Methods of treating CNS disorders

Abstract

Antidepressant therapy, methods for augmenting antidepressant therapy, particularly antidepressant therapy that has not provided an adequate response, and patient populations that would benefit from such augmentation therapy are provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 373,909, filed August 30, 2022, the entire contents of which are incorporated herein by reference as if fully set forth herein.

[0002] The present disclosure relates to antidepressant therapy, methods of augmenting antidepressant therapy, particularly those that have not provided an adequate response, and patient populations that would benefit from such augmentation therapy. [Background technology]

[0003] Major depressive disorder, or MDD, is a common, disabling illness that affects as many as 15% of people over the course of their lives. (Connolly 2011) While the introduction of newer generation antidepressants has significantly improved the prognosis for these patients, still only approximately 50–60% of patients respond to first-line treatment, and only 35–40% experience symptom remission during the initial 8-week trial. (Connolly 2011) Recommended first-line antidepressant medications include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), bupropion, and mirtazapine, among others.

[0004] Although many guidelines exist to aid in the management of major depressive disorder, recommendations for treating depression that has not adequately responded to antidepressant treatment (including treatment-resistant depression) are more limited. Professional guidelines include the American Psychiatric Association Practice Guideline for Treatment of Patients with Major Depressive Disorder, Clinical Practice Recommendations for Depression published in Malhi 2009, the Canadian Network for Mood and Anxiety Treatments (CANMAT), and Clinical Guidelines for the Management of Major Depressive Disorder in Adults. These guidelines recommend the addition of psychotherapy, lithium augmentation, augmentation with a second-generation antipsychotic (SGA), augmentation with triiodothyronine, and switching to another antidepressant after an initial antidepressant trial has failed. Although lithium and thyroid hormones have demonstrated efficacy in augmenting failing therapy, this only applies to their use in combination with tricyclic antidepressants (TCAs), and the trials supporting this use were conducted in patients less resistant to treatment than typical patients currently taking TCAs (Connolly 2011). Of all strategies for augmenting response to newer generation antidepressants, Connolly 2011 reported that quetiapine and aripiprazole are the most evidence-supported, although neither the cost-effectiveness nor the longer-term benefits of these strategies have been established (see also Marcus 2008). The development of adjunctive therapies is complicated by the fact that, as reported in the literature, the effects of combination drugs observed in preclinical efficacy assays in psychiatry generally do not translate to clinical trial results (DeMartinis 2019).

[0005] Urotalont (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity, currently in phase 3 clinical trials for the treatment of schizophrenia, and has the following chemical structure: [ka] It is neither a dopamine D2 nor a serotonin 5-HT2A receptor antagonist and has a novel mechanism of action (MOA) compared to antipsychotics. (Dedic 2019) According to a report in US2020 / 0179336 A1 (June 11, 2020), in a large-scale, randomized, double-blind, placebo-controlled clinical trial, urotalont demonstrated efficacy in treating worsening symptoms of schizophrenia, with continued improvement in a 6-month open-label follow-up study. Non-clinical studies suggest that agonism at TAAR1 and 5-HT1A receptors contributes to urotalont's mechanism of action. (Dedic 2019)

[0006] Urotalont was identified during a medicinal chemistry program designed to develop structurally and mechanistically novel antipsychotics using an in vivo mouse phenotypic screen combined with comprehensive in vitro and in vivo molecular profiling. As reported in Dedic 2019, this study found urotalont to be behaviorally active. At 0.3 mg / kg, urotalont was classified as an anxiolytic, but showed a dose-dependent increase in the antipsychotic classification, with dosage instructions at 1 and 10 mg / kg primarily resembling antipsychotics. Urotalont has also been reported to exhibit a moderate signal resembling antidepressants.

[0007] What is needed are therapies to augment conventional antidepressant therapies that have provided inadequate responses in major depressive disorder and treatment-resistant depression, as well as criteria for identifying patients who will respond to such therapies. Summary of the Invention

[0008] As reported in the Examples herein, urotalont has surprisingly been found to be behaviorally active against depression in a rat model in which many conventional antidepressants have failed. Accordingly, in certain embodiments, the present disclosure provides a method for adjunctively treating MDD (major depressive disorder) in a human subject in need thereof who has previously responded inadequately to antidepressant therapy, the method comprising administering to the subject a therapeutically effective amount of urotalont, or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, the present disclosure provides a method of adjunctively treating a subject suffering from treatment-resistant depression, the method comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof.

[0010] Additional methods for treating depression are based on patient characteristics. Thus, in another embodiment, the present disclosure provides a method for treating a subject suffering from depression, the method comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the subject has previously shown an inadequate response to antidepressant therapy, where an inadequate response is defined as a decrease in the MADRS total score of less than 50% since the start of antidepressant therapy.

[0011] In another aspect, the present disclosure relates to a method for the combined treatment of depression with urotalont and antidepressant therapy. Accordingly, in another embodiment, the present disclosure provides a method for treating a subject suffering from depression (e.g., MDD), comprising administering to the subject a therapeutically effective amount of urotalont or a pharmaceutically acceptable salt thereof, and administering antidepressant therapy.

[0012] Additional advantages of the present disclosure will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present disclosure. The advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. 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

[0013] All documents cited herein are hereby incorporated by reference in their entirety.

[0014] 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.

[0015] Unless otherwise specified, the term "comprises" (or any variations thereof, such as "comprises," "including," etc.) is intended to be non-limiting. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[0016] As used in this specification and claims, 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. When 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.

[0017] When a range is given by specifying a lower limit separately from an upper limit, or when a specific numerical value is specified, it will be understood that the range can be defined by combining any of the lower variable, upper variable, and mathematically possible specific numerical values ​​in any combination. Similarly, when a range is defined as spanning from one endpoint to another, it will be understood that the range encompasses the span between and excluding the two endpoints, and also includes all ranges and subranges therein. The range will be understood to encompass each discrete point within the range as if each point were fully set forth herein.

[0018] 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 combination. For example, embodiments of the present disclosure include treatment of various disorders, patient populations, dosage forms, various doses, minimization of various adverse events, and improvement in various efficacy criteria. All combinations of the various embodiments are within the scope of this disclosure.

[0019] 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 July 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.

[0020] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0021] (definition) "MDD adjunctive therapy" refers to the addition of a medication to an antidepressant regimen with the intent of improving efficacy because a subject has experienced an inadequate response to an antidepressant regimen optimized for dose and duration.

[0022] 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, for example, any suitable formulation or route of administration described herein.

[0023] The "AIMS" (Abnormal Involuntary Movement Scale) assessment consists of 10 items describing dyskinesia symptoms (Guy 1976). Facial and oral movements (items 1–4), limb movements (items 5 and 6), and trunk movements (item 7) are observed without interruption while the subject remains motionless; the investigator also provides a global assessment of the subject's dyskinesia (items 8–10). Each item is rated on a 5-point scale, with a score of 0 representing absence of symptoms (no awareness for item 10) and a score of 4 representing severe disease (awareness and severe distress for item 10). Additionally, the AIMS includes two yes / no questions addressing the subject's oral condition. The AIMS motor assessment score is defined as the sum of items 1–7 (i.e., items 1–4, facial and oral movements; items 5 and 6, limb movements; and item 7, trunk movements).

[0024] "Antidepressant regimen" or "antidepressant therapy" refers to any pharmacological treatment regimen implemented as a therapy for treating depression, and should be distinguished from augmentation, which is the addition of a drug (not considered to be an antidepressant itself) to an antidepressant regimen for the purpose of improving efficacy. Examples of medications for treating depression include, but are not limited to, SSRIs, SNRIs, bupropion, and mirtazapine, and pharmaceutically acceptable salts thereof.

[0025] "Anxiety distress" is used herein in accordance with DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). Thus, a subject with anxiety distress must have two of the following five symptoms that account for the majority of a major depressive episode: 1) feelings of tension or nervousness, 2) feeling unusually restless, 3) difficulty concentrating due to worry, 4) fear that something terrible might happen, and 5) a feeling that they might lose control. 0 or 1 symptom = no anxiety distress, 2 symptoms = mild anxiety distress, 3 symptoms = moderate anxiety distress, and 4-5 symptoms = moderate-to-severe anxiety distress (always accompanied by psychomotor agitation).

[0026] As used herein, an "at risk" individual is one who is at risk of developing the disorder being treated. This may be indicated, for example, by one or more risk factors, which are measurable parameters that correlate with the development of the disorder and are known in the art. When a method is referred to as treating a condition without causing or inducing an adverse event, it will be understood that the method can be performed on a patient who is at risk for the adverse event.

[0027] The "BARS" (Barnes Akathisia Rating Scale) is a comprehensive clinical assessment of akathisia. Barnes 1989. The BARS consists of four items related to akathisia: the rater's objective observation of akathisia, the subject's subjective feelings of restlessness, the subjective distress caused by akathisia, and an overall clinical assessment of akathisia. The first three items are rated on a 4-point scale, with a score of 0 representing no symptoms and a score of 3 representing severe disease. The overall clinical assessment is rated on a 6-point scale, with 0 representing no symptoms and a score of 5 representing severe akathisia.

[0028] The "CGI-C" (Clinical Global Impression-Change) scale measures the effectiveness of drug treatment by rating the subject's overall change since starting drug therapy and whether it is entirely attributable to the drug treatment. Response options include: 1 = very improved, 2 = improved, 3 = little improved, 4 = no change, 5 = slight worsening, 6 = worsening, and 7 = very worsening.

[0029] 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 more severe illness. To conduct 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 mentally ill; 2 = borderline psychotic; 3 = mild; 4 = moderate; 5 = somewhat severe; 6 = severe; and 7 = very severe patient.

[0030] As used herein, the term "clinically significant" or "clinically meaningful" refers to both a statistically significant symptom improvement and a symptom improvement that is meaningful from the patient's, clinician's, or caregiver's perspective, typically based on a statistical measure such as the CGI-S, or a retrospective assessment of improvement such as the CGI-C, as generally described in various U.S. Food and Drug Administration documents (including FDA 2018, FDA 2019, and FDA 2020). When a treatment or benefit is described herein, it will be understood that in certain embodiments, the treatment or benefit demonstrates clinically significant efficacy in a patient population to a statistically significant degree.

[0031] The "CSFQ-14" is a 14-item short questionnaire version of the CSFQ (Changes in Sexual Functioning Questionnaire) that provides an overall measure of sexual functioning and scores on two sets of subscales: a set of five scales corresponding to key aspects of sexual functioning and a set of three scales corresponding to three phases of the sexual response cycle. Keller 2006.

[0032] As used herein, "delaying" the onset of a disorder means deferring, hindering, slowing, stabilizing, and / or postponing the onset of the disorder. The duration of the delay can vary depending on the history of the disease and / or the individual being treated.

[0033] "Depression" has the meaning normally assigned to the term in the field of psychiatry, and may be the definition provided in DSM-5. When depression is referred to herein, it will be understood that MDD is a type of depression, and all aspects of the present disclosure are more specifically targeted to the treatment of MDD.

[0034] "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 term. 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.

[0035] The "FAST" (Functional Assessment Short Test) is a 24-item questionnaire designed to assess the degree to which subjects experience difficulty in various functional areas. Subjects rate their level of difficulty as 0 (no difficulty), 1 (mild difficulty), 2 (moderate difficulty), and 3 (severe difficulty).

[0036] The "HAM-A" (Hamilton Anxiety Rating Scale) assesses a patient's anxiety symptoms and, in one embodiment, is administered using the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). Williams 2008.

[0037] The "HAM-D17" (17-item Hamilton Rating Scale for Depression) is another well-known method for assessing a subject's level of depression and is administered using the Structured Interview Guide for the Hamilton Rating Scale for Depression (SIGH-D). Williams 1988.

[0038] "Inadequate response," unless otherwise specified, refers to the absence of clinically significant improvement in a subject's depressive symptoms from the start of therapy. An inadequate response is always based on a sufficient or therapeutically effective amount of antidepressant therapy over a therapeutically acceptable period. In some embodiments, an inadequate response is defined as a decrease in the MADRS total score of less than 50%, less than 40%, less than 30%, or less than 20% from the start of therapy, and / or a CGI-C score of 3 or greater from the start of therapy. In some embodiments, an inadequate response is defined as a decrease in the MADRS total score of less than 50% from the start of therapy. In other embodiments, an inadequate response is defined as a CGI-C score of 3 or greater. In yet other embodiments, an inadequate response is defined as a decrease in the MADRS total score of less than 50% from the start of therapy and a CGI-C score of 3 or greater. In some embodiments, an inadequate response is defined as a less than 50% improvement in symptom severity on the MGH-ATRQ (Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire). In other embodiments, an inadequate response is defined as less than a 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score. In other embodiments, an inadequate response is defined as a HAM-D17 total score of 14 or greater.

[0039] The "MADRS" (Montgomery-Asberg Depression Rating Scale) is a well-known method for assessing a subject's level of depression. Montgomery 1979. The MADRS consists of 10 items, each rated from 0 to 6. A higher score on the MADRS represents a more severe level of depression.

[0040] A "major depressive episode" or "MDE" has the definition assigned to that term in DSM-5: (i) the patient must have five or more depressive symptoms for two or more weeks; (ii) the patient must have either depressed mood or loss of interest / pleasure; (iii) the symptoms must cause significant distress or impairment; and (iv) the patient has never had a manic or hypomanic episode. Depressive symptoms are selected from the group consisting of: (i) depressed mood; (ii) markedly reduced interest or pleasure in most or all activities; (iii) significant weight loss (decreased appetite) or weight gain; (iv) insomnia or hypersomnia; (v) psychomotor retardation; (vi) fatigue or lack of energy; (vii) feelings of worthlessness or excessive or inappropriate guilt; (viii) decreased ability to think or concentrate or indecisiveness; and (ix) recurrent thoughts of death (not simply fear of death) or suicidal ideation, plans, or attempts.

[0041] The "PGI-C" (Patient Global Impression-Change) scale measures the effectiveness of drug treatment by rating the subject's overall change from the start of drug treatment from the patient's perspective, regardless of whether the change is entirely attributable to the drug treatment.

[0042] The "PGI-S" (Patient Global Impression-Severity) is a one-item report of symptom severity in a subject. Subjects are asked: "Please select the response below that best describes the severity of your depression over the past week." Typical answers include non-overlapping responses such as none, mild, moderate, and severe.

[0043] "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.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19, provide a detailed description of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of urotalont include those derived from suitable inorganic and organic acids and inorganic and organic bases.

[0045] 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 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, 2-hydroxy-ethanesulfonate, 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, and valerate. While pharmaceutically acceptable counterions are typically used to prepare pharmaceutical formulations, other anions (X) are well tolerated as synthetic intermediates. Therefore, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, or trifluoromethanesulfonate, when the salt is a chemical intermediate.

[0046] 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, which is approved or otherwise permitted by the U.S. Food and Drug Administration in appropriate quantities for use in humans or domestic animals.

[0047] 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.Therefore, "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 while there are no detectable symptoms of the disorder).The subject may be an individual at risk of developing a disorder.

[0048] The Pittsburgh Sleep Quality Index (PSQI) includes 19 self-rated questions and five questions rated by a bed partner or housemate (if available). Only the self-rated questions are included in the score. The 19 self-rated items are combined to form seven "component" scores, each ranging from 0 to 3 points. In all cases, a score of "0" indicates no difficulty, while a score of "3" indicates severe difficulty. The scores for the seven components are then added together to form a single "total" score, ranging from 0 to 21 points, with "0" indicating no difficulty and "21" indicating severe difficulty in all domains.

[0049] "Remission" of MDD means, unless otherwise specified, that the subject is no longer afflicted with MDD, e.g., as defined by DSM-5. Alternatively, in other embodiments, remission may be defined based on a MADRS total score of 10 or less since the start of therapy, and a reduction of 50% or more in the MADRS total score.

[0050] "Response" to a therapy refers to a clinically significant improvement in a subject's diagnosis since the start of therapy, unless otherwise specified. Alternatively, a response may be defined as a 50% or greater reduction in the MADRS total score since the start of therapy. Alternatively, a response may be defined as a CGI-C score of 1 or 2 (very improved or improved) since the start of therapy. Alternatively, a response may be defined as a 50% or greater reduction in the MADRS total score since the start of therapy and a CGI-C score of 1 or 2 (very improved or improved) since the start of therapy.

[0051] The "SAS" (Simpson-Angus Scale) consists of 10 parkinsonism symptoms (gait, arm drop, shoulder tremor, elbow stiffness, wrist stiffness, neck rolling, brow tapping, tremor, drooling, and akathisia). Simpson 1970. Each item is rated on a 5-point scale, with a score of 0 representing no symptoms and a score of 4 representing severe disease. The total score on the SAS is the sum of all 10 items.

[0052] The SF-36 (36-item Short Form Questionnaire) 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 composites: physical functioning, pain, role-physical, overall health, vitality / fatigue, social functioning, role-mental, and mental health. The SF-36 uses normative scoring to generate scores on a 0–100 scale, with lower scores on the physical component summary and mental component summary representing lower health-related quality of life, and a score of 50 refers to normative data derived from surveys of a representative sample of the general U.S. population. In addition to the composite score and individual health domain scores, the SF-36 provides a score for depression risk and an SF-6D health utility index, which scales from 0.0 (worst health state measured) to 1.0 (best health state measured).

[0053] 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 of the term are used. When a measurable result or effect is expressed or specified herein, it will be understood that the result or effect is typically 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 typically demonstrates efficacy in a patient group to a statistically significant degree.

[0054] "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.

[0055] "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.

[0056] 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 (including commercially relevant birds, e.g., chickens, ducks, geese, quail, and / or turkeys).

[0057] 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 varies 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 drugs. The appropriate dose of the co-administered compounds may be appropriately reduced due to the additive or synergistic combined action of the compounds.

[0058] 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 symptom history and / or general or other susceptibility factors). Treatment may also continue after symptoms have resolved, for example, to prevent or delay recurrence.

[0059] When treatment with two separate agents is described herein, it will be understood that these agents are administered concomitantly based on a simultaneous dosing regimen (which may differ in dosing frequency or time). Two agents do not necessarily have to be administered at the same time to be considered concomitant. For example, concomitant administration may include one agent administered three times daily and one agent administered once daily.

[0060] 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, where improvement is seen in a subject but the subject still suffers from the underlying disorder.

[0061] In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (e.g., alleviating one or more symptoms resulting from the disorder and / or reducing the extent of the disorder); (b) slowing or inhibiting the onset of one or more symptoms associated with the disorder (e.g., stabilizing the disorder and / or slowing the deterioration or progression of the disorder); and / or (c) alleviating the disorder (e.g., reversing clinical symptoms, alleviating the disorder, slowing the progression of the disorder, and / or improving quality of life).

[0062] "Treatment-resistant depression" or "treatment failure" has the same clinical criteria, and unless otherwise specified herein, uses the definition of the term by the US Food and Drug Administration. That is, after treatment with at least two different antidepressants prescribed at sufficient doses for a sufficient period (at least 6 weeks), there is no clinically meaningful improvement (25% or less in the total score of the MADRS) in the current major depressive episode. Alternatively, the term can be defined as an improvement of 25% or less in the total score of the MADRS despite the use of two or three previous antidepressants at sufficient doses and duration as described in the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (ATRQ).

[0063] "Urotalont," as referred to herein 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"). Urotalont has the following structure: [ka] Unless otherwise specified or the context requires otherwise, for 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.

[0064] Urotalont can be used in the methods described herein as a free base (free form) or in the form of a pharmaceutically acceptable salt. In some embodiments, the hydrochloride (HCl) salt of urotalont is used in the methods described herein. Urotalont or a pharmaceutically acceptable salt thereof (including its crystalline hydrochloride salt) can be obtained according to the production 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 entireties of which are incorporated herein by reference for all purposes), or similar methods.

[0065] Also provided herein are pharmaceutical compositions and dosage forms, comprising urotalont or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable additives.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.

[0066] In certain embodiments, the present disclosure provides a method for adjunctively treating MDD (major depressive disorder) in a human subject who has had an inadequate response to antidepressant therapy (e.g., after at least 8 weeks of antidepressant therapy), comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment, the present disclosure provides a method for adjunctively treating a subject suffering from treatment-resistant depression, the method comprising administering to the subject an antidepressant therapy and administering a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the present disclosure provides a method for treating a subject suffering from depression, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the subject has experienced an inadequate response to antidepressant therapy, wherein the inadequate response is defined as a decrease in the MADRS total score of less than 50% since the start of therapy. In some embodiments, the method is an adjunct to an antidepressant regimen, including antidepressant therapy, in a subject who has previously shown an inadequate response to antidepressant therapy (e.g., after at least 8 weeks of antidepressant therapy). In other embodiments, the inadequate response is further defined as a CGI-C score of 3 or more since the start of therapy.

[0069] In other embodiments, the present disclosure provides a method of treating a subject suffering from depression (e.g., MDD), comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof and administering antidepressant therapy.

[0070] In any embodiment of the present disclosure, the antidepressant therapy includes an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor). In some embodiments, the antidepressant therapy includes an SSRI, wherein the SSRI is selected from 10-20 mg / day of escitalopram, 20-60 mg / day of fluoxetine, 25-62.5 mg / day of paroxetine, or 50-200 mg / day of sertraline; or the SNRI is selected from 30-60 mg / day of duloxetine and 37.5-225 mg / day of venlafexine. When tailored to a particular subject, the aforementioned therapies are generally considered to be "tailored therapies." In any embodiment of the present disclosure, the subject has experienced an inadequate response or treatment failure to the antidepressant therapy mentioned in this paragraph.

[0071] Any embodiment of the present disclosure can be further defined by the subject being treated. That is, in some embodiments, the subject is suffering from a major depressive episode (MDE), for example, as defined by DSM-5. An MDE can vary in duration, including 4 weeks or more, 8 weeks or more, or 26 weeks or more. In some embodiments, an MDE is 8 weeks or more in duration and 52 weeks or less in duration. In other embodiments, the subject is in a current major depressive episode (MDE), as defined by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria and confirmed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

[0072] In other embodiments, the subject is characterized by an inadequate response to at least one but no more than three satisfactory antidepressant therapies (ADTs) during the current MDE. In some embodiments, the antidepressant therapy comprises an SSRI or SNRI, or one of the therapies described herein above.

[0073] In yet other embodiments, the subject is characterized by the extent of his or her pre-ADT depression, i.e., in other embodiments, the subject has a pre-ADT total score on the 17-item Hamilton Depression Rating Scale (HAM-D17) of 18 or greater, optionally 14 or greater, 16 or greater, 20 or greater, or 22 or greater.

[0074] In a further embodiment, prior to ADT, the treated subject meets all three of the aforementioned requirements for MDE status for at least 8 weeks, meets an inadequate response to a previous course of antidepressant treatment, and meets a HAM-D17 total score of 18 or greater.

[0075] In other embodiments, the subject has an inadequate response after at least 8 weeks of antidepressant therapy, defined as: (a) less than a 50% reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score; or (b) a HAM-D17 total score of 14 or greater; or (c) a CGI-C (Clinical Global Impression-Change) scale score of 3 or greater; or (d) less than a 50% reduction in the MADRS (Montgomery-Asberg Depression Rating Scale) total score; or (e) a combination of any two or more of (a)-(d).

[0076] Other embodiments are defined based on a patient's treatment response as measured by the MADRS. That is, in some embodiments, an inadequate response is defined as a decrease in the MADRS total score of 25% or less. In other embodiments, an inadequate response is defined as a decrease in the MADRS total score of less than 50% but more than 25%.

[0077] Further embodiments find particular utility in subjects with anxiety afflictions and are based on the subject's anxiety level, i.e., any of the methods of the present disclosure can be practiced in subjects with anxiety afflictions as defined by DSM-5.

[0078] The methods of the present disclosure can also be defined based on the dose of urotalont administered. That is, in certain embodiments, a therapeutically effective amount comprises 10-150 mg, 15-125 mg, 25-100 mg, 25-75 mg, or 50-100 mg of urotalont, or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont. In other embodiments, a therapeutically effective amount comprises 50 or 75 mg of urotalont, or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont. In further embodiments, a therapeutically effective amount comprises 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of urotalont, or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont.

[0079] In any of these embodiments, a therapeutically effective amount of urotalont is administered once daily for a period of at least six weeks.

[0080] The methods of the present disclosure may be further defined based on their effect on the disorder, i.e., any method of the present disclosure may result in remission of depression, including remission of depression, where depression is defined according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

[0081] Any method of the present disclosure can also change the mean score of the subject's Montgomery-Asberg Depression Rating Scale.In various embodiments, the method can reduce the MADRS total score by 1 point or more, 2 points or more, 3 points or more, 4 points or more, or 5 points or more than antidepressant therapy alone.In other embodiments, the treatment improves the subject's MADRS total score.In other embodiments, the treatment improves the subject's CGI-S score by 2 points or more, 3 points or more, or 4 points or more.In further embodiments, the treatment clinically significantly improves the subject's MADRS total score and CGI-S score.

[0082] Other embodiments may be defined based on another endpoint, i.e., in various embodiments, the method improves the subject's FAST (Functional Assessment Short Test) score.

[0083] In a further embodiment, the method improves the subject's PGI-S (Patient Global Impression-Severity) score.

[0084] In other embodiments, the method improves the subject's SF-36 (36-item Short Form Questionnaire) score.

[0085] In a further embodiment, the method improves the subject's HAM-A (Hamilton Anxiety Rating Scale) total score.

[0086] In a further embodiment, the method improves the subject's HAM D17 (17-item Hamilton Depression Rating Scale) total score.

[0087] In other embodiments, the method results in a CGI-C (Clinical Global Impression-Change) score of 1 or 2 (much improved or improved). In further embodiments, the method results in a reduction in the subject's MADRS total score by 50% or more. In further embodiments, the method results in a reduction in the subject's MADRS total score to 10 or less.

[0088] In other embodiments, the method reduces the subject's MADRS total score to 10 or less, and reduces the subject's MADRS total score by 50% or more.

[0089] The method can also be defined based on the duration of administration, and typically improves the subject's depressive symptoms at least by the end of that period. That is, any embodiment of the present disclosure can be implemented by administering urotalonto or a pharmaceutically acceptable salt thereof to improve the subject's depressive symptoms over a therapeutic effective period of 6 weeks or more, 8 weeks or more, 12 weeks or more, 18 weeks or more, 26 weeks or more, or 52 weeks or more. Improvement can be represented, for example, by a reduction in the subject's MADRS score (i.e., a reduction of 25% or more, a reduction of 40% or more, or a reduction of 50% or more), with a MADRS total score of 14 or less, 12 or less, 10 or less, or 8 or less; or by a combination of the score reduction and the absolute total score, for example, a reduction of 50% or less and a total score of 10 or less.

[0090] In other embodiments, improvement is represented by a 50% or greater decrease in the subject's MADRS score, resulting in a MADRS total score of 10 or less, observed over a treatment benefit period of at least 26 weeks.

[0091] The methods of the present disclosure can also be defined based on their favorable side effect profile. That is, in various embodiments, the method does not cause any clinically significant deterioration in a subject's (a) abnormal involuntary movements as measured by AIMS (Abnormal Involuntary Movement Scale); or (b) akathisia as measured, for example, by BARS (Barnes Akathisia Rating Scale); or (c) sexual function as measured, for example, by CSFQ-14 (Changes in Sexual Functioning Questionnaire, Short Form); or (d) suicidal ideation as measured, for example, by CSSRS (Columbia Suicide Severity Rating Scale); or (e) parkinsonism as measured, for example, by SAS (Simpson-Angus Scale); or (f) sleep quality as measured, for example, by PSQI (Pittsburgh Sleep Quality Index); or (g) a combination of any two or more of (a)-(f).

[0092] Despite their favorable side effect profile, the methods may further be monitored for the occurrence of any potential side effects, as appropriate. In some embodiments, the methods further include monitoring for CNS (central nervous system) stimulation, including agitation, restlessness, insomnia, and depression, including lethargy, somnolence, and shallow breathing; impaired muscle coordination; effects on heart rate; and changes in pupil size.

[0093] Some aspects of the present disclosure can be defined based on the following embodiments AA to BW: [Embodiment AA] A method for adjunctive treatment of MDD (major depressive disorder) in a human subject who has previously shown an inadequate response to antidepressant therapy and is in need of treatment, comprising administering to the subject the antidepressant therapy and a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof. [Embodiment AB] A method for adjunctively treating a human subject suffering from treatment-resistant depression, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof. Embodiment AC: The method of embodiment AB, wherein treatment-resistant depression is defined as treatment failure of two or more antidepressant therapies. [Embodiment AD] The method described in embodiment AA, wherein inadequate response is defined as less than a 50% reduction in the severity of depressive symptoms as assessed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ) after at least 8 weeks of antidepressant therapy. [Embodiment AE] A method for treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an inadequate response to antidepressant therapy, where inadequate response is defined as a decrease in the MADRS total score of less than 50% since the start of the antidepressant therapy. [Embodiment AF] A method for treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof, wherein the subject is experiencing an inadequate response to antidepressant therapy, wherein an inadequate response is defined as a decrease in the MADRS total score of less than 50% since the start of the antidepressant therapy and a CGI-C score of 3 or greater since the start of therapy. [Embodiment AG] A method according to embodiment AE or AF, wherein the method is an adjunct to an antidepressant regimen comprising the antidepressant therapy in a human subject in need of treatment who has previously shown an inadequate response to the antidepressant therapy. [Embodiment AH] A method described in any of embodiments AA to AG, wherein the antidepressant therapy includes an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor). [Embodiment AI] A method according to any one of embodiments AA-AG, wherein the antidepressant therapy comprises an SSRI selected from 10-20 mg / day of escitalopram, 20-60 mg / day of fluoxetine; 25-62.5 mg / day of paroxetine; and 50-200 mg / day of sertraline; or an SNRI selected from 30-60 mg / day of duloxetine and 37.5-225 mg / day of venlafexine. [Embodiment AJ] A method according to any of embodiments AA, AD, AH, and AI, wherein an inadequate response is defined as a decrease in the MADRS total score of less than 50% since the start of therapy. [Embodiment AK] A method according to any of embodiments AA, AD, AH, and AI, wherein an inadequate response is defined as a CGI-C score of 3 or greater since the start of therapy. [Embodiment AL] A method according to any of embodiments AA and AD-AI, wherein an inadequate response is defined as (a) (i) a reduction in the total score on the HAM-D17 (17-item Hamilton Depression Rating Scale) of less than 50%, or (ii) a total score on the HAM-D17 of 14 or greater; and (b) a score on the CGI-C (Clinical Global Impression-Change) scale of 3 or greater; and (c) a reduction in the total score on the MADRS (Montgomery Asberg Depression Rating Scale) of less than 50%. [Embodiment AM] A method according to any of embodiments AA and AD-AI, wherein an inadequate response is defined as (a) a reduction in the total score on the HAM-D17 (17-item Hamilton Depression Rating Scale) of less than 50%; and (b) a total score on the HAM-D17 of 14 or greater; and (c) a score on the CGI-C (Clinical Global Impression-Change) scale of 3 or greater; and (d) a reduction in the total score on the MADRS (Montgomery Asberg Depression Rating Scale) of less than 50%. [Embodiment AN] A method described in any of embodiments AA and AD-AM, wherein the subject had a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of 18 or greater prior to antidepressant therapy, and an inadequate response is defined as, after at least 8 weeks of antidepressant therapy, (a) a reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of less than 50%; or (b) a HAM-D17 total score of 14 or greater; or (c) a CGI-C (Clinical Global Impression-Change) scale score of 3 or greater; or (d) a reduction in the MADRS (Montgomery Asberg Depression Rating Scale) total score of less than 50%; or (e) a combination of (a)-(d). [Embodiment AO] A method according to any of embodiments AA and AD-AM, wherein the subject has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of 18 or greater prior to antidepressant therapy, and an inadequate response is defined as, after at least 8 weeks of antidepressant therapy, (a) a reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of less than 50%; and (b) a HAM-D17 total score of 14 or greater; and (c) a CGI-C (Clinical Global Impression-Change) scale score of 3 or greater; and (d) a reduction in the MADRS (Montgomery Asberg Depression Rating Scale) total score of less than 50%. [Embodiment AP] A method described in any of embodiments AA to AO, wherein the subject is in a current major depressive episode (MDE) as defined by the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition). [Embodiment AQ] A method described in any of embodiments AA to AO, wherein the subject is in a current major depressive episode (MDE) as defined by the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) for a period of 8 weeks or more. [Embodiment AR] A method described in any of embodiments AA to AQ, comprising administering urotalonto or a pharmaceutically acceptable salt thereof, and improving a subject's symptoms of depression for a treatment effective period of at least 6 weeks, at least 8 weeks, at least 12 weeks, at least 26 weeks, or at least 52 weeks. [Embodiment AS] A method described in any of embodiments AA to AR, wherein the therapeutically effective amount comprises 25 to 100 mg of urotalonto or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalonto. [Embodiment AT] A method described in any of embodiments AA to AR, wherein the therapeutically effective amount comprises 50 or 75 mg of urotalont, or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont. [Embodiment AU] A method described in any of embodiments AA and AD-AT, wherein the subject has shown an inadequate response after at least 8 weeks of antidepressant therapy. [Embodiment AV] A method according to any of embodiments AA-AU, comprising administering urotalonto or a pharmaceutically acceptable salt thereof for at least 6 weeks. [Embodiment AW] A method described in any of embodiments AA to AV, wherein the method increases the subject's Montgomery-Asberg Depression Rating Scale total score by 1 point or more, 2 points or more, 3 points or more, or 4 points or more compared to antidepressant therapy alone. [Embodiment AX] A method according to any one of embodiments AA to AW, wherein the method alleviates depression. [Embodiment AY] A method described in any of embodiments AA to AW, wherein the method results in remission of depression, and the remission is defined according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition). [Embodiment AZ] A method described in any of embodiments AA to AY, wherein the method improves the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score. [Embodiment BA] A method described in any of embodiments AA to AZ, wherein the method improves the subject's CGI-S (Clinical Global Impression-Severity) score by 2 points or more, 3 points or more, or 4 points or more. [Embodiment BB] A method described in any of embodiments AA to BA, wherein the method results in a clinically significant improvement in the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression-Severity) score. [Embodiment BC] A method described in any of embodiments AA to BB, wherein the method improves the subject's FAST (Functional Assessment Short Test) score or PGI-S (Patient Global Impression-Severity) score. [Embodiment BD] A method described in any of embodiments AA to BC, wherein the subject has anxiety distress as defined in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition). [Embodiment BE] A method according to any one of embodiments AA to BD, wherein the method improves a subject's SF-36 (36-item short-form questionnaire) score. [Embodiment BF] A method according to any one of embodiments AA to BE, wherein the method improves a subject's HAM-A (Hamilton Anxiety Rating Scale) total score. [Embodiment BG] A method according to any one of embodiments AA to BF, wherein the method improves the subject's total score on the HAM D17 (17-item Hamilton Depression Rating Scale). [Embodiment BH] A method described in any of embodiments AA to BG, wherein the method results in a CGI-C (Clinical Global Impression-Change) score of 1 or 2 (very improved or improved). [Embodiment BI] A method described in any of embodiments AA to BH, wherein the method reduces the subject's MADRS total score by 50% or more. [Embodiment BJ] A method described in any of embodiments AA to BI, wherein the method reduces the subject's MADRS total score to 10 or less. [Embodiment BK] A method described in any of embodiments AA to BJ, wherein the method reduces the subject's MADRS total score to 10 or less and reduces the subject's MADRS total score by 50% or more. [Embodiment BL] A method described in any of embodiments AA to BK, wherein the method does not clinically significantly worsen the subject's abnormal involuntary movements as measured by AIMS (Abnormal Involuntary Movement Scale); or akathisia as measured by BARS (Barnes Akathisia Rating Scale); or sexual function as measured by CSFQ-14 (Changes in Sexual Functioning Questionnaire, Short Form); or suicidal ideation as measured by C-SSRS (Columbia-Suicide Severity Rating Scale); or parkinsonism as assessed by SAS (Simpson-Angus Scale); or sleep quality as assessed by PSQI (Pittsburgh Sleep Quality Index); or any combination thereof. [Embodiment BM] A ​​method described in any of embodiments AA to BK, wherein the method does not result in clinically significant sedation, symptoms of metabolic syndrome (e.g., weight gain, diabetes, hyperlipidemia), or motor impairment. [Embodiment BN] A method described in any of embodiments AA to BL, further comprising monitoring for CNS (central nervous system) stimulation (including agitation, restlessness, insomnia, and depression including lethargy, somnolence, and shallow breathing), impaired muscle coordination, effects on heart rate, and changes in pupil size. [Embodiment BO] A method for treating a subject suffering from depression (e.g., MDD), comprising administering to the subject a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof and administering antidepressant therapy. [Embodiment BP] The method described in embodiment BO, wherein the antidepressant therapy comprises a therapeutically effective amount of an SSRI (selective serotonin reuptake inhibitor) or SNRI (serotonin-norepinephrine reuptake inhibitor). [Embodiment BQ] The method described in embodiment BO, wherein the antidepressant therapy includes an SSRI selected from escitalopram (e.g., 10-20 mg / day), fluoxetine (e.g., 20-60 mg / day), paroxetine (e.g., 25-62.5 mg / day), or sertraline (e.g., 50-200 mg / day); or an SNRI selected from duloxetine (e.g., 30-60 mg / day) and venlafaxine (e.g., 37.5-225 mg / day). [Embodiment BR] A method according to any of embodiments AA to BQ, wherein the patient has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of 14 or greater, 16 or greater, or 18 or greater prior to urotalonto therapy. [Embodiment BS] A method described in any of embodiments AA to BR, wherein the patient has a MADRS (Montgomery-Asberg Depression Rating Scale) total score of 20 or greater, 22 or greater, 24 or greater, 26 or greater, 28 or greater, 30 or greater, 32 or greater, or 34 or greater prior to urotalonto therapy. [Embodiment BT] A method according to any of embodiments AA, and AD-BS, wherein an inadequate response is defined as a treatment failure. [Embodiment BU] The method of any of embodiments AA, and AD-BS, wherein the patient does not have treatment-resistant depression. [Embodiment BV] A method according to any of embodiments AA and AD-BS, wherein an inadequate response is defined as a decrease in the MADRS total score of 25% or less. [Embodiment BW] A method according to any of embodiments AA, and AD-BS, wherein an inadequate response is defined as a decrease in the MADRS total score of less than 50% and more than 25%. [Example]

[0094] 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.

[0095] Example 1. Effect of urotalonto in combination with antidepressants in the mouse forced swimming test Urotal resistance was assessed in the mouse forced swimming test (FST), in which mice are placed in a small, inescapable chamber of water and their behavior is observed. In this test, acute administration of all major classes of commercially available antidepressants reduced immobility time.

[0096] These specific FST tests were performed on male Swiss mice (5-6 weeks old, n = 10 per group), including mice co-administered with imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram. A single dose of urotalonto (0.3, 1, 3, or 10 mg / kg, orally administered) did not significantly alter immobility time or significantly enhance the antidepressant activity of the subsequent single dose of co-administered imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram.

[0097] These results contradict those reported by Dedic in 2019 in a FST study using male BalbC / J mice. In that study, male BalbC / J mice (6 weeks old, n = 8 per group) were administered a single dose of vehicle (oral administration), urotalont (0.3, 1, 3, or 10 mg / kg, oral administration), or sertraline (20 mg / kg, intraperitoneal injection) as a positive control. Urotalont treatment significantly reduced immobility time at doses of 1, 3, and 10 mg / kg, with the maximal effect achieved at the 1 mg / kg dose level. These results indicate that urotalont exerts antidepressant-like effects in the mouse FST; however, this effect is species-specific. Varying sensitivity to established antidepressants has also been reported in various mouse strains (Lucki 2001; David 2003).

[0098] Example 2. Effect of urotalonto in the forced swimming test in rats We also tested the antidepressant-like effects of urotalonto in the rat FST assay using two different dosing protocols: in both procedures, rats were pre-exposed to a 15-min swim session prior to a 5-min FST session (day 0), and a 5-min FST session was performed 24 h later (day 1).

[0099] In the first test, adult male Wistar rats (206–260 g; n = 12 per group) were dosed three times with their assigned treatment: 24 h (i.e., immediately after the pre-swim), 4 h, and 1 h before the test. Treatment groups were as follows: vehicle (oral administration), urotalont (0.3, 1, 3, or 10 mg / kg oral administration), or imipramine (64 mg / kg oral administration) as a positive control. The time spent immobile during a 5-min test session was recorded by an observer blinded to the treatment condition, and the results were analyzed by one-way analysis of variance followed by Dunnett's post-hoc comparison. At 3 mg / kg oral administration, urotalont significantly reduced immobility time compared to vehicle-treated controls.

[0100] In the second test, adult male Sprague-Dawley rats (190–234 g, n = 10 per group) were dosed once immediately after pre-swim, i.e., 24 h before testing. This dosing protocol was used to demonstrate the antidepressant-like effects of acute ketamine treatment, whereas other drug classes (e.g., SSRIs and tricyclic antidepressants) are typically ineffective (Ardalan 2017; Cryan 2005; Koike 2014). Rats were treated with either vehicle (oral administration), urotalonto (0.3, 1, 3, or 10 mg / kg, oral administration), or ketamine (10 mg / kg, intraperitoneal injection), which was included as a positive control. Behavior during the 5-min test session was quantified using a time-sample method, and observed actual behaviors, i.e., immobility, wall climbing, or swimming, were recorded every 5 seconds for a total of 60 observations. Results were analyzed by one-way analysis of variance followed by Dunnett's post hoc comparisons.

[0101] Urotalont significantly reduced the frequency of immobility at all doses tested (Table 1). The magnitude of the effect was similar to that in ketamine-treated rats and was associated with a significant increase in swimming behavior. [Table 1]

[0102] Example 3: Effect of urotalonto in a rat model of learned helplessness Urotalontosis was assessed in a rat model of learned helplessness, which assesses the loss of behavioral control in an aversive situation and is responsive to antidepressant treatment (Willner 2015). In this model, rats are first exposed to an inescapable electric foot shock to induce helplessness, which is then expressed by a subsequent failure to avoid an evasive electric foot shock (active avoidance). Treatment with established antidepressants, typically using a subchronic regimen, reduces the number of avoidance failures in helpless rats.

[0103] Adult male Wistar rats (186–262 g; n = 16–17 per group) were randomly assigned to six different groups. Helplessness was induced in five of the groups on day 1 by exposing the animals to inescapable electric foot shocks delivered every 15 seconds for 1 hour through an electrified stainless steel grid floor. The remaining group did not receive the inescapable electric shocks and served as nonhelpless controls. Approximately 6 hours after the induction of helplessness on day 1, rats were orally dosed with vehicle, tricyclic antidepressant imipramine (32 mg / kg), or urotalonto (1, 3, or 10 mg / kg). Treatment continued on days 2–5, with all subjects receiving test drug or vehicle twice daily (AM and PM). Active avoidance was tested for 60 minutes after the morning dose on days 3, 4, and 5. All rats were tested in a two-compartment active avoidance chamber in which the delivery of an electric foot shock was signaled by a light stimulus. The test session began with 5 min of free exploration, followed by 30 stimulus-electric foot shock trials over a 15-min period. Each trial lasted 30 s, with the first 24 s of a rest period, followed by a 6 s light stimulus, and the final 3 s of an electric foot shock. Moving to the opposite compartment during the first 3 s of the light stimulus avoided the electric shock and constituted active avoidance. Failure to avoid the entire delivery of the electric foot shock (i.e., failure to move during the 3 s of the shock) was considered an escape failure. Moving to the opposite compartment of the shuttle box during the 24 s rest period was recorded as an intertrial interval (ITI) movement. Escape failures and ITI movements were analyzed using a two-way repeated measures ANOVA with treatment as the main factor and test session (i.e., day) as the repeated measure. Significant ANOVA results were followed by Dunnett's post-hoc test to examine the effect of treatment in each test session compared to vehicle-treated helpless rats.

[0104] Urotalont dose-dependently reduced the number of escape failures in helpless rats, with significant effects observed at 10 mg / kg orally on test days 4 and 5. A significant reduction in escape failures was also observed in imipramine-treated rats (Table 2). [Table 2]

[0105] Analysis of ITI locomotion on test days 3, 4, and 5 showed that ITI locomotion was not significantly different in non-helpless rats compared with helpless controls (Table 3). Treatment with 10 mg / kg urotalont significantly increased ITI locomotion on day 5 compared with helpless, vehicle-treated controls, but had no effect on ITI locomotion on days 3 and 4. This suggests that the interpretation of the antidepressant-like effect of urotalont on day 4 is not based on its effect on locomotor activity. [Table 3]

[0106] The present results demonstrate that urotalonto exhibits antidepressant-like activity in a rat model of learned helplessness.

[0107] Example 4: A Phase 2 / 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Flexible-Dose Urotalonto as Adjunctive Therapy in the Treatment of Adults with Major Depressive Disorder This is a Phase 2 / 3, multicenter, randomized, double-blind, placebo-controlled, flexible-dose trial designed to evaluate the safety and efficacy of urotalonto as adjunctive therapy to an assigned open-label antidepressant therapy (ADT) in subjects with MDD who have had an inadequate response to a previous 8-week trial of the same assigned open-label ADT.

[0108] The study population will include subjects aged 18–65 years (including at the time of informed consent for a primary diagnosis of MDD) who are in a current major depressive episode (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed by the MGH-ATRQ. The current MDE must be 8 weeks or longer in duration. In addition, subjects must have a reported history of a current MDE with an inadequate response to at least one and no more than three adequate ADTs. Subjects must have a total score of 18 or higher on the 17-item Hamilton Depression Rating Scale (HAM-D17) at screening and baseline visits.

[0109] The primary objective of this study is to compare the efficacy of urotalonto (50-75 mg / day) with placebo as adjunctive therapy to an assigned open-label ADT in subjects with MDD who have an inadequate response to a prior 8-week trial of the assigned open-label ADT. Primary efficacy will be assessed by the change in the MADRS total score from the end of Phase A (week 8 visit) to the end of Phase B (week 14 visit). Efficacy will also be assessed specifically by the change in the CGI-S from the end of Phase A (week 8 visit) to the end of Phase B (week 14 visit). References American Psychiatric Association practice guideline for treatment of patients with major depressive disorder, third edition [online]. Available at: http: / / www.psy chiatryonline.com / pracGuide / pracGuideTopic_7.aspx [Accessed July 17, 2022]. Ardalan M, Rafati AH, Nyengaard JR, Wegener G. Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. Br J Pharmacol 2017; 174:483-492. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672 676. Cryan JF, Valenton RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 2005; 29(4-5):547-569. David DJ, Renard CE, Jolliet P, Hascoet M, Bourin M. Antidepressant-like effects in various mice strains in the forced swimming test. Psychopharmacology (Berl) 2003;166:373-382. Dedic N, Jones PG, Hopkins SC, Lew R., Shao L, Campbell JE, Spear KL, Large TH, Campbell UC, Hanania T, Leahy E, & Koblan KS (2019). SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. Journal of Pharmacology and Experimental Therapeutics, 371(1), 1-14. DeMartinis, Nicholas; Lopez, Rene N.; Pickering, Eve H.; Schmidt, Christopher J. ; Gertsik, Lev; Walling, David; Ogden, Adam. A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia. Journal of Clinical Psychopharmacology: 7 / 8 2019 - Volume 39 - Issue 4 - p 318-328. 美国食品药品监督管理局。《患者聚焦药物研发公众研讨会关于指南3:选择、开发或修改适用的临床结局评估的讨论文件》(包括附录)(发布于《患者聚焦药物研发指南:识别对患者重要事项并选择、开发或修改适用的临床结局评估的方法》,2018年10月15 - 16日会议)(“FDA 2018”)。 美国食品药品监督管理局。以患者为中心的药物研发:确定对患者重要事项的方法,行业、食品药品监督管理局工作人员及其他利益相关者指南(2019年10月)(“FDA 2019”)。 美国食品药品监督管理局。以患者为中心的药物研发:收集全面且具代表性的意见;行业、食品药品监督管理局工作人员及其他利益相关者指南(2020年6月)(“FDA 2020”)。 盖伊·W.《精神药理学ECDEU评估手册 - 修订版》(美国卫生、教育与福利部出版物编号ADM 76 - 338)。美国马里兰州罗克维尔,美国卫生、教育与福利部,1976年:第218 - 22页。 赫弗南·M.L.R.、赫尔曼·L.W.、布朗·S.、琼斯·P.G.、邵·L.、休伊特·M.C.、坎贝尔·J.E.、德迪克·N.、霍普金斯·S.C.、科布兰·K.S.、谢·L.。乌洛托隆:一种用于治疗精神分裂症的TAAR1激动剂。《美国化学会药物化学通讯》。2022年,13卷,第92 - 98页。 Keller A, McGarvey EL, Clayton, AH. Reliability and construct validity of the changes in sexual functioning questionnaire short-form (CSFQ-14), J Sex Marital Ther, 2006;32(1): 43-52. Koike H, Chaki S. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res 2014; 271:111-115. Lam RW, Kennedy SH, Grigoriadis S, et al., Canadian Network for Mood and Anxiety Treatments (CANMAT). Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. III: pharmacotherapy. J Affect Disord 2009; 117 Suppl. 1: S26-43. Lucki I, Dalvi A, Mayorga AJ. Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology. (Berl) 2001;155:315-322. Malhi GS, Adams D, Porter R, et al., Northern Sydney Central Coast Mental Health Drug & Alcohol, NSW Health Clinical Redesign Program, CADE Clinic, University of Sydney. Clinical practice recommendations for depression. Acta Psychiatr Scand Suppl 2009; 119 (439): 8-26. Marcus RN, McQuade RD, Carson WH, Hennicken D, Fava M, Simon JS, Trivedi MH, Thase ME, Berman RM. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a second multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008 Apr;28(2):156-65. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389. Simpson GN, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand. 1970;212(Suppl 44):S11-S19. US 2020 / 0179336 A1 (June 11, 2020). Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988;45:742-747. Williams JBW. Structured interview guide for the Hamilton Anxiety Scale (SIGH-A). Biometrics Research Department, New York State Psychiatric Institute, New York, New York; Revision 15 Jan 2008. Willner P, Belzung C. Treatment-resistant depression: are animal models of depression fit for purpose? Psychopharmacology (Berl) 2015; 232(19):3473-3495.

[0110] 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. A method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need of treatment who has previously shown an inadequate response to antidepressant therapy, comprising administering to the subject the antidepressant therapy and a therapeutically effective amount of urotalonto or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein inadequate response is defined as less than a 50% reduction in the severity of depressive symptoms as assessed by the Massachusetts General Hospital-Antidepressant Treatment Response Questionnaire (MGH-ATRQ) after at least 8 weeks of antidepressant therapy.

3. 10. The method of claim 1, wherein the antidepressant therapy comprises an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor).

4. 10. The method of claim 1, wherein the antidepressant therapy comprises: a) an SSRI selected from escitalopram: 10-20 mg / day, fluoxetine: 20-60 mg / day, paroxetine: 25-62.5 mg / day, and sertraline: 50-200 mg / day; or b) SNRIs selected from duloxetine: 30-60 mg / day and venlafaxine: 37.5-225 mg / day A method comprising:

5. 10. The method of claim 1, wherein: a) the subject is suffering from a major depressive episode (MDE); b) the subject's current history of MDE has shown an inadequate response to at least one but not more than three adequate antidepressant therapies (ADT); and c) The subject has a 17-item Hamilton Depression Rating Scale (HAM-D17) total score of 18 or greater.

6. 10. The method of claim 1, wherein the inadequate response after at least 8 weeks of antidepressant therapy comprises: a) (i) a reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of less than 50%; or (ii) a HAM-D17 total score of 14 or greater; b) a score of 3 or greater on the CGI-C (Clinical Global Impression-Change) scale; and c) A reduction in MADRS of less than 50%; The way it is defined.

7. 10. The method of claim 1, wherein the inadequate response is at least 8 weeks after antidepressant therapy: a) a reduction in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of less than 50%; b) HAM-D17 total score ≥ 14; c) a score of 3 or greater on the CGI-C (Clinical Global Impression-Change) scale; and d) A reduction in the MADRS total score of less than 50%; The way it is defined.

8. 8. The method of any one of claims 1 to 7, wherein an inadequate response is defined as a reduction in the MADRS total score of more than 25% but less than 50%.

9. The method of claim 1, wherein the subject has anxiety distress.

10. 10. The method of claim 1, comprising administering urotalonto or a pharmaceutically acceptable salt thereof and improving the subject's symptoms of depression for a treatment-effective period of 6 weeks or more, 8 weeks or more, 12 weeks or more, 26 weeks or more, or 52 weeks or more.

11. 2. The method of claim 1, wherein the therapeutically effective amount comprises 25 to 100 mg of urotalont or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont.

12. 2. The method of claim 1, wherein the therapeutically effective amount comprises 50 or 75 mg of urotalont or a pharmaceutically acceptable salt thereof, based on the weight of the free form of urotalont.

13. 10. The method of claim 1, wherein the subject exhibits the inadequate response after at least 8 weeks of the antidepressant therapy.

14. 10. The method of claim 1, comprising administering urotalonto or a pharmaceutically acceptable salt thereof for a period of at least six weeks.

15. 10. The method of claim 1, which provides remission of depression.

16. 10. The method of claim 1, wherein the method provides remission of depression as defined according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition).

17. 10. The method of claim 1, wherein the method improves the subject's MADRS total score.

18. 10. The method of claim 1, wherein the subject's MADRS total score is reduced by 1 point or more, 2 points or more, 3 points or more, or 4 points or more compared to antidepressant therapy alone.

19. 10. The method of claim 1, wherein the subject's CGI-S (Clinical Global Impression-Severity) score improves by 2 or more points, 3 or more points, or 4 or more points.

20. 10. The method of claim 1, wherein the method provides a clinically significant improvement in the subject's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression-Severity) score.

21. 10. The method of claim 1, wherein the subject's FAST (Functional Assessment Short Form) score is improved.

22. 10. The method of claim 1, wherein the subject's PGI-S (Patient Global Impression-Severity) score is improved.

23. 10. The method of claim 1, wherein the subject improves their SF-36 (36-item short form questionnaire) score.

24. 10. The method of claim 1, wherein the subject's HAM-A (Hamilton Anxiety Rating Scale) total score is improved.

25. 10. The method of claim 1, wherein the subject's HAM-D17 (17-item Hamilton Depression Rating Scale) total score is improved.

26. 10. The method of claim 1, providing a CGI-C (Clinical Global Impression-Change) score of 1 or 2 (very improved or improved).

27. 10. The method of claim 1, wherein the subject's MADRS total score is reduced by 50% or more.

28. 10. The method of claim 1, wherein the subject's MADRS total score is reduced to 10 or less.

29. 10. The method of claim 1, wherein the subject's MADRS total score is reduced to 10 or less, and the subject's MADRS total score is reduced by 50% or more.

30. 10. The method of claim 1, wherein the subject: a) Abnormal involuntary movements as measured by the AIMS (Abnormal Involuntary Movement Scale); b) Akathisia as measured by the BARS (Barnes Akathisia Rating Scale); c) sexual function as measured by the CSFQ-14 (Changes in Sexual Function Questionnaire, Short Form); d) suicidal ideation as measured by the C-SSRS (Columbia-Suicide Severity Rating Scale); e) Parkinsonism as measured by the Simpson-Angus Scale (SAS); f) sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI); or g) Any combination of two or more of (a) to (f).

2. The method of claim 1, wherein the method does not result in clinically significant deterioration in the patient's condition.

31. 10. The method of claim 1, wherein the method does not result in clinically significant symptoms of metabolic syndrome selected from sedation, weight gain, diabetes, and hyperlipidemia, or motor impairment.

32. 10. The method of claim 1 , comprising: i) CNS (central nervous system) stimulation, including agitation, restlessness, and / or insomnia; ii) depression, including lethargy, somnolence, and / or shallow breathing; or iii) Impaired muscle coordination, effects on heart rate, and / or changes in pupil size The method further comprising monitoring for signs of

33. 10. The method of claim 1, wherein an inadequate response is defined as a 25% or less decrease in the MADRS total score.

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