Methods of Treating Anxiety and Related Conditions

Abstract

Neuropsychiatric treatments, including methods, regimens, and interventions for treating anxiety and related symptoms, based on urotalonto administration.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 381,327, filed October 28, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to pharmacological neuropsychiatric treatments and methods, regimens, and interventions for treating anxiety and related conditions based on urotalonto administration. [Background technology]

[0003] Generalized anxiety disorder (GAD), a prevalent and often recurrent disorder, is associated with significant medical and psychiatric morbidity and mortality, functional disability, and health care costs. Recent studies have shown that the 12-month prevalence of GAD in the American adult population is 2.9%, with a lifetime prevalence of 6.2% (Kessler 2012). International studies have found that the 12-month prevalence of GAD is 1.8%, with a lifetime prevalence of 3.7%, with both prevalence and functional impact being higher in high-income countries compared with low-income countries (Ruscio 2017). In general, anxiety disorders are a significant cause of impaired work performance and increased health care resource utilization, accounting for a substantial economic impact (Wittchen 2002; DuPont 1996; Greenberg 1999). GAD, in particular, results in substantial impact and economic burden on individuals and society (Pollack 2009).

[0004] Pharmacotherapy for GAD generally consists of antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs)) and benzodiazepines, as well as other medications used as augmentation, if needed (Garakani 2020). SSRIs and SNRIs generally have modest success in controlling GAD symptoms but have substantial side effects, which are important limiters of medication compliance and, ultimately, treatment outcomes (Kong 2020; Garakani 2020). Benzodiazepines have demonstrated high immediate efficacy for GAD symptoms (Gomez 2018; Garakani 2020), but their liability for abuse and dependence restricts their use to relatively short intervals in most treatment guidelines (Balon 2020). These factors, combined with the fact that GAD is a chronic disorder, result in a significant number of patients who either do not respond to or cannot tolerate first-line treatment (Bandelow 2008; Goodwin 2002; Altamura 2008; Allgulander 2002; Baldwin 2005). Relatedly, remission rates are low in GAD (Yonkers 1996), and the probability of relapse after remission is 27–39% within three years (Yonkers 2000).

[0005] For these reasons, there is a significant unmet need for novel agents for the treatment of GAD that improve symptoms and increase response and remission rates, but that do not have the burdensome side effect profile associated with available neuropsychiatric medications and the abuse and dependence liability associated with benzodiazepines and other neuropsychiatric medications. Summary of the Invention

[0006] In certain embodiments, the present disclosure provides a method of treating an anxiety disorder in a human subject who is not more than mildly depressed and is non-schizophrenic and in need of treatment, the method comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0007] In another embodiment, the present disclosure provides a method of treating an anxiety disorder in a human subject in need of treatment, having a HAM-A total score of 20 or greater, the method comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0008] Another embodiment provides a method of treating an anxiety disorder in a human subject in need of treatment having a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater, the method comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0009] Another embodiment provides a method of treating tension in a human subject who also suffers from a neuropsychiatric disorder, the method comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0010] Additional advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the specification, or may be learned by practice of the present disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. As asserted, 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 present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0011] All publications cited herein are hereby incorporated by reference in their entirety.

[0012] Terminology Use As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0013] Unless otherwise specified, the term "includes" (or any variation thereof, e.g., "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.

[0014] As used in this specification and the claims that follow, the term "comprise" and variations of that term, such as "comprising" and "comprises," mean "including, but not limited to," and are not intended to exclude, for example, other additional elements, components, integers, or steps. Where an element is described as comprising a plurality of components, steps, or conditions, it will be understood that the element may also be described as including any combination of such plurals, or may be described as "consisting of" or "consisting essentially of" a plurality or combination of components, steps, or conditions.

[0015] Apart from range qualifications, when a range is given by specifying a lower limit or when a specific specific numerical value is specified, it will be understood that the range can be defined by combining the lower variable, the upper variable, and any specific numerical value that is mathematically possible. When a range is stated as extending from one endpoint to another, it will be understood that both endpoints are included within the range. However, it will be understood that a range of from / to also includes embodiments in which the range is defined as between the two specified endpoints, and it will be understood that the term "between" can be substituted with the phrase "from / to" to omit the endpoints from the range.

[0016] This disclosure describes various embodiments. Those skilled in the art who review this disclosure will readily recognize that the various embodiments can be combined in any number of variations. For example, embodiments of the present disclosure include improvements in the treatment of various disorders, patient populations, administration of dosage forms, various doses, minimization of various adverse events, and various efficacy measures. All combinations of the various embodiments are within the scope of this disclosure.

[0017] When published test methodologies and diagnostic devices are referred to herein, it will be understood that the test methodology or diagnostic device is performed based on the version in effect as of October 1, 2022, unless otherwise specified herein. This is true even if the methodology or device is defined herein based on an earlier version of the publication.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] definition As used herein, "administering" or "administration" of urotalont or a pharmaceutically acceptable salt thereof includes delivering urotalont, or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein.

[0020] The term "atypical antidepressants" refers to antidepressants that do not fit into the conventional classification of antidepressants (e.g., SSRIs, SSNIs, tricyclic antidepressants, and MOAIs). Examples include bupropion (Wellbutrin®), vilazodone (Viibryd®), vortioxetine (Trintellix®), nefazodone, NASSAs (noradrenergic and specific serotonergic antidepressants) such as mirtazapine (Remeron®), SARIs (serotonin blockade reuptake inhibitors) such as trazodone (Molipaxin®), and NARIs (noradrenaline reuptake inhibitors) such as reboxetine.

[0021] The "CGI-C" (Clinical Global Impression-Change) scale measures the effectiveness of medication by rating the subject's overall change since starting medication and whether it is entirely attributable to medication. Response options include: 1 = much improved, 2 = improved, 3 = slightly improved, 4 = no change, 5 = slightly worse, 6 = worse, and 7 = much worse.

[0022] The "CGI-S" (Clinical Global Impression-Severity) scale is a standardized, clinician-administered global rating scale that measures the severity of illness on a 7-point Likert scale. Higher scores on the CGI-S represent greater illness severity. To perform this assessment, the rater or investigator answers the following question: "Considering your overall clinical experience with this particular population, how mentally ill is the patient at this time?" Response options include: 1 = healthy, not at all ill; 2 = borderline psychotic; 3 = mild; 4 = moderate; 5 = somewhat severe; 6 = severe; and 7 = very severe patient.

[0023] As used herein, a "clinically significant" or "clinically meaningful" improvement can mean both a statistically significant improvement and an improvement that is meaningful from the patient's, clinician's, or caregiver's perspective, typically based on improvement in statistical measures such as the CGI-S or retrospective assessments such as the CGI-C, as generally described in various U.S. Food and Drug Administration publications (including FDA2018, FDA2019, and FDA2020). It will be understood that when a treatment or benefit is described herein, the treatment or benefit preferably demonstrates clinically significant efficacy in a patient population to a statistically significant degree.

[0024] "Cyclic antidepressants" include tricyclic and tetracyclic antidepressants, which typically work by blocking the reuptake of the neurotransmitters serotonin and norepinephrine, increasing levels of these two neurotransmitters in the brain. Examples include amitriptyline, amoxapine, desipramine (Norpramin®), doxepin, imipramine (Tofranil®), nortriptyline (Pamelor®), protriptyline, trimipramine, and maprotiline.

[0025] As used herein, "delaying" the onset of a disorder means to defer, hinder, slow, stabilize, and / or postpone the onset of the disorder. The length of the delay can vary depending on the history of the disease and / or the individual being treated.

[0026] "DSM-5" refers to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition). Terms used herein may be defined with reference to DSM-5 where necessary to give life and meaning to the terms. When a person is defined herein in accordance with DSM-5, it will be understood that the person need not have been diagnosed using the criteria set forth in DSM-5; if so diagnosed, the person would meet the criteria specified in DSM-5.

[0027] The Hamilton Anxiety Rating Scale (HAM-A) is a clinician-administered rating scale developed to quantify the severity of anxiety symptoms. It consists of 14 items, each defined by a set of symptoms. Each item is rated on a 5-point (0-4) scale, with higher scores indicating greater severity (Hamilton 1959).

[0028] Healthcare resource utilization (HCRU) is the quantification or description of people's use of services to prevent and treat health problems, promote the maintenance of health and well-being, or obtain information about a person's health status and prognosis. HCRU includes questions about the number of doctor visits, emergency room (ER) visits, hospitalizations, length of hospital stay for any reason, and length of hospital stay for GAD-related treatment in the past month.

[0029] "MAOI" refers to the monoamine oxidase inhibitor class of antidepressants. Examples include isocarboxazid (Marplan®), phenelzine (Nardil®), selegiline (Emsam®), and tranylcypromine (Parnate®).

[0030] The Medication Satisfaction Questionnaire (MSQ) is a single-item, subject-rated, rater-administered questionnaire that requires subjects to use a 7-point Likert-type scale to rate how satisfied they are with their medication. Subjects are asked the following question: "Overall, how satisfied are you with your current GAD medication?" Subjects select one of seven possible responses based on their level of satisfaction, ranging from (1) very dissatisfied to (7) very satisfied.

[0031] The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated assessment of a subject's level of depression. The measure includes 10 items measuring apparent and reported sadness, inner tension, decreased sleep and appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal ideation. Each item is scored on a 0-6 scale, with higher scores indicating increased depressive symptoms (Montgomery 1979).

[0032] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for animal or human medical use.

[0033] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower organisms without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of urotalont include those derived from suitable inorganic and organic acids and inorganic and organic bases.

[0034] Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples of counterions include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. While pharmaceutically acceptable counterions are preferred for preparing pharmaceutical formulations, other anions (X) are well tolerated as synthetic intermediates. Thus, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, trifluoromethanesulfonate, and the like, when the salt is used as such a chemical intermediate.

[0035] As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, additive, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, emulsifier, anti-caking agent, flavoring agent, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system, and abrasive, approved or otherwise permitted by the U.S. Food and Drug Administration in appropriate quantities for use in humans or domestic animals.

[0036] As used herein, "prevention" or "preventing" refers to a regimen that protects against the onset of a disorder, so that the clinical symptoms of the disorder do not develop. Thus, "prevention" refers to administering a therapy to a subject before the symptoms of the disease become detectable in the subject (e.g., administering a therapy in the absence of detectable symptoms of the disorder). The subject may be an individual at risk of developing a disorder.

[0037] The Sheehan Disability Scale (SDS) is a clinician-assisted scale containing three items designed to measure the degree to which three major areas of a subject's life are impaired by mental or medical symptoms. This anchored visual analog scale simultaneously uses spatiovisual, numerical, and verbal descriptive anchors to assess impairment in three areas: work, social life, and family life. The subject rates the degree to which his or her 1) work, 2) social or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms on an 11-point visual analog scale ranging from 0 to 10. The scale includes verbal descriptors for points, as well as numeric scores that provide more precise levels of verbal descriptors. The three items may be summed to form a unidimensional measure of overall functional impairment ranging from 0 (not impaired) to 30 (very impaired).

[0038] The term "select" refers to the act of choosing from a number or group by aptitude or preference. In the context of this disclosure, urotalonto is selected from a group of commonly recognized neuropsychiatric drugs for the treatment of any of the neuropsychiatric conditions described herein.

[0039] The 36-item Short Form Questionnaire ("SF-36") is a self-report questionnaire with a standard 4-week look-back period that measures general health-related quality of life across eight health domain scales in two broad domains, physical and mental composite: physical functioning, pain, role-physical, overall health, vitality / fatigue, social functioning, role-mental, and mental health. The SF-36 uses norm-based scoring to generate scores on a scale of 1 to 100, with low scores on the physical component summary and mental component summary representing poor health-related quality of life and a score of 50 referring to normative data derived from surveys of representative samples of the general U.S. population.

[0040] As used herein, the term "significantly" refers to a statistically significant level. A statistically significant level can be p<0.1, p<0.05, p<0.01, p<0.005, or p<0.001. Unless otherwise specified, a statistically significant level is p<0.05 when the terms "significant," "significantly," or other variations are used. When a measurable result or effect is expressed or specified herein, it will be understood that the result or effect is preferably evaluated based on whether it is statistically significant compared to a baseline, such as a placebo. Similarly, when a treatment or benefit is described herein, it will be understood that the treatment or benefit preferably demonstrates efficacy in a patient group to a statistically significant degree.

[0041] "SNRIs" (serotonin-norepinephrine reuptake inhibitors) include, but are not limited to, desvenlafexine (Pristiq®), duloxetine (Cymbalta®), levomilnacipran (Fetzima®), and venlafexine (Effexor® XR), and pharmaceutically acceptable salts thereof.

[0042] "SSRIs" (selective serotonin reuptake inhibitors) include, but are not limited to, citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), paroxetine (Paxil®, Pexeva®), and sertraline (Zoloft®), and pharmaceutically acceptable salts thereof.

[0043] The Structured Clinical Interview for DSM-5 Axis I Disorders - Clinical Trial Version (SCID-5-CT) is a modified version of the SCID developed for use in clinical trials. It is a semi-structured interview for making DSM-5 diagnoses (First 2015).

[0044] As used herein, a "subject" or "patient" to whom administration is intended includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or geriatric adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals (including commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs); and / or birds (commercially relevant birds, e.g., chickens, ducks, geese, quail, and / or turkeys).

[0045] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response, and includes a compound in an amount sufficient to achieve treatment of the disorder when administered to a subject for treating the disorder. The effective amount will vary depending on the disorder and its severity, as well as the age, weight, etc., of the subject being treated. The effective amount may be a single dose or multiple doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount may be considered to be given in an effective amount when a desired or beneficial result is achieved, or is achieved, in combination with one or more other agents. The appropriate dose of the co-administered compounds may be appropriately reduced due to the additive or synergistic combined action of the compounds.

[0046] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder, or one or more symptoms thereof, including, but not limited to, therapeutic benefit. In some embodiments, treatment is administered after the onset of one or more symptoms (e.g., an acute exacerbation of symptoms). In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject before the onset of symptoms (e.g., in light of disease history and / or genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0047] Therapeutic benefit includes cure and / or amelioration of the underlying disorder being treated; and also includes cure and / or amelioration of one or more symptoms associated with the underlying disorder, such that an improvement may be observed in a subject, yet the subject may still be afflicted with the underlying disorder.

[0048] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., reducing one or more symptoms resulting from the disorder and / or reducing the extent of the disorder); (b) slowing or inhibiting the onset of symptoms associated with the disorder (e.g., stabilizing the disorder and / or slowing the worsening or progression of the disorder); and / or (c) alleviating the disorder (e.g., reversing clinical symptoms, alleviating the disorder, slowing the progression of the disorder, and / or improving quality of life).

[0049] "Urotalont" (a / k / a SEP-363856, SEP-856), when referred to herein for use in the methods of the 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"). Urotalont has the following structure: [ka] Unless otherwise specified or the context requires otherwise, for the purposes of this disclosure, the term "urotalont" alone includes the free form of urotalont, as well as its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms. If the free form is intended, or if any other form or salt is specifically intended, it will be explicitly stated.

[0050] Urotalont can be used in the methods described herein as a free base or a pharmaceutically acceptable salt. In a preferred embodiment, the hydrochloride (HCl) salt of urotalont is used in the methods described herein. Urotalont or its pharmaceutically acceptable salt (including its hydrochloride crystalline form) can be obtained according to the preparation methods described in PCT Patent Publication WO2011 / 069063 (U.S. Patent 8,710,245, issued April 29, 2014) or PCT Patent Publication WO2019 / 161238 (the entirety of which is incorporated herein by reference for all purposes), or similar methods.

[0051] Also provided herein are pharmaceutical compositions and dosage forms comprising urotalont 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.Urotalont or its pharmaceutically acceptable salt may be administered as part of the pharmaceutical composition described herein.

[0052] Consideration In certain embodiments, the present disclosure provides a method of treating an anxiety disorder in a non-schizophrenic, not more than mildly depressed human subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0053] In another embodiment, the present disclosure provides a method of treating an anxiety disorder in a human subject in need of treatment, having a HAM-A total score of 20 or greater, said method comprising administering to said subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein said treatment reduces the subject's HAM-A total score compared to placebo.

[0054] Another embodiment provides a method of treating an anxiety disorder in a human subject in need of treatment having a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater, said method comprising administering to said subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein said treatment reduces the subject's HAM-A total score compared to placebo.

[0055] Another embodiment provides a method of treating tension in a human subject who also suffers from a neuropsychiatric disorder, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0056] In various embodiments, the treatment achieves varying degrees of results. Thus, in some embodiments, the treatment results in a clinically significant reduction in the subject's HAM-A total score compared to placebo. In some embodiments, the treatment also results in a clinically significant reduction in the subject's CGI-S score compared to placebo. In some embodiments, the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score compared to placebo. In further embodiments, the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score after 8 weeks of administration compared to placebo. In further embodiments, the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score after 4 weeks and 8 weeks of administration compared to placebo.

[0057] Other embodiments are defined based on the numerical benefit achieved by the method. Thus, in some embodiments, the treatment reduces the subject's HAM-A total score to 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, or 6 or less. In some embodiments, the treatment reduces the subject's HAM-A total score by 40% or more, 50% or more, or 60% or more. In some embodiments, the treatment reduces the subject's CGI-S score by 1 or more, or 2 or more, or 3 or more.

[0058] It will be understood that when a treatment is referred to as producing a clinically significant therapeutic effect, the treatment may, in other embodiments, also be referred to as producing a reduction in the subject's CGI-S score by 2 or more. It will be understood that when a treatment is referred to as producing a clinically significant therapeutic effect, the treatment may, in other embodiments, also be referred to as producing a reduction in the subject's CGI-S score by 50% or more.

[0059] Given urotalont's unique behavioral signature (reported by Dedic 2019), human clinical results reported in PCT Patent Publication WO2020 / 118032, and urotalont's novel mechanism of action and receptor binding profile, urotalont is expected to treat neuropsychiatric disorders with high safety and efficacy. Thus, in one embodiment, urotalont is administered to a patient also suffering from a neuropsychiatric disorder selected from psychosis, depression, pain, cognition, mood disorders, and anxiety.

[0060] In other embodiments, neuropsychiatric disorders include schizophrenia, schizophrenia spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, dystopic personality disorder, schizotypal personality disorder, delusional disorder, psychosis, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder with systemic symptoms, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine), schizoaffective disorder, excited psychosis, organic or NOS psychosis, dyskinesia, mood disorders, anxiety, affective disorders (e.g., depression, e.g., major depressive disorder and dysthymia; bipolar disorders, e.g., bipolar depressive disorder, mania, seasonal affective disorder), pain (e.g., neuropathic pain, sensitization associated with neuropathic pain, and inflammatory pain), cognitive dysfunction, and movement disorders.

[0061] In some embodiments, the neuropsychiatric disorder is selected from schizophrenia, depression, and anxiety. In other embodiments, the neuropsychiatric disorder is schizophrenia. In other embodiments, the neuropsychiatric disorder is bipolar depression (particularly MDD as defined in DSM-5 and, more particularly, AMDD). In yet other embodiments, the neuropsychiatric disorder is anxiety (e.g., generalized anxiety disorder (GAD) as defined in DSM-5). In some embodiments, the neuropsychiatric disorder is an anxiety disorder.

[0062] In some embodiments, treating comprises ameliorating the tension or anxiety disorder. In some embodiments, treating comprises achieving a complete response to the tension or anxiety disorder. In other embodiments, treating comprises both ameliorating the tension or anxiety disorder and achieving a complete response to the tension or anxiety disorder.

[0063] In some embodiments, the subject is treatment naive.

[0064] In some embodiments, the subject has not responded adequately to previous buspirone or antidepressant therapy.

[0065] In some embodiments, the subject has poorly tolerated previous buspirone or antidepressant therapy.

[0066] As exemplary antidepressant therapies, SSRIs, SNRIs, cyclic antidepressants, atypical antidepressants, and MAOIs may be mentioned, although any molecule that exhibits an antidepressant mechanism of action is contemplated.

[0067] Anxiety disorders that may be treated by the methods of the present disclosure include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder. In some embodiments, the anxiety disorder is generalized anxiety disorder (GAD).

[0068] When the methods of the present disclosure are used to treat anxiety disorders, they can also be used to treat tension. Thus, if the patient also suffers from tension, the methods can further include treating the tension. In some embodiments, the patient suffers from tension, and the methods include treating the tension to a clinically significant extent.

[0069] Similarly, when the methods of the present disclosure are used to treat tension, they can also be used to treat anxiety disorders. Thus, if the patient also suffers from an anxiety disorder, the methods can further include treating the anxiety disorder.

[0070] In some embodiments, the methods of the present disclosure are used to treat a non-schizophrenic subject, hi other embodiments, the methods are used to treat a subject who is mildly or less depressed.

[0071] Where a score is provided (including but not limited to, the HAM-A, MADRS, CGI-S, etc.), the score is determined at the start of therapy unless otherwise specified. For example, a "method of treating an anxiety disorder in a human subject in need thereof having a HAM-A total score of 20 or greater" refers to the subject having a HAM-A total score of 20 or greater at the start of therapy.

[0072] The methods of the present disclosure can also be practiced based on a subject's score on the HAM-A. In some embodiments, the subject's HAM-A total score is 20 or greater. In some embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater.

[0073] In some embodiments, the subject's HAM-A anxious mood score is greater than or equal to 2. In some embodiments, the subject's HAM-A anxious mood score is greater than or equal to 2, greater than or equal to 4, or 4.

[0074] In some embodiments, the subject has a HAM-A tone score of 2 or greater. In some embodiments, the subject has a HAM-A tone score of 2 or greater, 3 or greater, or 4.

[0075] In other embodiments, the subject has a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater.

[0076] The methods of the present disclosure can also be practiced based on a subject's MADRS score. In some embodiments, the subject's MADRS total score is 22 or less. In some embodiments, the subject's MADRS total score is 22 or less, 20 or less, 18 or less, 16 or less, 14 or less, 12 or less, or 10 or less. When the term "mild depression" is used herein, it will be understood that, using the MADRS scoring system, a MADRS score in the range of 7 to 19 generally refers to "mild depression." However, for purposes of the present disclosure, the term "mild depression" includes patients with a MADRS score of 22 or less. A subject with "mild depression" or less can therefore alternatively be defined as having a MADRS total score of 22 or less, 19 or less, 16 or less, 14 or less, 12 or less, 10 or less, or 8 or less. Alternatively, subjects may be described based on a non-depressed MADRS score (i.e., less than 7) or a mildly depressed MADRS score (i.e., 7-22 or 7-19).

[0077] In some embodiments, the subject's MADRS inner strain score is 2 or greater, 3 or greater, 4 or greater, 5 or greater, or 6.

[0078] The methods of the present disclosure may also be practiced based on a subject's CGI-S score. In some embodiments, the subject's CGI-S score is 4 or greater. In some embodiments, the subject's CGI-S score is 4 or greater and treatment reduces the subject's CGI-S score by 2 or more points. In some embodiments, the subject's CGI-S score is 4 or greater and treatment reduces the CGI-S score to 3 or less.

[0079] The anxiety disorders of the present disclosure can be characterized based on one or a combination of sensations or symptoms. In some embodiments, the anxiety disorder comprises one or a combination of sensations or symptoms selected from anxious mood, tension, fear, insomnia, intelligence, depressed mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and anxious behavior.

[0080] In some embodiments, the anxiety disorder comprises one or more anxious mood sensations or symptoms selected from worry, worst-case anticipation, frightening anticipation, and irritability. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A anxious mood score is 2 or greater, 3 or greater, or 4.

[0081] In some embodiments, the anxiety disorder comprises one or more feelings or symptoms of tension selected from tension, easy fatigue, startle response, tearfulness, tremors, feeling restless, and inability to relax. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A tension score is 2 or greater, 3 or greater, or 4.

[0082] In some embodiments, the anxiety disorder comprises one or more fears selected from fear of the dark, fear of foreigners, fear of being alone, fear of animals, fear of vehicles, and fear of crowds. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A fear score is 2 or greater, 3 or greater, or 4.

[0083] In some embodiments, the anxiety disorder comprises one or more insomnia sensations or symptoms selected from difficulty falling asleep, disrupted sleep, unsatisfactory sleep and fatigue upon awakening, dreams, nightmares, and night terrors. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A insomnia score is 2 or greater, 3 or greater, or 4.

[0084] In some embodiments, the anxiety disorder includes one or more intellectual sensations or symptoms selected from difficulty concentrating and poor memory. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A intelligence score is 2 or greater, 3 or greater, or 4.

[0085] In some embodiments, the anxiety disorder comprises one or more of the following: a lack of interest, loss of pleasure in hobbies, depression, brisk walking, and diurnal variation in mood. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and their HAM-A depressed mood score is 2 or greater, 3 or greater, or 4.

[0086] In some embodiments, the anxiety disorder comprises one or more physical (muscle) sensations or symptoms selected from aches and pains, muscle twitching, stiffness, myoclonic jerks, teeth grinding, unsteady voice, and increased muscle tension. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A physical (muscle) score is 2 or greater, 3 or greater, or 4.

[0087] In some embodiments, the anxiety disorder comprises one or more somatic (sensory) sensations or symptoms selected from blurred vision, hot and cold flashes, feelings of weakness, and pricking sensations. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A somatic (sensory) score is 2 or greater, 3 or greater, or 4.

[0088] In some embodiments, the anxiety disorder comprises one or more cardiovascular symptoms selected from tachycardia, palpitations, chest pain, throbbing pain in the veins, fainting sensations, and arrhythmia. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A cardiovascular score is 2 or greater, 3 or greater, or 4.

[0089] In some embodiments, the anxiety disorder comprises one or more respiratory symptoms selected from chest tightness or pressure, choking, sighing, and shortness of breath. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A respiratory score is 2 or greater, 3 or greater, or 4.

[0090] In some embodiments, the anxiety disorder comprises one or more gastrointestinal symptoms selected from difficulty swallowing, abdominal pain, heartburn, bloating, nausea, vomiting, rumbling, diarrhea, weight loss, and constipation. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A gastrointestinal score is 2 or greater, 3 or greater, or 4.

[0091] In some embodiments, the anxiety disorder comprises one or more urogenital symptoms selected from urinary frequency, urinary urgency, amenorrhea, menorrhagia, and frigidity, premature ejaculation, loss of libido, and impotence. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A urogenital score is 2 or greater, 3 or greater, or 4.

[0092] In some embodiments, the anxiety disorder comprises one or more autonomic symptoms selected from dry mouth, flushing, pallor, sweet tooth preference, dizziness, tension headache, and hair standing on end. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A autonomic score is 2 or greater, 3 or greater, or 4.

[0093] In some embodiments, the anxiety disorder comprises one or more anxiety behaviors selected from fidgeting, restlessness or pacing, hand trembling, brow furrowing, facial tension, sighing or tachypnea, facial pallor, or swallowing. In other embodiments, the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A interview behavior score is 2 or greater, 3 or greater, or 4.

[0094] A therapeutically effective amount of urotalont may be variously described as 10-150 mg / day, 25-150 mg / day, 25-100 mg / day, 50-125 mg / day, 50-100 mg / day, or 50-75 mg / day, and may be administered orally. Alternatively, a therapeutically effective amount 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, and may be administered orally. In any embodiment of the present disclosure, a therapeutically effective amount may be administered once daily in a fed or fasted state. Urotalont may also be administered as the hydrochloride salt.

[0095] Preferred embodiments of the present disclosure can be defined based on the following embodiments AA to CM.

[0096] [Embodiment AA] A method for treating an anxiety disorder in a non-schizophrenic human subject who is mildly or less depressed and in need of treatment, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0097] [Embodiment AB] A method for treating an anxiety disorder in a human subject in need of treatment, having a HAM-A total score of 20 or greater, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0098] [Embodiment AC] A method for treating an anxiety disorder in a human subject in need of treatment, having a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

[0099] [Embodiment AD] A method according to any of embodiments AA to AC, wherein the treatment results in a clinically significant reduction in the subject's HAM-A total score compared to placebo.

[0100] [Embodiment AE] A method according to any one of embodiments AA to AC, wherein the treatment also results in a clinically significant reduction in the subject's CGI-S score compared to placebo.

[0101] [Embodiment AF] A method described in any of embodiments AA to AC, wherein the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score 8 weeks after initiating administration, compared to placebo.

[0102] [Embodiment AG] A method described in any of embodiments AA to AC, wherein the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score 4 and 8 weeks after initiating administration compared to placebo.

[0103] [Embodiment AH] A method described in any of embodiments AA to AG, wherein the treatment reduces the subject's HAM-A total score to 7 or less.

[0104] [Embodiment AI] A method described in any of embodiments AA to AH, wherein the treatment reduces the subject's HAM-A total score by 50% or more.

[0105] [Embodiment AJ] A method described in any of embodiments AA to AI, wherein the treatment reduces the subject's CGI-S score by 1 or more or 2 or more.

[0106] [Embodiment AK] A method described in any of embodiments AA to AI, wherein the treatment reduces the subject's CGI-S score to 3 or less.

[0107] [Embodiment AL] A method described in any of embodiments AA to AI, wherein the treatment reduces the subject's CGI-S score to 2 or less.

[0108] [Embodiment AM] A method according to any one of embodiments AB to AL, wherein the subject is non-schizophrenic.

[0109] [Embodiment AN] A method described in any of embodiments AB to AL, wherein the subject has mild or less depression.

[0110] [Embodiment AO] A method described in any of embodiments AA or AD-AL, wherein the subject has a total HAM-A score of 20 or greater.

[0111] [Embodiment AP] A method described in embodiment AA or AB, or any of embodiments AD to AL, wherein the subject has a HAM-A anxiety mood score of 2 or greater.

[0112] [Embodiment AQ] A method described in embodiment AA or AB, or any of embodiments AD to AL, wherein the subject has a HAM-A tension score of 2 or greater.

[0113] [Embodiment AR] A method described in embodiment AA or AB, or any of embodiments AD to AL, wherein the subject has a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater.

[0114] [Embodiment AS] A method described in any one of embodiments AA to AR, wherein the subject's MADRS total score is 22 or less.

[0115] [Embodiment AT] A method described in any one of embodiments AA to AS, wherein the subject's MADRS internal tension score is 2 or higher, 3 or higher, 4 or higher, 5 or higher, or 6.

[0116] [Embodiment AU] A method described in any one of embodiments AA to AT, wherein the subject has a CGI-S score of 4 or greater.

[0117] [Embodiment AV] A method described in any one of embodiments AA to AU, wherein the anxiety disorder includes one or a combination of sensations or symptoms selected from anxious mood, tension, fear, insomnia, intelligence, depressed mood, physical (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, urogenital symptoms, autonomic symptoms, and anxiety behavior.

[0118] [Embodiment AW] A method according to any one of embodiments AA to AV, wherein the anxiety disorder comprises one or more anxious mood sensations or symptoms selected from worry, worst-case anticipation, frightening anticipation, and irritability.

[0119] [Embodiment AX] A method described in any one of embodiments AA to AW, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A anxiety mood score is 2 or greater, 3 or greater, or 4.

[0120] [Embodiment AY] A method described in any one of embodiments AA to AX, wherein the anxiety disorder includes one or more feelings or symptoms of tension selected from tension, fatigue, startle response, tearfulness, tremors, restlessness, and inability to relax.

[0121] [Embodiment AZ] A method described in any one of embodiments AA to AY, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A tension score is 2 or greater, 3 or greater, or 4.

[0122] [Embodiment BA] A method described in any one of embodiments AA to AZ, wherein the anxiety disorder includes one or more fears selected from fear of the dark, fear of foreigners, fear of isolation, fear of animals, fear of vehicles, and fear of crowds.

[0123] [Embodiment BB] A method described in any one of embodiments AA to BA, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A fear score is 2 or greater, 3 or greater, or 4.

[0124] [Embodiment BC] A method according to any one of embodiments AA to BB, wherein the anxiety disorder includes one or more insomnia sensations or symptoms selected from difficulty falling asleep, intermittent sleep, unsatisfactory sleep and fatigue upon awakening, dreams, nightmares, and night terrors.

[0125] [Embodiment BD] A method described in any one of embodiments AA to BC, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A insomnia score is 2 or greater, 3 or greater, or 4.

[0126] [Embodiment BE] A method according to any one of embodiments AA to BD, wherein the anxiety disorder includes one or more intellectual sensations or symptoms selected from difficulty concentrating and poor memory.

[0127] [Embodiment BF] A method described in any one of embodiments AA to BE, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A intelligence score is 2 or greater, 3 or greater, or 4.

[0128] [Embodiment BG] A method described in any one of embodiments AA to BF, wherein the anxiety disorder includes one or more sensations or symptoms of depressed mood selected from lack of mind, loss of pleasure in hobbies, depression, brisk walking, and diurnal variation.

[0129] [Embodiment BH] A method described in any one of embodiments AA to BG, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A depressed mood score is 2 or greater, 3 or greater, or 4.

[0130] [Embodiment BI] A method according to any one of embodiments AA to BH, wherein the anxiety disorder includes one or more physical (muscular) sensations or symptoms selected from aches and pains, muscle twitching, stiffness, myoclonic jerks, teeth grinding, unsteady voice, and increased muscle tension.

[0131] [Embodiment BJ] A method described in any one of embodiments AA to BI, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A physical (muscle) score is 2 or greater, 3 or greater, or 4.

[0132] [Embodiment BK] A method described in any one of embodiments AA to BJ, wherein the anxiety disorder includes one or more physical (sensory) sensations or symptoms selected from tinnitus, blurred vision, hot and cold flashes, feelings of weakness, and pricking sensations.

[0133] [Embodiment BL] A method described in any one of embodiments AA to BK, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A physical (five sensory) score is 2 or greater, 3 or greater, or 4.

[0134] [Embodiment BM] A ​​method according to any one of embodiments AA to BL, wherein the anxiety disorder includes one or more cardiovascular symptoms selected from tachycardia, palpitations, chest pain, throbbing pain in the veins, a feeling of fainting, and arrhythmia.

[0135] [Embodiment BN] A method described in any one of embodiments AA to BM, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A cardiovascular score is 2 or greater, 3 or greater, or 4.

[0136] [Embodiment BO] A method described in any one of embodiments AA to BN, wherein the anxiety disorder includes one or more respiratory symptoms selected from chest tightness or constriction, choking sensation, sighing, and shortness of breath.

[0137] [Embodiment BP] A method described in any one of embodiments AA to BO, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A respiratory score is 2 or greater, 3 or greater, or 4.

[0138] [Embodiment BQ] A method described in any one of embodiments AA to BP, wherein the anxiety disorder includes one or more gastrointestinal symptoms selected from difficulty swallowing, wind abdominal pain, heartburn, abdominal bloating, nausea, vomiting, rumbling, diarrhea, weight loss, and constipation.

[0139] [Embodiment BR] A method according to any one of embodiments AA to BQ, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A gastrointestinal score is 2 or greater, 3 or greater, or 4.

[0140] [Embodiment BS] A method according to any one of embodiments AA to BR, wherein the anxiety disorder comprises one or more urogenital symptoms selected from frequent urination, urgency, amenorrhea, menorrhagia, and the development of anorgasmia, premature ejaculation, loss of libido, and impotence.

[0141] [Embodiment BT] A method described in any one of embodiments AA to BS, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A urogenital score is 2 or greater, 3 or greater, or 4.

[0142] [Embodiment BU] A method described in any one of embodiments AA to BT, wherein the anxiety disorder includes one or more autonomic nervous system symptoms selected from dry mouth, flushing, pallor, sweet tooth preference, dizziness, tension headache, and hair standing on end.

[0143] [Embodiment BV] A method described in any one of embodiments AA to BU, wherein the subject's HAM-A total score is 20 or more, 22.5 or more, 25 or more, 27.5 or more, 30 or more, 32.5 or more, or 35 or more, and the HAM-A autonomic nervous system score is 2 or more, 3 or more, or 4.

[0144] [Embodiment BW] A method described in any one of embodiments AA to BV, wherein the anxiety disorder includes one or more anxiety behaviors selected from fidgeting, restlessness or pacing, hand trembling, brow furrowing, tense face, sighing or hyperventilation, facial pallor, or swallowing.

[0145] [Embodiment BX] A method described in any one of embodiments AA to BW, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and the HAM-A interview behavior score is 2 or greater, 3 or greater, or 4.

[0146] [Embodiment BY] A method described in any one of embodiments AA to BX, wherein the subject's HAM-A total score is 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater.

[0147] [Embodiment BZ] A method described in any one of embodiments AA to BY, wherein the subject's HAM-A anxiety mood score is 2 or higher, 3 or higher, or 4.

[0148] [Embodiment CA] A method described in any one of embodiments AA to BZ, wherein the subject's HAM-A tension score is 2 or greater, 3 or greater, or 4.

[0149] [Embodiment CB] A method described in any one of embodiments AA to CA, wherein the subject's MADRS total score is 22 or less, 20 or less, 18 or less, 16 or less, 14 or less, 12 or less, or 10 or less.

[0150] [Embodiment CC] A method according to any one of embodiments AA to CB, wherein the subject is treatment-naive.

[0151] [Embodiment CD] The method described in any of Embodiments AA-CB, wherein the subject has failed to adequately respond to previous buspirone or antidepressant therapy.

[0152] [Embodiment CE] The method described in any of Embodiments AA-CB, wherein the subject has not tolerated previous buspirone or antidepressant therapy well.

[0153] [Embodiment CF] The method described in embodiment CD or CE, wherein the antidepressant therapy is selected from an SSRI, an SNRI, a cyclic antidepressant, a typical antidepressant, and an MAOI.

[0154] [Embodiment CG] The method of any one of embodiments AA-CF, wherein said treating comprises ameliorating said anxiety disorder.

[0155] [Embodiment CH] A method according to any one of embodiments AA-CF, wherein the treatment includes a complete response to the anxiety disorder.

[0156] [Embodiment CI] A method according to any one of embodiments AA to CH, wherein the anxiety disorder is selected from generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder.

[0157] [Embodiment CJ] The method of any one of embodiments AA-CI, wherein the anxiety disorder is generalized anxiety disorder (GAD).

[0158] [Embodiment CK] A method according to any one of embodiments AA to CJ, wherein the therapeutically effective amount is, by oral administration, 10 to 150 mg / day, 25 to 150 mg / day, 25 to 100 mg / day, 50 to 125 mg / day, 50 to 100 mg / day, or 50 to 75 mg / day.

[0159] [Embodiment CL] A method according to any one of embodiments AA to CK, wherein the therapeutically effective amount is 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.

[0160] [Embodiment CM] A method according to any one of embodiments AA to CL, wherein the therapeutically effective amount is administered once daily in a fed or fasted state.

[0161] [Embodiment CN] The method of any one of embodiments AA-CM, wherein the urotalonto is administered as a hydrochloride salt. [Example]

[0162] In the following examples, efforts have been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed in this application are made and evaluated, and are intended to be merely exemplary of the present disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0163] Example 1. Effects of SEP-363856 on Marble Burying and Locomotor Activity in Mice SEP-363856 was evaluated in a mouse marble-burying test, which is sensitive to several anxiolytic and antidepressant drugs (Nicolas 2006). Male Swiss mice (5 weeks old, n = 10 per group) received a single dose of vehicle (oral), SEP363856 (0.3, 1, 3, or 10 mg / kg, oral), or clobazam (8 mg / kg, intravenous), which served as a positive control. After 30 minutes, mice were individually placed in clear plastic cages with a 5 cm sawdust floor and 25 marbles grouped together in the center of the cage. The number of marbles covered by sawdust (2 / 3 or more covered) was counted at the end of the 30-minute test. Two days later, the same animals were assessed for general locomotor activity in a locomotor test. Mice were placed in an automated locomotor system 30 minutes after administration, and the number of crossings was recorded for 30 minutes in 5-minute increments. Chlorpromazine (4 mg / kg, intravenous administration) was included as a positive assay control. Results of SEP-363856 in the marble-burying test were analyzed by Kruskal-Walls test followed by a Mann-Whitney U test to determine group effects. Locomotor activity was analyzed by one-way analysis of variance followed by Dunnett's post-hoc comparisons. The effects of clobazam in the marble-burying test and locomotor measurement tests were examined using a Mann-Whitney U test and an unpaired Student's t-test, respectively.

[0164] SEP-363856 significantly reduced the number of marbles buried at dose levels of 0.3, 3, and 10 mg / kg (oral) compared with vehicle-treated controls (Table 1). In the locomotor test, a modest but significant decrease in the number of crossings was observed only at the highest dose (10 mg / kg, oral) (Table 2). This result indicates that the anxiolytic-like effect of SEP-363856 in the marble-burying test is unlikely to be due to locomotor confounds at dose levels of 3 mg / kg or less. [Table 1] [Table 2]

[0165] Example 2. A Phase 2 / 3, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Flexible-Dose, Multicenter Study to Evaluate the Efficacy and Safety of SEP-363856 in the Treatment of Adults with Generalized Anxiety Disorder This study is a multicenter, randomized, double-blind, parallel-group, flexible-dose, outpatient study evaluating the efficacy and safety of variable-dose SEP-363856 (50-75 mg / day) versus placebo in patients with GAD over an 8-week treatment period. The study is expected to randomize approximately 434 subjects 1:1 into two treatment groups (SEP-363856 [50-75 mg / day] or placebo). The study drug will be taken at approximately the same time each night at bedtime and may be taken with or without food.

[0166] The study consisted of three periods: screening / washout (maximum 21 days), treatment (8 weeks), and a follow-up visit (7 days after the last study drug dose for subjects who discontinued before the 8-week visit [Visit 7] or completed the study).

[0167] During the screening / washout period (maximum 21 days), subjects will be evaluated at a screening visit (Visit 1) to determine their eligibility to participate in the study. During the screening / washout period, subjects will taper off all psychotropic medications (except for acceptable concomitant medications) in accordance with label recommendations and good medical practice, and discontinue them completely for at least 3 days or 5 half-lives (whichever is longer) prior to randomization.

[0168] During the 8-week treatment period, subjects who successfully completed the washout of prior medication at baseline (Day 1) and met the eligibility criteria were randomly assigned 1:1 via the randomization and trial supply management (RTSM) system to one of two treatment groups: SEP-363856 (50-75 mg / day) or placebo. Study drug administration began the evening of the baseline visit. Treatment continued once daily at bedtime for the remainder of the 8-week treatment period.

[0169] All subjects will receive 25 mg / day or placebo for the first 3 days of the treatment period, and will begin receiving 50 mg / day or placebo on Day 4. All subjects will begin receiving 75 mg / day or placebo on Day 8. The investigator may request a dose reduction for safety or tolerability reasons at any time after Week 1 (Visit 3), at the investigator's discretion. Subjects who cannot tolerate the study drug after a dose reduction (blinded dummy dose reduction or actual dose reduction) will be discontinued from the study.

[0170] At the end of the treatment period, subjects will have an end-of-treatment (EOT) visit at week 8 (Visit 7). Subjects who discontinue or complete the study early will be required to complete a follow-up visit 7 days (± 2 days) after their last dose of study drug. During the 1-week follow-up period, subjects should not initiate new treatments unless required by the emergence of an adverse event or, in the investigator's judgment, for the subject's safety. Upon completion of the follow-up period, treatment may be initiated based on the discretion of the investigator or the subject's care physician.

[0171] Primary Efficacy Objective: To evaluate the efficacy of flexible doses of SEP-363856 (50-75 mg / day) compared with placebo in subjects with GAD, as measured by the Hamilton Anxiety Rating Scale (HAM-A) total score.

[0172] Secondary Efficacy Objective: To evaluate the efficacy of flexible doses of SEP-363856 (50-75 mg / day) compared with placebo in subjects with GAD, as measured by Clinical Global Impression-Severity (CGI-S) scores.

[0173] Other efficacy objectives: (i) To evaluate the efficacy of flexible doses of SEP-363856 (50-75 mg / day) compared with placebo in subjects with GAD as measured by the proportion of subjects meeting HAM-A response criteria (≥50% improvement from baseline score), the proportion of subjects meeting HAM-A remission criteria (total score ≤7), and the Montgomery-Åsberg Depression Rating Scale (MADRS); (ii) To evaluate the effect of flexible doses of SEP-363856 (50-75 mg / day) on health-related quality of life and productivity as measured by the 36-item Short Form Questionnaire (SF-36), Sheehan Disability Scale (SDS), and Healthcare Resource Utilization (HCRU); (iii) To evaluate medication satisfaction as measured by the Medication Satisfaction Questionnaire (MSQ).

[0174] Primary endpoint: Change from baseline in HAM-A total score at endpoint (week 8).

[0175] Secondary efficacy endpoint: Change from baseline in CGI-S score at endpoint (week 8).

[0176] Other efficacy endpoints were: (i) change from baseline in MADRS total score at weeks 4 and 8, SDS total score at weeks 4 and 8, SF-36 physical component score, mental component score, and subscales at week 8; (ii) change from screening in MSQ score at week 8; (iii) HAM-A response rate, defined as the proportion of subjects achieving a 50% or greater improvement from baseline in the HAM-A total score at each scheduled visit and at the endpoint (week 8); (iv) HAM-A remission rate, defined as the proportion of subjects achieving a HAM-A total score of 7 or less at each scheduled visit and at the endpoint (week 8); (v) HCRU at baseline and week 8.

[0177] Subject Selection and Inclusion Criteria: To be eligible to participate, subjects must meet all of the following selection and inclusion criteria: (i) male or female subjects who are 18–65 years of age (inclusive) at the time of consent; (ii) subjects meet criteria for GAD in the Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (DSM-5) as established by clinical interview (referenced to DSM-5 and confirmed using the Structured Clinical Interview for DSM-5 Clinical Trials Edition (SCID-5CT)); (iii) subjects may also have a comorbid diagnosis of panic disorder, social anxiety disorder, or specific phobia based on DSM-5; however, the symptoms are secondary to GAD and not the primary focus of treatment; (iii) the subject must have a HAM-A total score of 20 or greater and both HAM-A Item 1 (anxious mood) and HAM-A Item 2 (tension) scores of 2 or greater on the HAM-A administered by a clinician at screening and baseline; (iv) the subject must have a MADRS total score of 22 or less at screening and baseline; (v) the subject must have a CGI-S score of 4 or greater at screening and baseline. References Allgulander C, Hirschfeld RM, Nutt DJ. Long-term treatment strategies in anxiety disorders. Psychopharmacol Bull. 2002;36 Suppl 2:79-92. Altamura AC, Dell'osso B, D'Urso N, Russo M, Fumagalli S, Mundo E. Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder. CNS Spectr. 2008;13(5):415-422. Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JRT, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19(6):567-596. Balon R, Starcevic V. Role of Benzodiazepines in Anxiety Disorders. Adv Exp Med Biol. 2020;1191:367-388. Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders: first revision. World J Biol Psychiatry. 2008;9(4):248-312. DuPont RL, Rice DP, Miller LS, Shiraki SS, Rowland CR, Harwood HJ. Economic costs of anxiety disorders. Anxiety. 1996; 2(4):167-172. First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5-Clinical Trials Version (SCID-5-CT); Arlington, VA, American Psychiatric Association, 2015. Food and Drug Administration (U.S.). Discussion Document for Patient-Focused Drug Development Public Workshop on Guidance 3: SELECT, DEVELOP OR MODIFY FIT-FOR-PURPOSE CLINICAL OUTCOME ASSESSMENTS (including Appendices) (Published at Patient-Focused Drug Development Guidance: Methods to Identify What is Important to Patients and Select, Develop or Modify Fit-for-Purpose Clinical Outcome Assessments, Meeting October 15-16, 2018) (FDA 2018) Food and Drug Administration (U.S.). Patient-Focused Drug Development: Methods to Identify What Is Important to Patients Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (October 2019) (FDA 2019) Food and Drug Administration (U.S.). Patient-Focused Drug Development: Collecting Comprehensive and Representative Input; Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (June 2020) (FDA 2020). Garakani A, Murrough JW, Freire RC, Thom RP, Larkin K, Buono FD, et al. Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options. Front Psychiatry. 2020;11:595584. Gomez AF, Barthel AL, Hofmann SG. Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review. Expert Opin Pharmacother. 2018 June;19(8):883-894. Goodwin RD, Gorman JM. Psychopharmacologic treatment of generalized anxiety disorder and the risk of major depression. Am J Psychiatry. 2002;159(11):1935-1937. Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, et al. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60(7):427-435. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve‐month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. International journal of methods in psychiatric research. 2012 Sep;21(3):169-84. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50-55. Kong W, Deng H, Wan J, Zhou Y, Zhou Y, Song B, et al. Comparative Remission Rates and Tolerability of Drugs for Generalised Anxiety Disorder: A Systematic Review and Network Meta-analysis of Double-Blind Randomized Controlled Trials. Front Pharmacol. 2020;11:580858. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389. Nicolas LB, Kolb Y, Prinssen EPM. A combined marble burying-locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants.゜Eur J Pharmacol.゜2006;547:106-115. PCT Patent Publication No. WO 2020 / 118032 PCT Patent Publication No. WO2011 / 069063 PCT Patent Publication No. WO2019 / 161238 Pollack MH. Refractory generalized anxiety disorder. J Clin Psychiatry. 2009;70 Suppl 2:32-38. Ruscio AM, Hallion LS, Lim CCW, et al. Cross-sectional Comparison of the Epidemiology of DSM-5 Generalized Anxiety Disorder Across the Globe. JAMA Psychiatry. 2017;74(5):465-475. doi:10.1001 / jamapsychiatry.2017.0056 Vernon MK, Revicki DA, Awad AG, Dirani R, et al. Psychometric evaluation of the Medication Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among schizophrenia patients. Schizophr Res. 2010;118:271-278. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety. 2002;16(4):162-171. Yonkers KA, Dyck IR, Warshaw MG, Keller MB. Factors predicting the clinical course of generalized anxiety disorder. Br J Psychiatry. 2000;176:544-549. Yonkers KA, Warshaw MG, Massion AO, Keller MB. Phenomenology and Course of Generalized Anxiety Disorder. Br J Psychiatry. 1996;168:308-313.

[0178] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are incorporated herein by reference in order to more fully describe the state of the art to which this disclosure pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope and spirit of the disclosure. Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the disclosure being indicated by the following claims.

Claims

1. 1. A method for treating an anxiety disorder in a human subject in need of treatment, who is non-schizophrenic and not more than mildly depressed, comprising administering to said subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein said treatment reduces the subject's HAM-A total score compared to placebo.

2. 1. A method of treating an anxiety disorder in a human subject in need thereof, the subject having a HAM-A total score of 20 or greater, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

3. 1. A method of treating an anxiety disorder in a human subject in need thereof, having a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater, comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, wherein the treatment reduces the subject's HAM-A total score compared to placebo.

4. 4. The method of any one of claims 1 to 3, wherein said treatment results in a clinically significant decrease in the subject's HAM-A total score compared to placebo.

5. 4. The method of any one of claims 1 to 3, wherein the treatment also results in a clinically significant decrease in the subject's CGI-S score compared to placebo.

6. 4. The method of any one of claims 1 to 3, wherein the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score 8 weeks after initiating administration compared to placebo.

7. 4. The method of any one of claims 1 to 3, wherein the treatment results in a clinically significant reduction in the subject's HAM-A total score and CGI-S score at 4 and 8 weeks after initiation of administration compared to placebo.

8. 4. The method of any one of claims 1 to 3, wherein said treatment reduces the subject's HAM-A total score to 7 or less.

9. 4. The method of any one of claims 1 to 3, wherein said treatment reduces the subject's HAM-A total score by 50% or more.

10. 4. The method of any one of claims 1 to 3, wherein the treatment reduces the subject's CGI-S score by 1 or more or 2 or more.

11. 4. The method of any one of claims 1 to 3, wherein said treatment reduces the subject's CGI-S score to 3 or less.

12. 4. The method of any one of claims 1 to 3, wherein said treatment reduces the subject's CGI-S score to 2 or less.

13. The method according to any one of claims 2 to 3, wherein the subject is non-schizophrenic.

14. The method according to any one of claims 2 to 12, wherein the subject is suffering from mild or less depression.

15. 2. The method of claim 1, wherein the subject has a HAM-A total score of 20 or greater.

16. 3. The method of claim 1 or 2, wherein the subject has a HAM-A anxiety mood score of 2 or greater.

17. 3. The method of claim 1 or 2, wherein the subject has a HAM-A tone score of 2 or greater.

18. 3. The method of claim 1 or 2, wherein the subject has a HAM-A total score of 20 or greater, a HAM-A anxious mood score of 2 or greater, and a HAM-A tension score of 2 or greater.

19. The method of any one of claims 1 to 3, wherein the subject has a MADRS total score of 22 or less.

20. 4. The method of any one of claims 1 to 3, wherein the subject has a MADRS inner strain score of 2 or greater, 3 or greater, 4 or greater, 5 or greater, or 6.

21. The method of any one of claims 1 to 3, wherein the subject has a CGI-S score of 4 or greater.

22. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or a combination of sensations or symptoms selected from anxious mood, tension, fear, insomnia, intellectual, depressed mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and anxious behavior.

23. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more anxious mood sensations or symptoms selected from worry, worst-case anticipation, frightening anticipation, and irritability.

24. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A anxious mood score of 2 or greater, 3 or greater, or 4.

25. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more feelings or symptoms of tension selected from tension, easy fatigue, startle response, tearfulness, trembling, feeling restless, and inability to relax.

26. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A tension score of 2 or greater, 3 or greater, or 4.

27. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more fears selected from fear of the dark, fear of foreigners, fear of isolation, fear of animals, fear of vehicles, and fear of crowds.

28. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A fear score of 2 or greater, 3 or greater, or 4.

29. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more insomnia sensations or symptoms selected from difficulty falling asleep, intermittent sleep, unsatisfactory sleep and fatigue upon awakening, dreams, nightmares, and night terrors.

30. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A insomnia score of 2 or greater, 3 or greater, or 4.

31. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more cognitive sensations or symptoms selected from difficulty concentrating and poor memory.

32. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater and a HAM-A intelligence score of 2 or greater, 3 or greater, or 4.

33. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more feelings or symptoms of depressed mood selected from lack of interest, loss of pleasure in hobbies, depression, brisk walking, and diurnal variation.

34. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater and a HAM-A depressed mood score of 2 or greater, 3 or greater, or 4.

35. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more physical (muscular) sensations or symptoms selected from aches and pains (ache), muscle twitching, stiffness, myoclonic jerks, teeth grinding, unsteady voice, and increased muscle tension.

36. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A physical (muscle) score of 2 or greater, 3 or greater, or 4.

37. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more somatic (sensory) sensations or symptoms selected from tinnitus, blurred vision, hot and cold flashes, feelings of weakness, and a pricking sensation.

38. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A physical (sensory) score of 2 or greater, 3 or greater, or 4.

39. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more cardiovascular symptoms selected from tachycardia, palpitations, chest pain, throbbing pain in the veins, fainting sensations, and arrhythmia.

40. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A cardiovascular score of 2 or greater, 3 or greater, or 4.

41. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more respiratory symptoms selected from chest tightness or constriction, choking sensation, sighing, and difficulty breathing.

42. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A respiratory score of 2 or greater, 3 or greater, or 4.

43. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more gastrointestinal symptoms selected from difficulty swallowing, wind abdominal pain, heartburn, abdominal bloating, nausea, vomiting, rumbling in the abdomen, diarrhea, weight loss, and constipation.

44. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A gastrointestinal score of 2 or greater, 3 or greater, or 4.

45. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more urogenital symptoms selected from urinary frequency, urgency, amenorrhea, menorrhagia, and the occurrence of frigidity, premature ejaculation, loss of libido, and impotence.

46. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A genitourinary score of 2 or greater, 3 or greater, or 4.

47. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more autonomic symptoms selected from dry mouth, flushing, pallor, sweet tooth preference, dizziness, tension headache, and hair standing on end.

48. 4. The method of claim 1, wherein the subject has a HAM-A total score of 20 or more, 22.5 or more, 25 or more, 27.5 or more, 30 or more, 32.5 or more, or 35 or more, and a HAM-A autonomic score of 2 or more, 3 or more, or 4.

49. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder comprises one or more anxiety behaviors selected from fidgeting, restlessness or pacing, hand trembling, brow furrowing, tense face, sighing or tachypnea, facial pallor, or swallowing.

50. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater, and a HAM-A interview behavior score of 2 or greater, 3 or greater, or 4.

51. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A total score of 20 or greater, 22.5 or greater, 25 or greater, 27.5 or greater, 30 or greater, 32.5 or greater, or 35 or greater.

52. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A anxiety mood score of 2 or greater, 3 or greater, or 4.

53. 4. The method of any one of claims 1 to 3, wherein the subject has a HAM-A tone score of 2 or greater, 3 or greater, or 4.

54. 4. The method of any one of claims 1 to 3, wherein the subject's MADRS total score is 22 or less, 20 or less, 18 or less, 16 or less, 14 or less, 12 or less, or 10 or less.

55. The method of any one of claims 1 to 3, wherein the subject is treatment naive.

56. 4. The method of any one of claims 1 to 3, wherein the subject has failed to adequately respond to previous buspirone or antidepressant therapy.

57. 4. The method of any one of claims 1 to 3, wherein the subject has poorly tolerated previous buspirone or antidepressant therapy.

58. 57. The method of claim 56, wherein the antidepressant therapy is selected from an SSRI, an SNRI, a cyclic antidepressant, an atypical antidepressant, and an MAOI.

59. 4. The method of any one of claims 1 to 3, wherein the treating comprises ameliorating an anxiety disorder.

60. 4. The method of any one of claims 1 to 3, wherein the treatment comprises a complete response to the anxiety disorder.

61. 4. The method of any one of claims 1 to 3, wherein the anxiety disorder is selected from generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and panic disorder.

62. The method of any one of claims 1 to 3, wherein the anxiety disorder is generalized anxiety disorder (GAD).

63. 4. The method of any one of claims 1 to 3, wherein the therapeutically effective amount is 10 to 150 mg / day, 25 to 150 mg / day, 25 to 100 mg / day, 50 to 125 mg / day, 50 to 100 mg / day, or 50 to 75 mg / day, administered orally.

64. 4. The method of any one of claims 1 to 3, wherein the therapeutically effective amount is 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.

65. The method of any one of claims 1 to 3, wherein the therapeutically effective amount is administered once daily in a fed or fasted state.

66. The method of any one of claims 1 to 3, wherein the urotalont is administered as the hydrochloride salt.

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