminergic withdrawal adverse events, and adrenergic withdrawal adverse events.

[0177] [Embodiment 30] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a cholinergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing one or more cholinergic withdrawal adverse events or does not experience one or more cholinergic withdrawal adverse events.

[0178] [Embodiment 31] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a cholinergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing cholinergic withdrawal adverse events or does not experience cholinergic withdrawal adverse events, and the cholinergic withdrawal adverse events are selected from: restlessness, insomnia, anxiety, depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal colic, tremor, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucination, confusion, disorientation, hypothermia, and sweating.

[0179] [Embodiment 32] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (nigrostriatal) or does not experience dopaminergic withdrawal adverse events (nigrostriatal).

[0180] [Embodiment 33] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (nigrostriatal) or does not experience dopaminergic withdrawal adverse events (nigrostriatal), and the dopaminergic withdrawal adverse events (nigrostriatal) are selected from withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia.

[0181] [Embodiment 34] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (mesolimbic or striatal) or does not experience dopaminergic withdrawal adverse events (mesolimbic or striatal).

[0182] [Embodiment 35] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (mesolimbic or striatal) or does not experience dopaminergic withdrawal adverse events (mesolimbic or striatal), and the dopaminergic withdrawal adverse events (mesolimbic or striatal) are selected from auditory hallucinations, persecutory delusions, and other psychotic symptoms.

[0183] [Embodiment 36] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a serotonergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing serotonergic withdrawal adverse events or does not experience serotonergic withdrawal adverse events.

[0184] [Embodiment 37] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a serotonergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing serotonergic withdrawal adverse events or does not experience serotonergic withdrawal adverse events, and the serotonergic withdrawal adverse events are selected from flu-like symptoms, sweating or chills, dizziness, lightheadedness or tachycardia, paresthesia, a feeling of electric shock, anxiety, restlessness, depression, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and reduced concentration.

[0185] [Embodiment 38] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a histaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing histaminergic withdrawal adverse events or does not experience histaminergic withdrawal adverse events.

[0186] [Embodiment 39] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is a histaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing histaminergic withdrawal adverse events or does not experience histaminergic withdrawal adverse events, the histaminergic withdrawal adverse events being: irritability, insomnia, restlessness, depressive mood, anorexia, nausea, tremors, ataxia, drowsiness or amnesia.

[0187] [Embodiment 40] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is an adrenergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing adrenergic withdrawal adverse events or does not experience adrenergic withdrawal adverse events.

[0188] [Embodiment 41] The method according to any one of Embodiments 1-29, wherein the neuropsychiatric drug is an adrenergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing adrenergic withdrawal adverse events or does not experience adrenergic withdrawal adverse events, the adrenergic withdrawal adverse events being selected from headache, anxiety, restlessness, hypertension, tachycardia, angina, palpitations, risk of myocardial infarction, presyncope, tremors and sweating.

[0189] [Embodiment 42] The method according to any one of Embodiments 1-41, wherein the ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the disorder.

[0190] [Embodiment 43] The method according to any one of Embodiments 1-42, wherein the neuropsychiatric drug fails to improve one or more symptoms of the disorder, while the ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the symptoms.

[0191] [Embodiment 44] The method according to any one of Embodiments 1-43, wherein the neuropsychiatric drug produces one or more adverse events, and the ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the adverse events.

[0192] [Embodiment 45] The method according to any one of Embodiments 1-44, wherein: the neuropsychiatric drug fails to produce a clinically significant improvement in the neuropsychiatric disorder; and ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the neuropsychiatric disorder.

[0193] [Embodiment 46] The method according to any one of Embodiments 1-45, wherein: the neuropsychiatric drug fails to produce a clinically significant improvement in one or more symptoms of the disorder; and ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the symptoms.

[0194] [Embodiment 47] The method according to any one of Embodiments 1-46, wherein: the neuropsychiatric drug produces one or more moderate or severe adverse events; and ulotaront or a pharmaceutically acceptable salt thereof improves the one or more moderate or severe adverse events.

[0195] [Embodiment 48] The method according to any one of Embodiments 1-47, wherein: the neuropsychiatric drug produces one or more severe adverse events; and ulotaront or a pharmaceutically acceptable salt thereof improves the one or more severe adverse events.

[0196] [Embodiment 49] The method according to any one of Embodiments 1-48, wherein the neuropsychiatric drug is selected from cholinergic drugs, dopaminergic drugs, serotonergic drugs, histaminergic drugs, and adrenergic drugs.

[0197] [Embodiment 50] The method according to any one of Embodiments 1-48, wherein the neuropsychiatric drug is an antipsychotic selected from: acetylpromazine, aceperone, benperidol, bromperidol, butaperazine, carperone, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyanopromazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, loxapine, mesoridazine, metiapine, molindone, mopidone, oxypipamide, oxyprothepine, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, pizotifen, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulfadiazine, aceperone acetate, thioproperazine, thioridazine, tiotixene, timiperone, trifluoperazine, triflupromazine, triflupropazine, and zuclopenthixol.

[0198] [Embodiment 51] The method according to any one of Embodiments 1-48, wherein the neuropsychiatric drug is an antipsychotic selected from the following: amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, cariprazine, carpipramine, chlorcarbepine, clotiapine, clothiapine, clozapine, iloperidone, levosulpride, lumateperone, lurasidone, meperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpride, sultopride, tiapride, veralipride, ziprasidone, and zotepine.

[0199] [Embodiment 52] The method according to any one of Embodiments 1-51, wherein the first NM transition dose is the same as the therapeutic NM dose.

[0200] [Embodiment 53] The method according to any one of Embodiments 1-52, wherein the first NM transition dose is the same as the therapeutic NM dose, and further comprising administering a second transition dose of the neuropsychiatric drug (second NM transition dose) during the transition period, the second transition dose being less than the therapeutic NM dose and the first NM transition dose.

[0201] [Embodiment 54] The method according to any one of Embodiments 1-53, wherein the transition period is 2-6 weeks, during the first week of the transition period, the first NM transition dose is the same as the therapeutic NM dose, and a second transition dose of the neuropsychiatric drug (second NM transition dose) less than the first NM transition dose is administered during the remaining time of the transition period.

[0202] [Embodiment 55] The method according to any one of Embodiments 53-54, wherein the neuropsychiatric drug has a strong binding affinity for muscarinic-cholinergic (M1) and / or histaminergic (H1) receptors, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

[0203] [Embodiment 56] The method according to any one of Embodiments 53-54, wherein the neuropsychiatric drug is selected from asenapine, olanzapine, and quetiapine, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

[0204] [Embodiment 57] The method according to any one of Embodiments 53-54, wherein the neuropsychiatric drug has a strong binding affinity for dopaminergic receptors, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 2-4 weeks.

[0205] [Embodiment 58] The method according to any one of embodiments 53-54, wherein the neuropsychiatric drug is selected from lurasidone, paliperidone, risperidone, ziprasidone, haloperidol, and other typical antipsychotics, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 2-4 weeks.

[0206] [Embodiment 59] The method according to any one of embodiments 53-54, wherein the neuropsychiatric drug has a long half-life, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 1-3 weeks.

[0207] [Embodiment 60] The method according to any one of embodiments 53-54, wherein the neuropsychiatric drug is selected from aripiprazole, brexpiprazole, and cariprazine, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 1-3 weeks.

[0208] [Embodiment 61] The method according to any one of embodiments 53-54, wherein the therapeutic NM dose is at the upper limit of the recommended daily dose range, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

[0209] [Embodiment 62] The method according to any one of embodiments 53-54, wherein the neuropsychiatric drug is a D2 antagonist, and the first treatment period exceeds 6 months, 1 year, 2 years, 3 years, or 5 years, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

[0210] [Embodiment 63] The method according to any one of embodiments 1-62, wherein the first ulotaront transition dose is less than the final ulotaront dose.

[0211] [Embodiment 64] The method according to any one of embodiments 1-63, wherein the first ulotaront transition dose is less than the final ulotaront dose, which further comprises administering a second dose of ulotaront or a pharmaceutically acceptable salt thereof (second ulotaront transition dose) during the transition period, the second dose being greater than the first ulotaront transition dose and optionally the same as the final ulotaront dose.

[0212] [Embodiment 65] The method according to embodiment 64, wherein the transition period is 2 - 6 weeks, the first ulotaront transition dose is administered on days 1 - 3 of the transition period, the second ulotaront transition dose is administered on days 4 - 7 of the transition period, and optionally a third ulotaront transition dose, which is the same as the final ulotaront dose, is administered during the remaining time of the transition period.

[0213] [Embodiment 66] The method according to any one of embodiments 64 - 65, wherein the first ulotaront transition dose is 50 mg / day, the second ulotaront transition dose is 75 mg / day, and the final ulotaront dose is 50 - 100 mg / day.

[0214] [Embodiment 67] The method according to any one of embodiments 1 - 66, wherein the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety disorder.

[0215] [Embodiment 68] The method according to any one of embodiments 1 - 66, wherein the neuropsychiatric disorder is schizophrenia.

[0216] [Embodiment 69] The method according to any one of embodiments 1 - 66, wherein the neuropsychiatric disorder is MDD.

[0217] [Embodiment 70] The method according to any one of embodiments 1 - 66, wherein the neuropsychiatric disorder is GAD.

[0218] [Embodiment 71] The method according to any one of embodiments 1 - 70, wherein the first transition ulotaront dose and the final ulotaront dose are independently selected from 10 - 150 mg / day or 25 - 100 mg / day or 50 - 125 mg / day or 50 - 100 mg / day or 50 - 75 mg / day, and are administered orally.

[0219] [Embodiment 72] The method according to any one of embodiments 1 - 70, wherein the first transition ulotaront dose and the final ulotaront dose are independently selected from 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, or 150 mg / day, and are administered orally.

[0220] [Embodiment 73] The method according to any one of Embodiments 1-72, wherein the first transition ulotaront dose and the final ulotaront dose are administered once daily in the fed or fasted state.

[0221] [Embodiment 74] The method according to any one of Embodiments 1-73, wherein ulotaront is administered as the hydrochloride salt.

[0222] Example

[0223] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. The following examples are presented to provide a complete disclosure and description of how the methods claimed herein are carried out and evaluated, and are intended to be purely illustrative of the present disclosure and not intended to limit the scope which the inventors regard as their disclosure.

[0224] Example 1: Effect of SEP-363856 on body weight of female Sprague Dawley rats previously treated with olanzapine

[0225] SEP-363856 was studied to explore the effect of administering SEP-363856 on body weight and metabolic parameters of rats previously treated with olanzapine, including exploring whether administration of the test compound restores body weight to or above control levels. Animals received vehicle or olanzapine once daily for a period of 7 days. Compared to vehicle-treated animals, animals receiving olanzapine showed an increase in body weight. Subsequently, starting on Day 8, olanzapine-treated animals either continued to receive olanzapine or were switched to vehicle or switched to SEP-363856 (0.3, 1, and 3 mg / kg, po).

[0226] Materials and Methods

[0227] Animals: Seventy-four (2 spares) female Sprague Dawley rats (weight range 200 - 250 g) were ordered from Charles River, Margate, Kent. The rats were housed individually in cages with sawdust bedding and enrichment at an ambient temperature of 21 ± 2 °C. On arrival (Thursday), the rats were weighed and given a wet paste to aid recovery from transport. The rats were weighed on the following day and on the Monday of the following week. The animals were maintained on a reversed light-dark cycle (lights off for 8 h from 10:00 - 18:00 h), during which the room was illuminated by red light. The rats were weighed on the Friday and Monday of the following week. The relative humidity was generally 55 ± 15%, and prolonged periods below 40% RH or above 70% RH were avoided, as detailed in the UK Code of Practice. All animals had free access to a high-fat powdered diet (VRF1 plus 20% lard), and all rats had access to filtered water at all times. The diet was placed in glass feeding jars with aluminium lids (Solmedia Laboratory Suppliers, Romford, Essex). Each lid was cut with holes 3 - 4 cm in length to allow access to the food. Prior to the experiment, the animals were acclimatized to these conditions for at least two weeks.

[0228] Experimental procedure: The animals had a 3-day baseline run-in period during which all rats were dosed once daily with vehicle. Dosing was timed to start at approximately 08:45 so that the midpoint was approximately the time of lights out. The animals, food, and water were weighed at the time of dosing. At the end of this baseline period, the animals were weighed (using an electronic top pan balance accurate to 0.1 g) and allocated by a statistician into 2 weight-matched treatment groups. Subsequently, the rats were dosed once daily as follows: Treatment 1 (po) Days 1 - 4 or 1 - 7: Group A - vehicle (3 mL / kg) (n = 12); Groups B - F - olanzapine (3 mg / kg) (n = 62).

[0229] Olanzapine (3 mg / kg po) has previously been shown internally to cause a 4 - 6% increase in body weight in this model. Administration began at approximately 08:45 h (0 h) each day, such that the midpoint of all administrations was approximately at lights out. This strategy was employed to maximize the effect of the drug on food intake. Administration continued for 7 consecutive days, and rats were weighed (to the nearest 0.1 g) at 0 h each day. Animals were examined before and at the end of each dosing session, and any overt behavioral / physiological effects or other relevant observations regarding the animal's condition were recorded manually. Starting on day 4, body weight data were analyzed to assess whether there was a statistically significant increase in body weight with olanzapine compared to vehicle-treated controls fed a high-fat diet. When statistical significance was reached, the statistician further allocated the rats in groups B - F as follows based on the body weights available: Treatment 2: Group A - vehicle (aqueous methylcellulose, 1%, 3 mL / kg po) (n = 12); Group B - olanzapine (3 mg / kg po) (n = 12); Group C - SEP-363856 (0.3 mg / kg po) (n = 12); Group D - SEP-363856 (1 mg / kg po) (n = 12); Group E - SEP-363856 (3 mg / kg po) (n = 12); Group F - vehicle (water, 3 mL / kg) (n = 12). Subsequently, starting on day 8, animals either continued on olanzapine or switched to vehicle or SEP-363856 (0.3, 1, and 3 mg / kg, po). Body intake and food intake were evaluated daily.

[0230] Administration began at approximately 08:45 h (0 h) each day, i.e., the midpoint of administration was approximately at the time of lights out. Body weight, food, and water intake were recorded daily at the time of administration. All rats were observed before and after administration, and comments on the condition were recorded as appropriate. Animals were fasted according to schedule on the afternoon of Day 14 (approx. 16:00). The experiment ended in the morning of Day 15. On the morning of Day 15, final readings (i.e., body weight measurements) were taken 16 h after fasting. The animals were then dosed (as described). Four hours later, two blood samples (20 μL and 1 mL) were collected from the lateral tail vein into tubes containing lithium heparin. The 20 μL sample (whole blood) was frozen and stored prior to HbA1c determination (Roche Tina-quant A2c Gen 3, Cobas C111). The larger blood sample was centrifuged at 2,400 g for 5 min at 4 °C to yield 5 aliquots of plasma, which were frozen and stored for optional plasma analysis (glucose, insulin, triglycerides, cholesterol (HDL, LDL, total cholesterol), and NEFA) at Sygnature Discovery Ltd. The animals were then sacrificed by the method in Schedule 1 (exposed to increasing concentrations of CO2 and death confirmed by cervical dislocation). Terminal blood samples (approx. 4 mL) were collected into EDTA-coated tubes, and individual plasma aliquots (approx. 1 mL) were frozen and stored (approx. -80 °C) in clean equal-volume tubes. The liver was dissected and the caudate lobe removed. Both the caudate lobe and the remaining liver were weighed and frozen and stored separately (on dry ice and then transferred to a freezer at approx. -80 °C). Further analysis of liver triglycerides was performed on the caudate lobe. The carcasses were frozen and stored (approx. -20 °C) for potential body composition analysis. Metabolic parameters, including fasting glucose and insulin levels, liver triglycerides, and body fat composition, were determined at the end of the study.

[0231] Results

[0232] Consistent with previous publications, olanzapine (3 mg / kg / day, po) significantly increased body weight (Table 2.2.1) and food intake (Table 2.2.2) compared to vehicle-treated rats. Initial effects were observed as early as 2 - 3 days after dosing. On day 8, animals either continued on olanzapine or were switched to vehicle or SEP-363856 treatment. At all tested doses (0.3, 1, and 3 mg / kg, po), switching to SEP-363856 treatment reversed olanzapine-induced increases in body weight and food intake. Importantly, reversal of olanzapine-induced body weight gain was observed more rapidly in rats switched to SEP-363856 treatment compared to vehicle. Additionally, body composition analysis revealed that animals switched to SEP-363856 treatment had a significantly lower percentage of fat compared to rats that continued on olanzapine (Table 2.2.3). SEP-363856 decreased liver triglyceride levels, but the decrease did not reach statistical significance (Table 2.2.4). These preliminary results suggest that SEP-363856 reduces weight gain associated with previous antipsychotic treatment. Note that SEP-363856 is referred to as Compound 1 in the tables.

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] Example 2. An 8-week, open-label study to evaluate the efficacy, safety, and tolerability of SEP-363856 in patients with schizophrenia switching from typical or atypical antipsychotic agents

[0239] This is an 8-week, open-label study to evaluate the efficacy, safety, and tolerability of SEP-363856 in patients with schizophrenia who are switching from typical or atypical antipsychotic agents. An 8-week, outpatient, single-group, open-label design with flexible dosing and flexible switch duration was chosen to mimic the routine care setting of stable outpatient patients with schizophrenia who need to switch from a prior antipsychotic. There is a screening period to confirm the diagnosis and ensure eligibility criteria are met. Subjects who meet the eligibility criteria remain on antipsychotic treatment and enter an 8-week switch period, during which SEP-363856 will be introduced in the first week (i.e., starting at 50 mg / day on days 1 - 3, then increasing to 75 mg / day on days 4 - 7). In the first week of the study, the prior antipsychotic will not be adjusted when the investigator introduces SEP-363856.

[0240] Starting on day 8, the investigator may choose to gradually reduce the prior antipsychotic by the end of week 2, 3, 4, 5, or 6. The variable duration for tapering the prior antipsychotic is intended to mimic the real-life clinical setting where the investigator would consider the individual patient's needs and clinically relevant issues that may affect the outcome of the drug switch, such as the reason for the switch, type of prior antipsychotic, dose, etc. All study subjects who complete the 8-week switch period will undergo at least 2 weeks of SEP-363856 monotherapy. For the purpose of evaluating the long-term safety, tolerability, and efficacy of SEP-363856 in subjects switching from typical or atypical antipsychotic agents, study completers are eligible to roll over into the 24-week open-label extension study described in Example 3.

[0241] Objectives

[0242] Primary objective: To evaluate the safety and efficacy of switching clinically stable outpatient patients with schizophrenia from typical or atypical antipsychotics to SEP-363856 over an 8-week period, as assessed by the percentage of subjects who discontinue from the study due to adverse events or lack of efficacy

[0243] Secondary objective: To evaluate the safety and efficacy of switching clinically stable outpatient patients with schizophrenia from typical or atypical antipsychotics to SEP-363856 over an 8-week period, as assessed by the percentage of subjects who discontinue for any reason (i.e., all discontinuation reasons)

[0244] Other objective (1): Use the following to evaluate the tolerability and safety of switching clinically stable outpatient patients with schizophrenia from typical or atypical antipsychotics to SEP-363856 over an 8-week period: adverse event reports, clinical laboratory tests, vital sign measurements, 12-lead electrocardiogram (ECG), Columbia-Suicide Severity Rating Scale (C-SSRS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), and Simpson-Angus Scale (SAS)

[0245] Other objective (2): Use the following to evaluate the efficacy of SEP-363856: Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) scale, Clinical Global Impression-Improvement (CGI-I) scale, and Brief Negative Symptom Scale (BNSS)

[0246] Other objective (3): Evaluate the effect of SEP-363856 on health-related quality of life, as measured by the Short Form Health Survey (SF 12)

[0247] Other objective (4): Evaluate the impact of SEP-363856 on functional capacity, as measured by the Personal and Social Performance Scale (PSP)

[0248] Other objective (5): Evaluate drug satisfaction, as measured by the Medication Satisfaction Questionnaire (MSQ)

[0249] Other objective (6): Evaluate sleep, as measured by the Pittsburgh Sleep Quality Index (PSQI)

[0250] Other objective (7): Evaluate the impact of SEP-363856 on healthcare resource utilization (HCRU)

[0251] Endpoint

[0252] Primary endpoint: Percentage of subjects who discontinued due to clinical reasons (i.e., discontinued due to adverse events [AE] or lack of efficacy)

[0253] Secondary endpoint: Percentage of subjects who discontinued for any reason (i.e., all reasons for discontinuation)

[0254] Other endpoints:

[0255] • Incidence of overall AEs, serious adverse events (SAEs), and AEs leading to discontinuation

[0256] • Observed values and changes relative to baseline in clinical laboratory tests (hematology, chemistry, and urine analysis)

[0257] • Observed values of vital signs (including weight, body mass index [BMI], waist circumference, body temperature, blood pressure [supine and standing], heart rate [supine and standing], and respiratory rate) and changes relative to baseline

[0258] • Observed values of 12 - lead ECG parameters and changes relative to baseline

[0259] • Frequency of subjects with suicidal ideation and suicidal behavior based on C - SSRS

[0260] • Changes in BARS, AIMS, and SAS scores relative to baseline

[0261] • Changes from baseline to week 8: (i) PANSS total score and subscale scores (positive, negative, and general psychopathology), (ii) PANSS Marder factor (five - factor) scores (positive, disorganized, negative, hostile, and depressive / anxiety), and uncorrelated PANSS score matrix (UPSM), (iii) CGI - S score, (iv) CGI - I score, (v) BNSS total score, (vi) SF - 12 score, (vii) PSP total score, (viii) MSQ score, (ix) PSQI overall score

[0262] • HCRU (including number of doctor's office visits, number of emergency room [ER] visits and hospitalizations, length of hospitalization, employment status, and average number of hours per week that a caregiver helps the subject.)

[0263] • Nicotine use at baseline and week 8 (end of treatment [EOT] / early termination [ET])

[0264] Overall study design

[0265] This is an 8 - week, outpatient, multicenter, open - label, single - group, flexible - dose study designed to evaluate the safety, tolerability, and efficacy of switching clinically stable adult subjects with schizophrenia from typical or atypical antipsychotics to SEP - 363856. This study is expected to enroll approximately 120 subjects into a single treatment group (SEP - 363856). During the 8 - week treatment period, subjects receive flexible dosing of SEP - 363856 (50 to 100 mg / day), and the investigator has the right to discontinue the pre - switch antipsychotic treatment of each subject at the end of week 2, 3, 4, 5, or 6. The duration of the gradual reduction of the pre - switch antipsychotic is also provided according to the individual subject.

[0266] Once the antipsychotic drug before conversion is completely discontinued, the subject continues to receive SEP-363856 flexibly at 50 to 100 mg / day until the end of the study at week 8. The study drug is taken at the same time every night before bedtime and may be taken with or without food.

[0267] Figure 1 A schematic diagram of the study design is provided. The study consists of three periods: screening / washout (up to 21 days), treatment (8 weeks), and follow-up (for subjects who discontinued before the week 8 visit or who completed the study but did not enroll in the open-label extension study described in Example 3, 7 ± 2 days after the last dose of the study drug).

[0268] Subjects are evaluated for eligibility during a screening period of up to 21 days. During this period, subjects continue to take their pre-conversion antipsychotic drugs while all other psychotropic medications (except as noted in the “Concomitant Medications” section below) are tapered in a manner consistent with label recommendations and routine medical practice. Subjects treated with two antipsychotic drugs are allowed to enter the screening period. At the start of screening, the investigator determines which antipsychotic drug is considered the “primary” one, and the other drug is tapered during the screening period.

[0269] Open-label treatment period (8 weeks): At baseline (day 1) (pre-switch [PS] baseline), subjects who have successfully completed screening and meet the eligibility criteria start open-label treatment with SEP-363856 while continuing to take the full dose of their pre-switch (PS) antipsychotic drug. Administration of SEP-363856 starts on the evening of the PS baseline visit and continues once daily at bedtime for the remainder of the treatment period (during which study procedures are conducted). Subjects are evaluated at PS baseline and weekly for the remainder of the study.

[0270] Subjects receive SEP-363856 at 50 mg / day from day 1 to day 3 and are maintained at 75 mg / day from day 4 to day 7. Every effort is made to maintain subjects at 75 mg / day from day 4 to day 7. An attempt is made to maintain subjects at 75 mg / day from day 8 until the end of the 8-week open-label treatment period. However, starting from day 8, if the investigator determines that it is clinically necessary based on the following pre-determined requirements, the dose of SEP-363856 will be adjusted in 25 mg increments among three dose levels (50 mg, 75 mg, and 100 mg):

[0271] • On Day 8, increase the dose of SEP-363856 to 100 mg / day to help ensure adequate symptom coverage, provided that the investigator determines that there are no significant tolerability issues. The dose is increased to the next highest dose level no more frequently than once a week (in 25 mg increments). When possible, dose increases occur during regular study visits.

[0272] • For safety and intolerance issues as determined by the investigator, decrease the dose of SEP-363856 to the next lowest dose level (in 25 mg increments) at any time starting on Day 8.

[0273] Starting on Day 8, the investigator is permitted to begin tapering the pre-switch antipsychotic of the subject. Discontinuation of the pre-switch antipsychotic is completed by the end of Week 2, 3, 4, 5, or 6. Once the pre-switch antipsychotic is completely discontinued, the subject continues to receive SEP-363856 (50 to 100 mg / day) until the end of Week 8. Subjects who complete the 8-week open-label treatment period are eligible to participate in the open-label extension study described in Example 3. Subjects who are prematurely terminated (ET) are not eligible for enrollment in the extension study.

[0274] Subject Inclusion Criteria

[0275] To be eligible for participation, subjects must meet all of the following selected inclusion criteria:

[0276] • Male or female subjects aged 18 to 65 years (inclusive) at the time of consent.

[0277] • The subject meets the DSM-5 diagnostic criteria for schizophrenia, as established by clinical interview (using DSM-5 as a reference and confirmed using the DSM-5 Structured Clinical Interview for Clinical Trials Version [SCID-5-CT]). The time since the subject's diagnosis must be ≥1 year prior to screening.

[0278] • The subject must have a CGI-S score ≤4 at screening and at baseline.

[0279] • The subject must have a PANSS total score ≤80 at screening and at baseline.

[0280] • The subject is determined by the investigator to be clinically stable (i.e., no evidence of acute exacerbation of schizophrenia) for at least 8 weeks prior to baseline.

[0281] • The subject has not been hospitalized for a psychiatric illness for at least 8 weeks prior to screening.

[0282] • The subject must be a suitable candidate for switching the current antipsychotic medication as determined by the investigator due to safety or tolerability issues and / or lack of efficacy.

[0283] • The subject is taking an oral antipsychotic, and the antipsychotic treatment regimen has been stable for at least 6 weeks prior to screening.

[0284] • Subjects taking two antipsychotics (but no more than two) at the time of screening are eligible for inclusion in the study, provided that the total daily dose is equivalent to ≤ 12 mg / day of haloperidol. However, the antipsychotic determined by the investigator to be "secondary" must be discontinued prior to receiving SEP-363856. All subjects must be taking a single antipsychotic at study baseline (Day 1).

[0285] • The body mass index (BMI) of the subject at the time of screening must be 18 kg / m 2 to 40 kg / m 2 (including the end values).

[0286] • Based on the screening medical history, physical examination (PE), neurological examination, vital signs, electrocardiogram (ECG), and clinical laboratory values (hematology, chemistry, and urine analysis), the investigator determines that the subject is generally healthy.

[0287] Example 3. Open-Label Extension Study to Evaluate the Safety and Tolerability of SEP-363856 in Subjects with Schizophrenia Who Are Switching from Typical or Atypical Antipsychotics

[0288] This is a 24-week open-label extension study to evaluate the safety and tolerability of SEP-363856 in patients with schizophrenia who are switching from typical or atypical antipsychotics. The study aims to evaluate the effectiveness, safety, and tolerability of switching clinically stable outpatient patients with schizophrenia (who may benefit from switching due to tolerance or efficacy reasons) from their pre-switch antipsychotic to SEP-363856. The open-label extension study provides additional long-term safety, tolerability, and effectiveness data for subjects who completed the 8-week switch trial described in Example 2.

[0289] The purpose of this study is to demonstrate that clinically stable outpatient patients with schizophrenia who have completed the switch from their current antipsychotic treatment can be safely and effectively maintained on open-label treatment with SEP-363856 for a period of 24 weeks. Outcome measures include standard safety measures (e.g., AE, SAE, motor function measures, suicide risk assessment, laboratory assessments, and ECG). For the purpose of providing long-term effectiveness data, additional validated effectiveness assessments for schizophrenia (e.g., PANSS, CGI-S) are also included. In addition, measures to evaluate function, medication satisfaction, quality of life, sleep, and healthcare utilization are designed to provide information on real-world and overall health aspects related to the transition between treatments.

[0290] Primary objective: To evaluate the long-term safety and tolerability of flexible dosing of SEP-363856 (50, 75, 100 mg / day) in adult subjects with schizophrenia who have completed the Study of Example 2, as assessed by the incidence of overall adverse events (AE), serious AEs (SAEs), and AEs leading to discontinuation.

[0291] Other objectives:

[0292] • To evaluate the long-term safety and tolerability of SEP-363856 by assessing the following: (i) 12-lead electrocardiogram (ECG), (ii) vital sign measurements, (iii) clinical laboratory tests, (iv) Columbia-Suicide Severity Rating Scale (C-SSRS), (v) Simpson-Angus Scale (SAS), (vi) Barnes Akathisia Rating Scale (BARS), (vii) Abnormal Involuntary Movement Scale (AIMS)

[0293] • To evaluate the long-term efficacy of SEP-363856 using the following: (i) Positive and Negative Syndrome Scale (PANSS), (ii) Clinical Global Impression-Severity (CGI-S) scale, (iii) Clinical Global Impression-Improvement (CGI-I) scale, (iv) Brief Negative Symptom Scale (BNSS)

[0294] • To evaluate the long-term effect of SEP-363856 on health-related quality of life, as measured by the Short Form-12 Health Survey (SF12)

[0295] • To evaluate the long-term effect of SEP-363856 on functional capacity, as measured by the Personal and Social Performance Scale (PSP)

[0296] • To evaluate long-term drug satisfaction, as measured by the Medication Satisfaction Questionnaire (MSQ)

[0297] • To evaluate long-term sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI)

[0298] • To evaluate the long-term impact of SEP-363856 on healthcare resource utilization (HCRU)

[0299] Primary endpoint: Incidence of overall AE, SAE, and AEs leading to discontinuation

[0300] Other safety endpoints (1): Observed values of clinical laboratory tests (including hematology, chemistry [including but not limited to lipid parameters and glycated hemoglobin A1c (HbA1c)] and urine analysis), and changes relative to the baseline of the Study of Example 2 (pre-switch baseline [PS baseline]) and the baseline of the Study of Example 3 (open-label extension [OLE] baseline)

[0301] Other safety endpoints (2): Observed values of vital signs (including body temperature, body weight, body mass index [BMI], waist circumference, blood pressure [supine and standing], pulse rate [supine and standing], and respiratory rate) and 12-lead ECG parameters, and changes relative to the PS baseline and OLE baseline

[0302] Other safety endpoints (3): Frequency of subjects with suicidal ideation and suicidal behavior based on C-SSRS

[0303] Other safety endpoints (4): Changes in SAS, BARS, and AIMS scores relative to the PS baseline and OLE baseline

[0304] Other safety endpoints (5): Changes in PSQI scores relative to the PS baseline and OLE baseline

[0305] Other endpoints (1): Changes relative to the PS baseline and OLE baseline in: (i) PANSS total score and subscale scores (positive, negative, and general psychopathology), (ii) PANSS Marder factor (five-factor) scores (positive, disorganized, negative, hostile, and depressive / anxious), (iii) Unrelated PANSS (seven-factor) score matrix (UPSM) (positive, disorganized, negative apathy / avolition, negative expressive deficit, hostile, anxious, and depressive), (iv) CGI-S score, (v) CGI-I score, (vi) BNSS total score, (vii) SF 12 score, (viii) PSP score, (ix) MSQ score

[0306] Other endpoints (2): HCRU (including number of physician office visits, number of emergency room (ER) visits, number of hospitalizations, length of hospitalization, employment status, and average number of hours per week that a caregiver helps the subject)

[0307] Other endpoints (3): Nicotine use

[0308] Overall study design

[0309] This is a 24-week, outpatient, multi-center, flexible-dose, open-label extension study designed to evaluate the long-term safety and tolerability of SEP-363856 (50 to 100 mg / day) in patients with schizophrenia who have completed the treatment period of Example 2 study (during which they switched from previous antipsychotic treatment to SEP-363856).

[0310] Figure 2A schematic diagram of the study design is provided. The study consists of two periods: an open-label extension (OLE) treatment period (up to 24 weeks); and a follow-up period, which is visited 7 ± 2 days after the last study drug dose (for subjects who completed the treatment period and subjects who discontinued the study prematurely). Subjects who meet the entry criteria and are selected to enter the extension study will transition immediately at the end-of-treatment (EOT) visit of the Example 2 study. Subjects who prematurely terminated (ET) the Example 2 study are not eligible to enroll in this study. The EOT visit of the Example 2 study serves as the OLE baseline visit for this study.

[0311] Subjects attend a baseline visit on Day 1 (the same day as the EOT visit of the Example 2 study). Subjects are met at baseline and then every 4 weeks until Week 24. Members of the clinical research staff call subjects between visits weekly to collect AEs and concomitant medications, and to remind subjects to comply with study drug administration and upcoming visits.

[0312] All subjects start receiving open-label SEP-363856 at the same dose they were taking at the completion of the Example 2 study. Thereafter, if the investigator deems it clinically necessary, the dose is adjusted within the range of 50 to 100 mg / day. Throughout the study, safety and tolerability are monitored by collecting physical examination (PE) results, ECG, vital signs, AEs, and clinical laboratory parameters. Sleep quality is evaluated using the PSQI, and suicidal tendency is evaluated using the C-SSRS.

[0313] Motor function is evaluated using the SAS, BARS, and AIMS scales. HCRU is also collected in this study. Efficacy is evaluated using the PANSS total score and subscale scores, CGI-S score and CGI-I score, BNSS score, and PSQI overall score. Function, quality of life, and treatment satisfaction are evaluated using the PSP, SF 12, and MSQ.

[0314] Subject Inclusion Criteria

[0315] To be eligible to participate, subjects must meet all of the following selected inclusion criteria:

[0316] • Subjects must give written informed consent and privacy authorization prior to participating in the study and the investigator determines that they are able to comply with the protocol. If required by local law, obtain separate consent from the caregiver or legal guardian.

[0317] • During the Example 2 study, subjects did not take any medications for the treatment of psychosis other than the study drug, the pre-switch antipsychotic, and medications permitted by the protocol.

[0318] References

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] Throughout this application, various publications are cited. The disclosures of these publications are hereby incorporated by reference in their entirety into this application so as to more fully describe the prior art relevant to this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made to this disclosure without departing from the scope or spirit thereof. By considering the specification and practicing the disclosure herein, other embodiments of this 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 this disclosure are indicated by the following claims.

Claims

1. A method of converting a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During the transition period, administer to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and b) After the transition period, administer the final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein the first NM transition dose is the same as the therapeutic NM dose, and the first ulotaront transition dose is optionally less than the final ulotaront dose.

2. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a) During a first treatment period, administer to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose), b) After the first treatment period, during the transition period, administer a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and c) After the transition period, administer the final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein: i) the first NM transition dose is the same as the therapeutic NM dose, and ii) the first ulotaront transition dose is optionally less than the final ulotaront dose.

3. A method of converting a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During the transition period, administer to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and b) After the transition period, administer the final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period, wherein the first ulotaront transition dose is optionally less than the final ulotaront dose.

4. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a) During a first treatment period, administer to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose), b) After the first treatment period, during the transition period, administer a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and c) After said transition period, administer a final dose of said ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering said neuropsychiatric drug for a therapeutically effective period of time, wherein said first ulotaront transition dose is optionally less than said final ulotaront dose.

5. A method of converting a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During a transition period, administer to said subject a dose of said neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and b) After said transition period, administer a final dose of said ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering said neuropsychiatric drug for a therapeutically effective period of time, wherein said first ulotaront transition dose is optionally less than said final ulotaront dose, and wherein said subject takes said neuropsychiatric drug for at least two weeks during said transition period.

6. A method of treating a neuropsychiatric disorder in a human subject in need thereof, comprising: a) During a first treatment period, administer to said subject a therapeutic dose of a neuropsychiatric drug for said disorder (therapeutic NM dose), b) After said first treatment period, during a transition period, administer a transition dose of said neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and c) After said transition period, administer a final dose of said ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering said neuropsychiatric drug for a therapeutically effective period of time, wherein: i) said first ulotaront transition dose is optionally less than said final ulotaront dose, and ii) said subject takes said neuropsychiatric drug for at least two weeks during said transition period.

7. A method of converting a human subject being treated with a dose of a neuropsychiatric drug for a neuropsychiatric disorder (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During a transition period, administer to said subject a dose of said neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and b) After said transition period, administer a final dose of said ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering said neuropsychiatric drug for a therapeutically effective period of time, wherein: i) said neuropsychiatric drug fails to adequately improve said neuropsychiatric disorder; and ii) said ulotaront or a pharmaceutically acceptable salt thereof improves said neuropsychiatric disorder to a greater extent than said neuropsychiatric drug, optionally wherein said subject takes said neuropsychiatric drug for at least two weeks during said transition period.

8. A method for treating neuropsychiatric disorders in human subjects in need thereof, comprising: a) During a first treatment period, a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) is administered to the subject. b) After the first treatment period, during a transition period, a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) are administered; and c) After the transition period, a final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) is administered without administering the neuropsychiatric drug for a therapeutically effective period, wherein: i) The neuropsychiatric drug fails to adequately improve the neuropsychiatric disorder; and ii) The ulotaront or a pharmaceutically acceptable salt thereof improves the neuropsychiatric disorder to a greater extent than the neuropsychiatric drug, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

9. A method for switching a human subject treated with a dose of a neuropsychiatric drug for neuropsychiatric disorders (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During a transition period, a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) are administered to the subject; and b) After the transition period, a final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) is administered without administering the neuropsychiatric drug for a therapeutically effective period, wherein: i) The neuropsychiatric drug affects the target receptor of the subject; and ii) The ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuing the drug that affects the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuing the drug that affects the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

10. A method for treating neuropsychiatric disorders in human subjects in need thereof, comprising: a) During a first treatment period, a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose) is administered to the subject. b) After the first treatment period, during a transition period, a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose) are administered; and c) After the transition period, a final dose of ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) is administered without administering the neuropsychiatric drug for a therapeutically effective period, wherein: i) The neuropsychiatric drug affects the target receptor of the subject; and ii) The ulotaront or a pharmaceutically acceptable salt thereof reduces the risk that the subject will experience one or more withdrawal adverse events associated with discontinuation of a drug that affects the target receptor or prevents the subject from experiencing one or more withdrawal adverse events associated with discontinuation of a drug that affects the target receptor, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

11. A method for switching a human subject treated with a dose of a neuropsychiatric drug for neuropsychiatric disorders (treatment NM dose) during a first treatment period to ulotaront, comprising: a) During a transition period, administer to the subject a dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and b) After the transition period, administer a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: i) The neuropsychiatric drug produces one or more adverse events in the subject; and ii) The ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

12. A method for treating neuropsychiatric disorders in human subjects in need thereof, comprising: a) During a first treatment period, administer to the subject a therapeutic dose of a neuropsychiatric drug for the disorder (therapeutic NM dose), b) After the first treatment period, during a transition period, administer a transition dose of the neuropsychiatric drug (first NM transition dose) and a first dose of ulotaront or a pharmaceutically acceptable salt thereof (first ulotaront transition dose); and c) After the transition period, administer a final dose of the ulotaront or a pharmaceutically acceptable salt thereof (final ulotaront dose) without administering the neuropsychiatric drug for a therapeutically effective period of time, wherein: i) The neuropsychiatric drug produces one or more adverse events in the subject; and ii) The ulotaront or a pharmaceutically acceptable salt thereof does not produce one or more of the adverse events in the subject, optionally wherein the subject takes the neuropsychiatric drug for at least two weeks during the transition period.

13. The method according to claim 11 or 12, wherein the ulotaront or a pharmaceutically acceptable salt thereof alleviates the one or more adverse events.

14. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is schizophrenia; b) The neuropsychiatric drug fails to improve the PANSS score of the subject; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject.

15. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is schizophrenia; b) The neuropsychiatric drug fails to improve the PANSS score of the subject to a clinically significant extent; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves the PANSS score of the subject to a clinically significant extent.

16. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is schizophrenia; b) Prior to the impending commencement of ulotaront administration, the subject's PANSS score ≤ 80, and optionally ≥ 30, 34, 38, 42, 46, 50, 54, 58, 62, 66 or 70; and c) The subject's PANSS score improves by ≥ 10, 12, 14, 16 or 18 points on an absolute basis.

17. The method according to any one of claims 1-12, wherein: a) During the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

18. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is schizophrenia; b) During the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms being selected from negative symptoms, positive symptoms, disorganized symptoms, hostile symptoms and depressive / anxiety symptoms; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

19. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is schizophrenia; b) During the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms being selected from: delusions, suspiciousness / persecution, hallucinatory behavior, grandiosity, conceptual disorganization, poor concentration, volitional disturbances, lack of judgment and insight, peculiar habits and postures, stereotyped thinking, unusual thought content, preoccupations, difficulty with abstract thinking, disorientation, anxiety, tension, guilt feelings, depression, somatic concerns, hostility, non - cooperation, poor impulse control, excitement, emotional withdrawal, negative / apathetic social withdrawal, active social avoidance, lack of spontaneity and conversational fluency, poor rapport, blunted affect and psychomotor retardation; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

20. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is depression; b) During the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms being selected from: obvious sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, anhedonia, pessimistic thoughts and suicidal thoughts; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the persistent or worsening symptoms in the subject.

21. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric disorder is anxiety disorder; b) During the administration of the neuropsychiatric drug, one or more symptoms of the disorder persist or worsen in the subject, the symptoms being selected from: anxious mood, tension, fear, insomnia, intellectual - related, depressive mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms and anxious behavior; and c) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more persistent or deteriorating symptoms of the subject.

22. The method according to any one of claims 1-12, wherein the ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in the subject.

23. The method according to any one of claims 1-12, wherein: a) Nicotine use increases during administration of the neuropsychiatric drug; b) The ulotaront or a pharmaceutically acceptable salt thereof reduces nicotine use in the subject.

24. The method according to any one of claims 1-12, wherein: a) During administration of the neuropsychiatric drug, the functional level of the subject deteriorates; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of the subject.

25. The method according to any one of claims 1-12, wherein: a) During administration of the neuropsychiatric drug, the functional level of the subject deteriorates; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves the functional level of the subject to a clinically significant extent.

26. The method according to any one of claims 1-12, wherein: a) During administration of the neuropsychiatric drug, one or more adverse events occur in the subject; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the adverse events in the subject.

27. The method according to any one of claims 1-12, wherein: a) During administration of the neuropsychiatric drug, one or more adverse events occur in the subject; b) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more adverse events in the subject; and c) The adverse events are selected from: (a) abnormal involuntary movements, as measured by the AIMS (Abnormal Involuntary Movement Scale); (b) akathisia, preferably as measured by the BARS (Barnes Akathisia Rating Scale); (c) suicidal tendency, preferably as measured by the C-SSRS (Columbia Suicide Severity Rating Scale); (d) parkinsonism, preferably as measured by the SAS (Simpson Angus Scale); and (e) sleep quality, preferably as measured by the PSQI (Pittsburgh Sleep Quality Index).

28. The method according to any one of claims 1-12, wherein: a) During administration of the neuropsychiatric drug, one or more adverse events occur in the subject; b) The ulotaront or a pharmaceutically acceptable salt thereof improves one or more of the adverse events in the subject; and c) The adverse events are selected from akathisia, abnormal blood prolactin, elevated blood prolactin, elevated blood triglycerides, elevated body mass index, bradykinesia, bruxism, cogwheel rigidity, dermatillomania, diabetes, drooling, dyskinesia, dyslipidemia, sleep disorder, dystonia, prolonged QT interval on electrocardiogram, enuresis, excessive blinking, extrapyramidal disorder, galactorrhea, impaired glucose tolerance, glycosuria, hyperkinesia, hyperprolactinemia, impaired fasting glucose, increased appetite, metabolic syndrome, muscle rigidity, neck rigidity, obesity, obsessive-compulsive disorder, oculogyric crisis, oromandibular dystonia, orthostatic hypertension, overweight, chronic pancreatitis, parkinsonian gait, parkinsonism, psychomotor retardation, restless legs syndrome, restlessness, excessive salivation, sedation, sexual dysfunction, tardive dyskinesia, convulsion, tongue biting, tongue spasm, torticollis, type 2 diabetes, and weight gain.

29. The method according to any one of claims 1-12, wherein during and / or after the transition period, the subject has a reduced risk of experiencing clinically significant withdrawal adverse events or does not experience clinically significant withdrawal adverse events, the withdrawal adverse events being selected from: cholinergic withdrawal adverse events, dopaminergic withdrawal adverse events (nigrostriatal), dopaminergic withdrawal adverse events (mesolimbic or striatal), serotonergic withdrawal adverse events, histaminergic withdrawal adverse events, and adrenergic withdrawal adverse events.

30. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a cholinergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing one or more cholinergic withdrawal adverse events or does not experience one or more cholinergic withdrawal adverse events.

31. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a cholinergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing cholinergic withdrawal adverse events or does not experience cholinergic withdrawal adverse events, and the cholinergic withdrawal adverse events are selected from the group consisting of agitation, insomnia, anxiety, depression, dizziness, lightheadedness, tachycardia, nausea, vomiting, salivation, diarrhea, abdominal colic, tremors, parkinsonism, restlessness, myalgia, rigidity, paresthesia, fear, hallucinations, confusion, disorientation, hypothermia, and sweating.

32. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (nigrostriatal) or does not experience dopaminergic withdrawal adverse events (nigrostriatal).

33. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (nigrostriatal) or does not experience dopaminergic withdrawal adverse events (nigrostriatal), and the dopaminergic withdrawal adverse events (nigrostriatal) are selected from the group consisting of withdrawal dyskinesia, parkinsonism, neuroleptic malignant syndrome, and akathisia.

34. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (mesolimbic or striatal) or does not experience dopaminergic withdrawal adverse events (mesolimbic or striatal).

35. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a dopaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing dopaminergic withdrawal adverse events (mesolimbic or striatal) or does not experience dopaminergic withdrawal adverse events (mesolimbic or striatal), and the dopaminergic withdrawal adverse events (mesolimbic or striatal) are selected from the group consisting of auditory hallucinations, persecutory delusions, and other psychotic symptoms.

36. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is a serotonergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing serotonergic withdrawal adverse events or does not experience serotonergic withdrawal adverse events.

37. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug is a serotonergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing serotonergic withdrawal adverse events or does not experience serotonergic withdrawal adverse events, the serotonergic withdrawal adverse events being selected from the group consisting of flu-like symptoms, sweating, chills, dizziness, lightheadedness, tachycardia, paresthesia, electric shock sensation, anxiety, restlessness, depression, insomnia, nightmares, nausea, vomiting, diarrhea, confusion, and reduced concentration.

38. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug is a histaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing histaminergic withdrawal adverse events or does not experience histaminergic withdrawal adverse events.

39. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug is a histaminergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing histaminergic withdrawal adverse events or does not experience histaminergic withdrawal adverse events, the histaminergic withdrawal adverse events being selected from the group consisting of irritability, insomnia, restlessness, depressive mood, anorexia, nausea, tremor, ataxia, drowsiness, and amnesia.

40. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug is an adrenergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing adrenergic withdrawal adverse events or does not experience adrenergic withdrawal adverse events.

41. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug is an adrenergic drug, and during and / or after the transition period, the subject has a reduced risk of experiencing adrenergic withdrawal adverse events or does not experience adrenergic withdrawal adverse events, the adrenergic withdrawal adverse events being selected from the group consisting of headache, anxiety, restlessness, hypertension, tachycardia, angina pectoris, palpitations, risk of myocardial infarction, presyncope, tremor, and sweating.

42. The method according to any one of claims 1 - 12, wherein ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the disorder.

43. The method according to any one of claims 1 - 12, wherein the neuropsychiatric drug fails to improve one or more symptoms of the disorder, and ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the one or more symptoms.

44. The method according to any one of claims 1-12, wherein the neuropsychiatric drug produces one or more adverse events, and ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in one or more of the adverse events.

45. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric drug fails to produce a clinically significant improvement in the neuropsychiatric disorder; and b) The ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the neuropsychiatric disorder.

46. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric drug fails to produce a clinically significant improvement in one or more symptoms of the disorder; and b) The ulotaront or a pharmaceutically acceptable salt thereof produces a clinically significant improvement in the symptoms.

47. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric drug produces one or more moderate or severe adverse events; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves the one or more moderate or severe adverse events.

48. The method according to any one of claims 1-12, wherein: a) The neuropsychiatric drug produces one or more severe adverse events; and b) The ulotaront or a pharmaceutically acceptable salt thereof improves the one or more severe adverse events.

49. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is selected from cholinergic drugs, dopaminergic drugs, serotonergic drugs, histaminergic drugs, and adrenergic drugs.

50. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is an antipsychotic drug selected from the following: acetylpromazine, aceperone, benperidol, bromperidol, butaperazine, carphenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyanopromazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, loxapine, mesoridazine, metitepine, molindone, mopidone, oxyphenbutazone, oxyprothepine, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, pithiatine, pipotiazine, prochlorperazine, promazine, propiomazine, spiperone, sulfadiazine, aceperone acetate, thiopropazate, thioridazine, tiotixene, timiperone, trifluoperazine, trifluoroperidol, triflupromazine, and zuclopenthixol.

51. The method according to any one of claims 1-12, wherein the neuropsychiatric drug is an antipsychotic drug selected from the group consisting of amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, cariprazine, carpipramine, chlorcarbepine, clotiapine, clothiapine, clozapine, iloperidone, levosulpiride, lumateperone, lurasidone, meperidone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine.

52. The method according to any one of claims 1-12, wherein the first NM transition dose is the same as the therapeutic NM dose.

53. The method according to any one of claims 1-12, wherein the first NM transition dose is the same as the therapeutic NM dose, further comprising administering a second transition dose of the neuropsychiatric drug (second NM transition dose) during the transition period, the second transition dose being less than the therapeutic NM dose and the first NM transition dose.

54. The method according to any one of claims 1-12, wherein the transition period is 2-6 weeks, during the first week of the transition period, the first NM transition dose is the same as the therapeutic NM dose, and during the remaining time of the transition period, a second transition dose of the neuropsychiatric drug (second NM transition dose) less than the first NM transition dose is administered.

55. The method according to claim 53, wherein the neuropsychiatric drug has a strong binding affinity for muscarinic-cholinergic (M1) and / or histaminergic (H1) receptors, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

56. The method according to claim 53, wherein the neuropsychiatric drug is selected from asenapine, olanzapine, and quetiapine, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3-5 weeks.

57. The method according to claim 53, wherein the neuropsychiatric drug has a strong binding affinity for dopaminergic receptors, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 2-4 weeks.

58. The method according to claim 53, wherein the neuropsychiatric drug is selected from lurasidone, paliperidone, risperidone, ziprasidone, haloperidol, and other typical antipsychotic drugs, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 2-4 weeks.

59. The method according to claim 53, wherein the neuropsychiatric drug has a long half-life, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 1 - 3 weeks.

60. The method according to claim 53, wherein the neuropsychiatric drug is selected from aripiprazole, brexpiprazole, and cariprazine, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 1 - 3 weeks.

61. The method according to claim 53, wherein the therapeutic NM dose is at the upper limit of the recommended daily dose range, wherein the first NM transition dose is administered for 1 week, and the second NM transition dose is administered for 3 - 5 weeks.

62. The method according to claim 53, wherein the neuropsychiatric drug is a D2 antagonist and the first treatment period exceeds 6 months, 1 year, 2 years, 3 years, or 5 years, wherein the first NM transition dose is administered for 1 week and the second NM transition dose is administered for 3 - 5 weeks.

63. The method according to any one of claims 1 - 12, wherein the first ulotaront transition dose is less than the final ulotaront dose.

64. The method according to any one of claims 1 - 12, wherein the first ulotaront transition dose is less than the final ulotaront dose, which further comprises administering a second dose of ulotaront or a pharmaceutically acceptable salt thereof (second ulotaront transition dose) during the transition period, the second dose being greater than the first ulotaront transition dose and optionally the same as the final ulotaront dose.

65. The method according to claim 64, wherein the transition period is 2 - 6 weeks, the first ulotaront transition dose is administered during days 1 - 3 of the transition period, the second ulotaront transition dose is administered during days 4 - 7 of the transition period, and optionally a third ulotaront transition dose that is the same as the final ulotaront dose is administered during the remaining time of the transition period.

66. The method according to claim 64, wherein the first ulotaront transition dose is 50 mg / day, the second ulotaront transition dose is 75 mg / day, and the final ulotaront dose is 50 - 100 mg / day.

67. The method according to any one of claims 1 - 12, wherein the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety disorder.

68. The method according to any one of claims 1-12, wherein the neuropsychiatric disorder is schizophrenia.

69. The method according to any one of claims 1-12, wherein the neuropsychiatric disorder is MDD.

70. The method according to any one of claims 1-12, wherein the neuropsychiatric disorder is GAD.

71. The method according to any one of claims 1-12, wherein the first transition ulotaront dose and the final ulotaront dose are independently selected from 10-150 mg / day or 25-100 mg / day or 50-125 mg / day or 50-100 mg / day or 50-75 mg / day, administered orally.

72. The method according to any one of claims 1-12, wherein the first transition ulotaront dose and the final ulotaront dose are independently selected from 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day or 150 mg / day, administered orally.

73. The method according to any one of claims 1-12, wherein the first transition ulotaront dose and the final ulotaront dose are administered once daily in the fed or fasted state.

74. The method according to any one of claims 1-12, wherein the ulotaront is administered as the hydrochloride salt.

Images