TW202416952A - Methods of treating cns disorders - Google Patents

Abstract

Provided are antidepressant therapies, methods for augmenting antidepressant therapies, particularly antidepressant therapies that have failed to produce an adequate response, and to patient populations who benefit from such augmentation.

Description

Methods of treating CNS disorders

This disclosure relates to antidepressant therapy, methods for enhancing antidepressant therapy, particularly antidepressant therapy that has failed to produce an adequate response, and patient groups that benefit from such enhancement. Cross-references to Related Applications

This application claims priority to U.S. Provisional Application No. 63/373,909 filed on August 30, 2022, the entire contents of which are incorporated herein by reference as if fully set forth herein.

Major depressive disorder or MDD is a common and disabling illness that affects up to 15% of the population over their lifetime. See Connolly 2011. The introduction of newer antidepressants has greatly improved outcomes for these patients, but still only about 50-60% of patients respond to first-line treatment, and only 35-40% experience symptom relief during the initial 8-week trial period. See Connolly 2011. Drugs recommended as first-line antidepressants include, in particular, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, and mirtazapine.

Although there are many guidelines to help treat major depression, there are more limited recommendations for the treatment of depression that is inadequately responsive to antidepressant medications, including treatment-resistant depression. Professional guidelines include the American Psychiatric Association Practice Guideline for Treatment of Patients with Major Depressive Disorder, Malhi's Clinical Practice Recommendations for Depression (2009), the Canadian Network for Mood and Anxiety Treatments (CANMAT), and the Clinical Guidelines for the Management of Major Depressive Disorder in Adults. These guidelines include several recommendations after failure of an initial antidepressant trial, including additional psychotherapy, lithium-augmented chemotherapy, second-generation antipsychotic (SGA)-augmented chemotherapy, triiodothyronine-augmented chemotherapy, and switching to another antidepressant. Although lithium and thyroid hormone have been shown to enhance the efficacy of failed treatments, this has only been done in combination with tricyclic antidepressants (TCAs), and the trials supporting this use were conducted in fewer treatment-resistant patients than are typically treated with TCAs today. See Connolly 2011. Connolly 2011 reported that of all strategies to enhance the efficacy of newer-generation antidepressants, quetiapine and aripiprazole have the best evidence support, even though their cost-effectiveness and long-term benefits have not yet been established. See also Marcus 2008. As reported in that article, the development of adjunctive therapies is complicated by the fact that the efficacy of combination drugs observed in preclinical efficacy tests in psychiatry has generally not yet been translated into clinical trial results. See DeMartinis 2019.

Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity that is currently in Phase 3 clinical trials for the treatment of schizophrenia. It has the following chemical structure: It has a novel mechanism of action (MOA) compared to antipsychotics, as it is not an antagonist of dopamine D2 or serotonin 5-HT2A receptors. See Dedic 2019. A large randomized, double-blind, placebo-controlled clinical trial demonstrated the efficacy of arotaran in treating exacerbations of schizophrenia, with sustained improvements in a 6-month open-label extension study, as reported in US 2020/0179336 A1 (June 11, 2020). Nonclinical studies suggest that agonism of TAAR1 and 5-HT1A receptors contributes to arotaran's mechanism of action. See Dedic 2019.

Arodran was identified in a medicinal chemistry program designed to develop structurally and mechanistically novel antipsychotics using in vivo mouse phenotypic screening combined with comprehensive in vitro and in vivo molecular profiling. The testing showed that Arodran was behaviorally active, as reported in Dedic 2019. Arodran is classified as an anxiolytic at 0.3 mg/kg, but exhibits dose-dependent increases in antipsychotic classification, so that at 1 and 10 mg/kg, the characteristics are primarily antipsychotic-like. Arodran is also reported to exhibit a modest antidepressant-like signal.

Conventional antidepressant therapy has shown insufficient response in the treatment of severe depression and refractory depression, so there is a need to enhance the treatment methods of conventional antidepressant therapy and to identify criteria for patients who will respond to such therapy.

As reported in the Examples herein, it was surprisingly found that alotarol has behavioral activity against depression in a rat model, whereas many traditional antidepressants are ineffective in this setting. Thus, in one embodiment, the present disclosure provides a method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof, wherein the subject has shown an inadequate response to antidepressant therapy, the method comprising administering an antidepressant and therapeutically effective amount of alotarol or a pharmaceutically acceptable salt thereof to the subject.

In another embodiment, the present disclosure provides a method for adjunctive treatment of a subject suffering from refractory depression, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof.

Other methods of treating depression depend on the characteristics of the patient. Therefore, in another embodiment, the present disclosure provides a method of treating an individual suffering from depression, comprising administering to the individual a therapeutically effective amount of arotolan or a pharmaceutically acceptable salt thereof, wherein the individual has experienced an inadequate response to antidepressant therapy, and inadequate response is defined as a decrease in the total MADRS score of <50% since the start of antidepressant therapy.

In other aspects, the present disclosure relates to a method of treating depression using a combination of aloferol and an antidepressant therapy. Thus, in another embodiment, the present disclosure provides a method of treating an individual suffering from depression (e.g., MDD) comprising administering to the individual a therapeutically effective amount of aloferol or a pharmaceutically acceptable salt thereof and an antidepressant therapy.

Additional advantages of the present disclosure are partially described below, and partially can be easily inferred from the description, or can be understood by practicing the present disclosure. The advantages of the present disclosure will be realized and obtained by the elements and combinations particularly indicated in the attached patent claims. It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and are not intended to limit the present disclosure.

The entire contents of all public documents cited in this article are hereby incorporated by reference. Use of Terms

As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Unless otherwise indicated, the term "include" (or any variation thereof, such as "include", "including", etc.) is intended to be an open-ended term. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to 1, 2, and 3.

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

When a range is defined using the lower end of a range and the upper end of the range separated from each other, or when a range is defined using a specific numerical value, it should be understood that any mathematically possible lower end variable, upper end variable and specific numerical value can be selectively combined to define a range. In a similar manner, when a range is defined as spanning from one endpoint to another, the range will also be understood to cover the span between the two endpoints and not including the two endpoints, including any and all ranges and sub-ranges therein. The range is understood to cover every discrete point within the range, just as if it were fully described herein.

This disclosure describes various specific aspects. Those of ordinary skill in the art who review this disclosure will readily recognize that the various specific aspects can be combined with any variant. For example, the specific aspects of this disclosure include various diseases, treatment of patient populations, dosage forms administered in various doses, minimization of various adverse events, and improvements in various efficacy measurements. Any combination of various specific aspects is within the scope of this disclosure.

When this document refers to published test methods and diagnostic instruments, it should be understood that the test method or diagnostic instrument is based on the version effective July 1, 2022, unless otherwise stated herein. This is true even when the method or instrument defined in this document is based on an earlier version of the publication.

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. Definitions

Adjunctive MDD therapy refers to the addition of medications to an antidepressant regimen to enhance treatment effectiveness because the individual has experienced an inadequate response to an antidepressant regimen optimized for dose and duration.

As used herein, "administering" or "administration" of aladolan or a pharmaceutically acceptable salt thereof encompasses delivering aladolan 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 (as described herein).

The "AIMS" (Abnormal Involuntary Movement Scale) assessment consists of 10 items describing symptoms of movement disorders. See Guy 1976. While the individual is at rest, facial and oral movements (items 1 to 4), limb movements (items 5 and 6), and trunk movements (item 7) are observed without interference; the researcher also makes an overall judgment on the individual's movement disorder (items 8 to 10). Each item is scored on a 5-point scale, with 0 indicating no symptoms (for item 10, no awareness) and 4 indicating severe condition (for item 10, awareness, severe distress). In addition, the AIMS includes 2 yes/no questions concerning the individual's dental condition. The AIMS Movement Rating Score is defined as the sum of items 1 to 7 (i.e., items 1 to 4, face and mouth movements; items 5 and 6, limb movements; and item 7, trunk movements).

"Antidepressant regimen" or "antidepressant therapy" refers to any medication regimen administered as part of a treatment regimen for depression and should be distinguished from augmentation therapy, which is the addition of a medication (not considered an antidepressant in itself) to an antidepressant regimen to improve the efficacy of the treatment. Examples of medications used to treat depression include, but are not limited to, SSRIs, SNRIs, bupropion, and mirtazapine, and their pharmaceutically acceptable salts.

The term "anxious distress" used in this article is based on DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). Therefore, an individual with anxious distress must have 2 of the following 5 symptoms found in most major depressive episodes: 1) feeling agitated (keyed up) or nervous, 2) feeling extremely restless, 3) having trouble concentrating because of worry, 4) fear that something terrible might happen, and 5) a feeling that they might lose self-control. 0 or 1 symptom = no anxiety disturbance, 2 symptoms = mild anxiety disturbance, 3 symptoms = moderate anxiety disturbance, and 4-5 symptoms = moderate to severe anxiety disturbance (psychomotor agitation must be present).

As used herein, an "at-risk" individual is one who is at risk for developing the condition to be treated. This can be manifested, for example, by one or more risk factors, which are measurable parameters that correlate with the development of the condition and are known in the art. When a method is considered to treat a condition without causing or inducing an adverse event, it is understood that the method can be performed in a patient at risk for an adverse event.

The "BARS" (Barnes Akathisia Rating Scale) is a global clinical assessment of akathisia. See Barnes 1989. The BARS consists of 4 items related to akathisia: the researcher's objective observation of akathisia, the individual's subjective feeling of restlessness, the subjective distress caused by akathisia, and the global clinical assessment of akathisia. The first 3 items are scored on a 4-point scale, with 0 representing no symptoms and 3 representing severe symptoms. The global clinical assessment is scored on a 6-point scale, with 0 representing no symptoms and 5 representing severe akathisia.

The "CGI-C" (Clinical Global Impression - Change) scale is used to measure the effectiveness of drug treatment. It assesses the individual's overall change since the start of drug treatment, regardless of whether the change is entirely attributable to drug treatment. Response options include: 1 = very improved, 2 = very improved, 3 = very little improved, 4 = no change, 5 = slightly worse, 6 = very worse, and 7 = very worse.

The "CGI-S" (Clinical Global Impression – Severity) scale is a standardized, clinician-administered global rating scale that uses a 7-point Likert scale to measure the severity of illness. Higher CGI-S scores represent greater severity of illness. To conduct this assessment, the assessor or researcher answers the following question: "Based on your overall clinical experience with this particular population, what is the level of mental illness in this patient at this time?" Response options include: 1 = normal, not at all ill; 2 = borderline mental illness; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = the sickest patient.

As used herein, the term "clinically significant" or "clinically meaningful" refers to an improvement in symptoms that is both statistically significant and meaningful from the perspective of the patient, clinician, or caregiver, typically based on static measures such as the CGI-S or retrospective assessments of improvement such as the CGI-C, as generally described in various publications of the United States Food and Drug Administration, including FDA 2018, FDA 2019, and FDA 2020. When a treatment or benefit is described herein, it is understood that, in a specific aspect, the treatment or benefit demonstrates clinically significant efficacy in a patient population to a degree of statistical significance.

The CSFQ-14 is a 14-item shorter version of the Changes in Sexual Functioning Questionnaire (CSFQ) that produces scores for a global measure of sexual function and two sets of subscales: one set of five scales corresponding to important dimensions of sexual function and the other set of three scales corresponding to three phases of the sexual response cycle. See Keller 2006.

As used herein, "delaying" the progression of a disease means delaying, impeding, slowing, stabilizing and/or postponing the progression of the disease. The length of delay can vary, depending on the history of the disease and/or the individual being treated.

"Depression" has the meaning generally described in the psychiatric field, and the definition in DSM-5 may be used. When depression is mentioned herein, it should be understood that MDD is a type of depression, and all aspects of this disclosure are more specifically directed to the treatment of MDD.

“DSM-5” refers to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Where necessary, reference is made to the DSM-5 to define terms used in this document in order to give life and meaning to the term. When a person is defined in this document based on the DSM-5, it should be understood that the person does not necessarily have to have been diagnosed using the criteria of the DSM-5, but if so diagnosed, the person would meet the criteria defined in the DSM-5.

"FAST" (Functional Assessment Short Test) is a 24-item questionnaire designed to assess the degree of difficulty the individual is experiencing in various aspects of functioning. The individual rates their difficulty as 0 (no difficulty), 1 (mild difficulty), 2 (moderate difficulty), and 3 (severe difficulty).

The "HAM-A" (Hamilton Anxiety Rating Scale) is designed to assess anxiety symptoms in patients and in one specific aspect, it was introduced using the Structured Interview Guide for the Hamilton Anxiety Rating Scale (SIGH-A). See Williams 2008.

The HAM-D ₁₇ (17-item Hamilton Depression Rating Scale) is another well-known instrument for assessing depression in individuals and was introduced using the Structured Interview Guide for the Hamilton Depression Rating Scale (SIGH-D). See Williams 1988.

Unless otherwise specified, an "inadequate response" means the absence of a clinically significant improvement in the individual's depressive symptoms since the start of self-treatment. An inadequate response is always based on adequate or therapeutically effective doses of antidepressant therapy for an acceptable duration of time. In some embodiments, an inadequate response is defined as a decrease in the MADRS total score of <50%, <40%, <30%, or <20% since the start of self-treatment, and/or a CGI-C score of ≥3 since the start of self-treatment. In one embodiment, an inadequate response is defined as a decrease in the MADRS total score of <50% since the start of self-treatment. In another embodiment, an inadequate response is defined as a CGI-C score of ≥3. In another embodiment, inadequate response was defined as a <50% decrease in the total MADRS score since the start of self-treatment and a CGI-C score of ≥ 3. In one embodiment, inadequate response was defined as a <50% improvement in symptom severity (per the MGH-ATRQ (Massachusetts General Hospital Antidepressant Treatment Response Questionnaire)). In another embodiment, inadequate response was defined as a <50% decrease in the total score of the HAM-D17 (17-item Hamilton Depression Rating Scale). In another embodiment, inadequate response was defined as a HAM-D17 total score of ≥ 14.

The "MADRS" (Montgomery-Asberg Depression Rating Scale) is a well-known tool for assessing the severity of depression in individuals. See Montgomery 1979. The MADRS consists of 10 items, each with a score of 0 to 6. A higher MADRS score indicates a more severe depression.

A "Major Depressive Episode" or "MDE" has the DSM-5 definition of that term. Thus, (i) the patient must have 5 or more depressive symptoms lasting ≥ 2 weeks; (ii) the patient must have low mood or loss of interest/pleasure; (iii) the symptoms must cause significant distress or impairment; and (iv) the patient must not have had a manic or hypomanic episode. Depressive symptoms are selected from the group consisting of: (i) low mood, (ii) markedly decreased interest or pleasure in most or all activities, (iii) marked weight loss (or loss of appetite) or weight gain, (iv) insomnia or hypersomnia, (v) mental and motor retardation, (vi) fatigue or loss 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 just fear of death) or suicidal ideation, plans, or attempts.

The "PGI-C" (Patient Global Impression – Change) scale measures the efficacy of drug therapy by rating the individual's global change since the start of drug therapy from the patient's perspective, regardless of whether the efficacy is entirely attributable to drug therapy.

The "PGI-S" (Patient Global Impression – Severity) is a single-item report of the severity of the individual's symptoms. The individual is asked: "Please select the answer below that best describes the severity of your depression in the past week." Representative answers include non-overlapping responses such as none, mild, moderate, and severe.

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

As used herein, the term "pharmaceutically acceptable salt" means a salt which is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions and the like within the scope of sound medical judgment and which is commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S. M. Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of alodrat include those derived from appropriate inorganic and organic acids and bases.

Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed from an amine group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with an organic acid (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 (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, Laurate, dodecyl sulfate, appletate, cis-malonate, 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. Although pharmaceutically acceptable counter ions are usually used to prepare pharmaceutical formulations, other anions (X) are also very acceptable for use as synthetic intermediates. Thus, when the salts are chemical intermediates, X may be a pharmaceutically undesirable anion, such as iodide, oxalate, triflate, and the like.

As used herein, the term "pharmaceutically acceptable excipient" includes, but is not limited to, any binder, filler, adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, anti-caking agent, flavor, desiccant, plasticizer, disintegrant, lubricant, polymer matrix system and polishing agent that has been approved by the United States Food and Drug Administration after appropriate review or otherwise accepted for use in humans or domestic animals.

As used herein, "prevent" or "preventing" means a regimen that protects against the onset of a disease so that clinical symptoms of the disease do not develop. Thus, "preventing" relates to a therapy that is administered to an individual before symptoms of a disease are detected in the individual (e.g., a therapy is administered when detectable symptoms of the disease are not present). The individual may be a person at risk of developing the disease.

The "PSQI" (Pittsburgh Sleep Quality Index) consists of 19 self-report questions and 5 questions rated by your bed partner or roommate (if applicable). The score includes only the self-report questions. The 19 self-report items are combined to form 7 "component" scores, each ranging from 0 to 3 points. In all cases, a score of "0" indicates no difficulty and a score of "3" indicates severe difficulty. The scores of the 7 components are then added together to form an "overall" score, which ranges from 0 to 21 points, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas.

Unless otherwise specified, "remission" of MDD means that the individual no longer suffers from MDD as defined by DSM-5. Alternatively, in other embodiments, remission may be defined based on a MADRS total score ≤ 10 and a decrease in the MADRS total score of ≥ 50% since the start of self-treatment.

Unless otherwise specified, a "response" to treatment means that the individual is diagnosed with clinically significant improvement since the start of self-treatment. Alternatively, a response may be defined as a decrease in the MADRS total score of ≥ 50% since the start of self-treatment. Alternatively, a response may be defined as a CGI-C score of 1 or 2 (very improved or very improved) since the start of self-treatment. Alternatively, a response may be defined as a decrease in the MADRS total score of ≥ 50% since the start of self-treatment and a CGI-C score of 1 or 2 (very improved or very improved) since the start of self-treatment.

The "SAS" (Simpson Angus Scale) consists of 10 Parkinson's symptoms (gait, arm drop, shoulder tremor, elbow stiffness, wrist stiffness, head rotation, glabella tap, tremor, drooling, and akathisia). See Simpson 1970. Each item is scored on a 5-point scale, with 0 representing no symptoms and 4 representing severe disease. The total SAS score is the sum of the scores for all 10 items.

The SF-36 (36-Item Short-form Survey) is a self-report questionnaire with a standardized 4-week recall period that measures general health-related quality of life in 2 broad domains (physical and mental composite) across 8 health domain scales: physical function, pain, role physical, global health, vitality/fatigue, social functioning, role emotional, and mental health. The SF-36 uses norm-based scoring to generate scores on a scale of 0 to 100, where lower scores for the physical component summary and the mental component summary represent lower health-related quality of life, and 50 is referenced to normative data derived from a representative sample of the general U.S. population. In addition to the composite score and individual health domain scores, the SF-36 also provides a depression risk score and the SF-6D health utility index is scaled from 0.0 (worst measured health status) to 1.0 (best measured health status).

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

"SNRIs" (Serotonin-norepinephrine Reuptake Inhibitors) include, but are not limited to, desvenlafaxine (Pristiq®), duloxetine (Cymbalta®), levomilnacipran (Fetzima®), and venlafaxine (Effexor® XR) and their pharmaceutically acceptable salts.

"SSRIs" (Selective Serotonin Reuptake Inhibitors) include, but are not limited to, citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), paroxetine (Paxil®, Pexeva®), and sertraline (Zoloft®), and their pharmaceutically acceptable salts.

As used herein, "individuals" or "patients" intended to be administered include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric individuals (e.g., infants, children, adolescents) or adult individuals (e.g., young adults, middle-aged adults, or elderly adults) and/or other primates (e.g., crab-eating macaques, Gangetic monkeys); mammals, including commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds, such as chickens, ducks, geese, quails, and/or turkeys.

As used herein, the term "therapeutically effective amount" or "effective amount" means an amount that is effective to induce a desired biological or medicinal response, including an amount of a compound sufficient to achieve treatment of a condition when the compound is administered to a subject to treat the condition. The effective amount will vary depending on the condition, its severity, and the age, weight, etc. of the subject to be treated. An effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint). An effective amount administered may be considered an effective amount if it is able to achieve or has achieved the desired or beneficial result when used in combination with one or more other agents. Due to the co-action, additive or synergistic effect of the compounds, the appropriate dose of any co-administered compound may be reduced as necessary.

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

When treatment with two separate agents is described herein, it is understood that the agents will be administered concomitantly based on a concurrent dosing regimen that may differ in frequency or timing of administration. Concomitant administration does not mean that the two agents must be administered at the same time. For example, concomitant administration may include administering one agent three times a day and administering one agent once a day.

A therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated; it also includes eradication and/or amelioration of one or more symptoms associated with the underlying disorder such that an improvement is observed in the individual even though the individual may still be suffering from the underlying disorder.

In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting a disease (e.g., alleviating one or more symptoms caused by the disease, and/or reducing the extent of the disease); (b) slowing down or preventing the development of one or more symptoms associated with the disease (e.g., stabilizing the disease and/or delaying the deterioration or progression of the disease); and/or (c) relieving the disease (e.g., causing clinical symptoms to subside, improving the disease, delaying the progression of the disease and/or improving the quality of life.)

“Refractory depression” or “treatment failure” have the same clinical criteria and, unless otherwise specified herein, will be defined by the U.S. FDA as the absence of a clinically meaningful improvement (MADRS total score ≤ 25%) in the current depressive episode after treatment with at least 2 different antidepressants at appropriate doses and for an appropriate duration (at least 6 weeks). Alternatively, the term may be defined as an improvement of ≤ 25% in the MADRS total score after treatment with 2 or 3 prior antidepressants at appropriate doses and durations, as documented by the Massachusetts General Hospital – Antidepressant Treatment Response Questionnaire (ATRQ).

As referred to herein, "ulotaront" used in the disclosed methods has the chemical name (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (which may be abbreviated as "(S)-TPMA"). Ulotaront has the following structure: Unless otherwise stated, or unless the context requires otherwise, for the purpose of this disclosure, the term "aladran" alone includes aladran in free form, and also includes its pharmaceutically acceptable salts, hydrates, solvates, amorphous and crystalline forms. When the free form is intended, or any other form or salt is specifically intended, it will be expressly stated.

When used in the methods disclosed herein, alotarol can be a free base (free form) or a pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein use the hydrochloric acid (HCl) salt of alotarol. Alotarol or its pharmaceutically acceptable salt, including its HCl crystalline form, can be obtained according to the production method disclosed in PCT Patent Publication No. WO2011/069063 (U.S. Patent No. 8,710,245, granted on April 29, 2014) or PCT Patent Publication No. WO2019/161238 or a similar method thereof, which are incorporated herein by reference in their entirety for all purposes.

The present invention also provides pharmaceutical compositions and dosage forms, which include aloferol or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable formulations. The compositions and dosage forms provided herein may further include one or more additional active ingredients. Aloferol or a pharmaceutically acceptable salt thereof may be administered as part of the pharmaceutical compositions disclosed herein. Discussion

In one embodiment, the present disclosure provides a method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof, wherein the human subject has shown an inadequate response to antidepressant therapy after at least 8 weeks of antidepressant therapy, the method comprising administering the antidepressant therapy and a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof to the subject.

In another embodiment, the present disclosure provides a method for adjunctive treatment of a subject suffering from refractory depression, comprising administering to the subject an antidepressant therapy and a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof.

In another embodiment, the present disclosure provides a method for treating an individual suffering from depression, comprising administering to the individual a therapeutically effective amount of arotolan or a pharmaceutically acceptable salt thereof, wherein the individual has experienced an inadequate response to antidepressant therapy, and inadequate response is defined as a decrease in the total MADRS score of <50% since the start of self-treatment. In one embodiment, the method is used in an individual to assist an antidepressant treatment regimen comprising antidepressant therapy, wherein the individual has shown an inadequate response to antidepressant therapy after, for example, at least eight weeks of antidepressant therapy. In another embodiment, inadequate response is further defined as a CGI-C score of ≥3 since the start of self-treatment.

In another embodiment, the present disclosure provides a method for treating a subject suffering from depression (eg, MDD), comprising administering to the subject a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof and an anti-depressant therapy.

In any embodiment disclosed herein, the antidepressant therapy comprises an SSRI (selective serotonin reuptake inhibitor) or an SNRI (serotonin-norepinephrine reuptake inhibitor). In some embodiments, the antidepressant therapy comprises an SSRI selected from escitalopram 10 to 20 mg/day, fluoxetine 20 to 60 mg/day, paroxetine 25 to 62.5 mg/day, or sertraline 50 to 200 mg/day; or an SNRI selected from duloxetine 30 to 60 mg/day and venlafaxine 37.5 to 225 mg/day. The aforementioned therapies are generally considered "adequate therapies" when tailored to a particular individual. In any embodiment disclosed herein, the individual has experienced an inadequate response to or treatment failure of an antidepressant therapy as described in this paragraph.

Any embodiment disclosed herein can be further defined by the individual to be treated. Thus, in one embodiment, the individual suffers from a major depressive episode (MDE) as defined in DSM-5. The length of the MDE can vary, including a duration of ≥ 4 weeks, ≥ 8 weeks, or ≥ 26 weeks. In some embodiments, the MDE is a duration of ≥ 8 weeks and ≤ 52 weeks. In another embodiment, the individual is currently in a major depressive episode (MDE) as defined by the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) and validated by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ).

In another embodiment, the individual is characterized by an inadequate response to at least one and no more than three adequate antidepressant therapies (ADT) during the current MDE. In some embodiments, the antidepressant therapy comprises an SSRI or SNRI, or one of the therapies described above.

In other embodiments, however, the individual is characterized by his or her level of depression prior to the ADT. Thus, in another embodiment, the individual has a 17-item Hamilton Depression Rating Scale (HAM-D17) total score of ≥ 18 (but ≥ 14, ≥ 16, ≥ 20, or ≥ 22 as appropriate) prior to the ADT.

In a further specific embodiment, however, the treated individual will meet all three of the aforementioned requirements for MDE status for at least 8 weeks prior to ADT, an inadequate response to an early course of antidepressant therapy, and a HAM-D17 total score of ≥ 18.

In other embodiments, the individual having an inadequate response after at least 8 weeks of antidepressant therapy is defined as: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; (b) a HAM-D17 total score ≥14; (c) a CGI-C (Clinical Global Impression-Change) scale score of ≥3; or (d) a decrease in the MADRS (Montgomery Asberg Depression Rating Scale) total score of <50%; or (e) a combination of any two or more of (a) to (d).

Other specific aspects are defined based on the patient's treatment response as measured by MADRS. Thus, in one specific aspect, an inadequate response is defined as a decrease in the total MADRS score of ≤ 25%. In another specific aspect, an inadequate response is defined as a decrease in the total MADRS score of < 50% and > 25%.

Still other embodiments find particular utility in individuals suffering from anxiety disorders and are based on the individual's level of anxiety. Thus, any method disclosed herein can be applied to individuals suffering from anxiety disorders as defined in DSM 5.

The methods disclosed herein can also be defined based on the dosage of arodalan administered. Thus, in one embodiment, the therapeutically effective amount comprises from 10 to 150 mg, from 15 to 125 mg, from 25 to 100 mg, from 25 to 75 mg, or from 50 to 100 mg of arodalan or a pharmaceutically acceptable salt thereof, based on the weight of the free form of arodalan. In another embodiment, the therapeutically effective amount comprises 50 or 75 mg of arodalan or a pharmaceutically acceptable salt thereof, based on the weight of the free form of arodalan. In further embodiments, the therapeutically effective amount comprises 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg of aladolan or a pharmaceutically acceptable salt thereof by weight of free aladolan.

In any of these embodiments, the therapeutically effective amount of aladolan is administered once daily for a period of at least six weeks.

The methods disclosed herein can be further defined according to their effects on the disease. Thus, any method disclosed herein can produce relief from depression, including relief from depression as defined in DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition).

Any method disclosed herein can further produce a mean change in the individual's Montgomery-Asberg Depression Rating Scale. In different embodiments, the method can increase the reduction in the total MADRS score by ≥ 1, ≥ 2, ≥ 3, ≥ 4, or ≥ 5 points over a single antidepressant therapy. In other embodiments, the treatment improves the total MADRS score of the individual. In other embodiments, the treatment improves the CGI-S score of the individual by ≥ 2, ≥ 3, or ≥ 4 points. In further embodiments, the treatment produces a clinically significant improvement in the total MADRS score and the CGI-S score of the individual.

Other specific aspects can be defined based on alternative endpoints. Thus, in different specific aspects, the method improves the individual's FAST (Functional Assessment Short Test) score.

In a further specific aspect, the method improves the individual's PGI-S (Patient Global Impression – Severity) score.

In other specific aspects, the method improves the individual's SF-36 (36-Item Short‑form Survey) score.

In a further specific aspect, the method improves the individual's HAM-A (Hamilton Anxiety Rating Scale) total score.

In a further specific aspect, the method improves the individual's HAM D17 (17-item Hamilton Depression Rating Scale) total score.

In other embodiments, the method produces a CGI-C (Clinical Global Impression – Change) score of 1 or 2 (very improved or very improved). In further embodiments, the method reduces the individual's MADRS total score by ≥ 50%. In further embodiments, the method reduces the individual's MADRS total score to ≤ 10.

In another embodiment, the method reduces the individual's MADRS total score to ≤ 10 and reduces the individual's MADRS total score by ≥ 50%.

The method can also be defined based on the administration period, generally resulting in an improvement in the subject's depressive symptoms at least until the end of the period. Thus, any embodiment of the present disclosure can be implemented by administering alotralan or a pharmaceutically acceptable salt thereof and can improve the subject's depressive symptoms for a therapeutic 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. The improvement is represented, for example, by a decrease in the individual's MADRS score (i.e., a decrease of ≥ 25%, a decrease of ≥ 40%, or a decrease of ≥ 50%), resulting in a total MADRS score of ≤ 14, ≤ 12, ≤ 10, or ≤ 8, or by a combination of a decrease in score and an absolute total score, such as a decrease of ≤ 50% and a total score of ≤ 10.

In another embodiment, the improvement is represented by a decrease in the individual's MADRS score of ≥ 50%, resulting in a total MADRS score of ≤ 10, and the treatment response is observed for at least 26 weeks.

The methods of the present disclosure may also be defined based on their superior side effect profile. Thus, in various embodiments, the method does not result in a clinically significant worsening in the individual's: (a) abnormal involuntary movements as measured by the AIMS (Abnormal Involuntary Movement Scale); or (b) akathisia as measured by the BARS (Barnes Akathisia Rating Scale); or (c) sexual function as measured by the CSFQ-14 (Changes in Sexual Functioning Questionnaire); or (d) suicidal tendencies as measured by the C SSRS (Columbia-Suicide Severity Rating Scale); or (e) suicidal tendencies as measured by the SAS (Simpson Angus Scale); or (f) suicidal tendencies as measured by the SAS (Simpson Angus Scale). or (g) any combination of two or more of (a) to (f).

Even if they have a superior side effect profile, the methods further monitor if necessary whether any potential side effects occur. In some embodiments, the methods further comprise monitoring CNS (central nervous system) stimulation, which includes agitation, restlessness, insomnia, depression (including listlessness, sleepiness and shallow breathing), impaired muscle coordination, effects on heart rate and changes in pupil size.

Certain aspects of the present disclosure may be defined based on the following embodiments AA to BW: [Aspect AA] A method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof, wherein the human subject has demonstrated an inadequate response to an antidepressant therapy, the method comprising administering the antidepressant therapy and a therapeutically effective amount of arotolan or a pharmaceutically acceptable salt thereof to the subject. [Aspect AB] A method for adjunctive treatment of a human subject suffering from refractory depression, comprising administering the antidepressant therapy and a therapeutically effective amount of arotolan or a pharmaceutically acceptable salt thereof to the subject. [Aspect AC] The method of embodiment AB, wherein refractory depression is defined as failure of treatment with more than one antidepressant therapy. [Specific Aspects AD] The method of Embodiment AA, wherein an inadequate response is defined as a <50% decrease 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. [Specific Aspects AE] A method for treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof, wherein the subject has experienced an inadequate response to antidepressant therapy, and an inadequate response is defined as a <50% decrease in the total score on the MADRS since the start of the antidepressant therapy. [Specific Aspects AF] A method for treating a human subject suffering from depression, comprising administering to the subject a therapeutically effective amount of arotolan or a pharmaceutically acceptable salt thereof, wherein the subject has experienced an inadequate response to antidepressant therapy, and inadequate response is defined as a decrease in MADRS total score of < 50% since the start of antidepressant therapy, and a CGI-C score of ≥ 3 since the start of antidepressant therapy. [Specific Aspects AG] A method as in Embodiments AE or AF, wherein the method is used as an adjunct to an antidepressant regimen comprising antidepressant therapy in a human subject in need thereof, the human subject having demonstrated an inadequate response to antidepressant therapy. [Embodiments AH] The method of any one of Embodiments AA to AG, wherein the antidepressant therapy comprises an SSRI (Selective Serotonin Reuptake Inhibitors) or an SNRI (Serotonin-norepinephrine Reuptake Inhibitor). [Embodiments AI] The method of any one of Embodiments AA to AG, wherein the antidepressant therapy comprises an SSRI selected from escitalopram 10 to 20 mg/day, fluoxetine 20 to 60 mg/day, paroxetine 25 to 62.5 mg/day, and sertraline 50 to 200 mg/day; or an SNRI selected from duloxetine 30 to 60 mg/day and venlafaxine 37.5 to 225 mg/day. [Specific Aspect AJ] Methods as in any of Specific Aspects AA, AD, AH, and AI, where inadequate response is defined as a decrease in the total MADRS score of ≤ 50% since the start of self-treatment. [Specific Aspect AK] Methods as in any of Specific Aspects AA, AD, AH, and AI, where inadequate response is defined as a CGI-C score of ≥ 3 since the start of self-treatment. [Specific Aspect AL] A method as in Specific Aspects AA and any of Aspects AD to AI, wherein the under-response is defined as: (a) (i) a decrease in the total score of the HAM-D17 (17-item Hamilton Depression Rating Scale) of < 50% or (ii) a total score of the HAM-D17 ≥ 14; and (b) a score of ≥ 3 on the CGI-C (Clinical Global Impression – Change) scale; and (c) a decrease in the total score of the MADRS (Montgomery Asberg Depression Rating Scale) of < 50%. [Specific Aspect AM] A method as in Specific Aspects AA and any of Aspects AD to AI, wherein the under-response is defined as: (a) a decrease in the total score of the HAM-D17 (17-item Hamilton Depression Rating Scale) of <50%; and (b) a total score of the HAM-D17 of ≥ 14; and (c) a score of ≥ 3 on the CGI-C (Clinical Global Impression – Change) scale; and (d) a decrease in the total score of the MADRS (Montgomery Asberg Depression Rating Scale) of < 50%. [Specific aspect AN] The method of any of aspects AA and AD to AM, wherein the individual has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score ≥ 18 before antidepressant therapy, and after at least 8 weeks of antidepressant therapy, an inadequate response is defined as: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; or (b) a HAM-D17 total score ≥ 14; or (c) a CGI-C (Clinical Global Impression – Change) scale score of ≥ 3; or (d) a MADRS (Montgomery Asberg Depression Rating Scale) score of ≥ 3. (e) a combination of (a) to (d). [Specific aspect AO] The method of any of aspects AA and AD to AM, wherein the individual has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of ≥ 18 before antidepressant therapy, and after at least 8 weeks of antidepressant therapy, an inadequate response is defined as: (a) a decrease in the HAM-D17 (17-item Hamilton Depression Rating Scale) total score of <50%; and (b) a HAM-D17 total score of ≥ 14; and (c) a CGI-C (Clinical Global Impression – Change) scale score of ≥ 3; and (d) a MADRS (Montgomery Asberg Depression Rating Scale) score of ≥ 3. Asberg Depression Rating Scale) total score decreased by < 50%. [Specific Aspect AP] Method as any of Specific Aspects AA to AO, wherein the individual is currently in a major depressive episode (MDE) as defined by the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). [Specific Aspect AQ] Method as any of Specific Aspects AA to AO, wherein the individual has been in a major depressive episode (MDE) as defined by the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) for ≥ 8 weeks. [Specific Aspect AR] A method according to any one of Embodiments AA to AQ, comprising administering aloferol or a pharmaceutically acceptable salt thereof, and improving the depressive symptoms of the subject for a therapeutically 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. [Specific Aspect AS] A method according to any one of Embodiments AA to AR, wherein the therapeutically effective amount comprises from 25 to 100 mg of aloferol or a pharmaceutically acceptable salt thereof, based on the weight of the free form of aloferol. [Specific Aspect AT] A method according to any one of Embodiments AA to AR, wherein the therapeutically effective amount comprises 50 or 75 mg of aloferol or a pharmaceutically acceptable salt thereof, based on the weight of the free form of aloferol. [Specific Aspect AU] The method of any of Embodiments AA and AD to AT, wherein the individual has demonstrated an inadequate response to antidepressant therapy after at least eight weeks. [Specific Aspect AV] The method of any of Embodiments AA to AU, comprising administering alotralan or a pharmaceutically acceptable salt for a period of at least six weeks. [Specific Aspect AW] The method of any of Embodiments AA to AV, wherein the method increases the individual's Montgomery-Asberg Depression Rating Scale total score by ≥ 1, ≥ 2, ≥ 3, or ≥ 4 points compared to antidepressant therapy alone. [Specific Aspect AX] The method of any of Embodiments AA to AW, wherein the method produces relief of depression. [Specific Aspect AY] A method as in any of aspects AA to AW, wherein the method produces remission of depression as defined in DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). [Specific Aspect AZ] A method as in any of aspects AA to AY, wherein the method improves the individual's MADRS (Montgomery Asberg Depression Rating Scale) total score. [Specific Aspect BA] A method as in any of aspects AA to AZ, wherein the method improves the individual's CGI-S (Clinical Global Impression – Severity) score by ≥ 2, ≥ 3, or ≥ 4 points. [Specific Aspect BB] A method as in any of Specific Aspects AA to BA, wherein the method produces a clinically significant improvement in the individual's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression – Severity) score. [Specific Aspect BC] A method as in any of Specific Aspects AA to BB, wherein the method improves the individual's FAST (Functional Assessment Short Test) score or PGI-S (Patient Global Impression – Severity) score. [Specific Aspect BD] A method as in any of Specific Aspects AA to BC, wherein the individual suffers from anxiety disorders as defined in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). [Specific Aspect BE] A method as in any of Specific Aspects AA to BD, wherein the method improves the individual's SF-36 (36-Item Short-form Survey) score. [Specific Aspect BF] A method as in any of Specific Aspects AA to BE, wherein the method improves the individual's HAM-A (Hamilton Anxiety Rating Scale) total score. [Specific Aspects BG] A method as in any of Specific Aspects AA to BF, wherein the method improves the individual's HAM D17 (17-item Hamilton Depression Rating Scale) total score. [Specific Aspects BH] A method as in any of Specific Aspects AA to BG, wherein the method produces a CGI-C (Clinical Global Impression – Change) score of 1 or 2 (very improved or very improved). [Specific Aspects BI] A method as in any of Specific Aspects AA to BH, wherein the method reduces the individual's MADRS total score by ≥ 50%. [Specific Aspects BJ] A method as in any of Specific Aspects AA to BI, wherein the method reduces the individual's MADRS total score to ≤ 10. [Embodiment BK] The method of any one of Embodiments AA to BJ, wherein the method reduces the individual's MADRS total score to ≤ 10 and reduces the individual's MADRS total score by ≥ 50%. [Specific Aspect BL] A method as in any of Aspects AA through BK, wherein the method does not result in a clinically significant worsening of the individual's abnormal involuntary movements as measured by the AIMS (Abnormal Involuntary Movement Scale); or akathisia as measured by the BARS (Barnes Akathisia Rating Scale); or sexual function as measured by the CSFQ-14 (Changes in Sexual Functioning Questionnaire); or suicidal tendencies as measured by the C SSRS (Columbia-Suicide Severity Rating Scale); or Parkinsonism as measured by the SAS (Simpson Angus Scale); or [Specific Aspect BM] The method of any of Embodiments AA to BK, wherein the method does not cause clinically significant sedation, symptoms of metabolic syndrome (e.g., weight gain, diabetes, hyperlipidemia), or movement disorders. [Specific Aspect BN] The method of any of Embodiments AA to BL, further comprising monitoring CNS (central nervous system) stimulation, including irritability, restlessness, insomnia, depression (including listlessness, drowsiness, and shallow breathing), impaired muscle coordination, effects on heart rate, and changes in pupil size. [Embodiment BO] A method for treating an individual suffering from depression (e.g., MDD) comprising administering to the individual a therapeutically effective amount of arotaran or a pharmaceutically acceptable salt thereof and an antidepressant therapy. [Embodiment BP] The method of embodiment BO, wherein the antidepressant therapy comprises a therapeutically effective amount of an SSRI (selective serotonin reuptake inhibitor) or a SNRI (serotonin-norepinephrine reuptake inhibitor). [Embodiment BQ] The method of Embodiment BO, wherein the antidepressant therapy comprises an SSRI selected from escitalopram (e.g., 10 to 20 mg/day), fluoxetine (e.g., 20 to 60 mg/day), paroxetine (e.g., 25 to 62.5 mg/day), or sertraline (e.g., 50 to 200 mg/day); or an SNRI selected from duloxetine (e.g., 30 to 60 mg/day) and venlafaxine (e.g., 37.5 to 225 mg/day). [Embodiment BR] The method of any one of Embodiments AA to BQ, wherein the patient has a HAM-D17 (17-item Hamilton Depression Rating Scale) total score of ≥ 14, ≥ 16, or ≥ 18 before alotrauma therapy. [Specific Aspect BS] A method as in any of aspects AA to BR, wherein the patient has a total score of ≥ 20, ≥ 22, ≥ 24, ≥ 26, ≥ 28, ≥ 30, ≥ 32, or ≥ 34 on the MADRS (Montgomery-Asberg Depression Rating Scale) prior to alotrauma therapy. [Specific Aspect BT] A method as in any of aspects AA and AD to BS, wherein an inadequate response is defined as treatment failure. [Specific Aspect BU] A method as in any of aspects AA and AD to BS, wherein the patient does not have treatment-resistant depression. [Specific Aspect BV] A method as in any of aspects AA and AD to BS, wherein an inadequate response is defined as a decrease in the total score of the MADRS of ≤ 25%. [Specific Aspect BW] The method of any of aspects AA and AD to BS, wherein under-response is defined as a decrease in the total MADRS score of < 50% and > 25%.

In the following examples, every effort has been made to ensure the accuracy of the numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should still be accounted for. The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and evaluate the methods claimed herein, and are intended to be purely illustrative and not to limit the scope of what the inventors consider to be their disclosure. Example 1. Efficacy of a combination of alodol and antidepressants in the forced swim test in mice

Arandolan was evaluated in the mouse forced swim test (FST). In this test, mice are placed in a small water tank from which they cannot escape, and their behavior is monitored. Rapid administration of all major classes of commercial antidepressants shortens the immobility time in this test.

These specific FST studies were conducted in male Swiss mice (5-6 weeks of age, n=10 per group) that were co-administered with imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram. Administration of alodolone (0.3, 1, 3, or 10 mg/kg, po) alone did not significantly alter immobility time nor enhance the antidepressant activity of subsequent single-dose co-administered imipramine, fluoxetine, paroxetine, venlafaxine, or citalopram.

These results are in contrast to those reported by Dedic (2019) in the FST in male BalbC/J mice. In Dedic (2019), male BalbC/J mice (6 weeks of age, n = 8 per group) received a single dose of vehicle (oral), arodalan (0.3, 1, 3, or 10 mg/kg, oral), or sertraline (20 mg/kg, intraperitoneal injection) as a positive control. Arodalan treatment significantly shortened the immobility time at doses of 1, 3, and 10 mg/kg, with the maximal effect achieved at the 1 mg/kg dose level. The results demonstrate that arodalan exhibits antidepressant-like effects in the mouse FST, but this effect is strain specific. It has been reported that different strains of mice have different sensitivities to existing antidepressant drugs (Lucki 2001; David 2003). Example 2. Efficacy of alotralan in the forced swimming test in rats

The antidepressant-like effects of alodrat were also tested in the rat FST assay using two different dosing protocols. In both sessions, rats were pre-trained in a 15-min swim session on day 0 and in a 5-min FST session 24 hours later (day 1).

In the first study, adult male Wistar rats (206-260 g; n=12 per group) were given the indicated treatments at 3 times: 24 h (i.e., immediately after pre-swim), 4 h, and 1 h before testing. Treatment groups were as follows: vehicle (oral), arotaran (0.3, 1, 3, or 10 mg/kg, oral), or imipramine (64 mg/kg, oral) as a positive control. Immobility time during the 5-min test session was recorded by an observer blinded to treatment conditions, and results were analyzed using one way ANOVA followed by Dunnett’s post hoc comparisons. Arotaran at 3 mg/kg (oral) significantly shortened the duration of immobility compared to the vehicle-treated control group.

In the second study, adult male Sprague-Dawley rats (190-234 g, n=10 per group) were dosed only once, immediately after a swim session (i.e., 24 hours before testing). This dosing regimen has been used to show the antidepressant-like efficacy of acute ketamine treatment, whereas other drug classes (e.g., SSRIs and tricyclics) are generally ineffective (Ardalan 2017; Cryan 2005; Koike 2014). Rats were treated with vehicle (oral), alodralan (0.3, 1, 3, or 10 mg/kg, orally), or ketamine (10 mg/kg, intraperitoneally) as a positive control. Behavior was quantified using a time sampling technique during the 5-min test session, where the actual behavior observed (i.e., immobility, climbing, or swimming) was recorded every 5 s for a total of 60 observations. Results were analyzed using one-way ANOVA followed by Dunnett's post hoc comparisons.

All doses of alodrat tested significantly reduced the frequency of immobility (Table 1). The magnitude of this effect was similar to that seen in rats treated with ketamine and was associated with a significant increase in swimming behavior. Group FST immobility frequency (mean ± SEM) Carrier 44.7 ± 2.4 Aladalan 0.3 mg/kg, oral 29.6 ± 2.6 ^a Aladalan 1 mg/kg, oral 30.1 ± 3.0 ^a Aladalan 3 mg/kg, oral 32.6 ± 2.0 ^a Aladalan 10 mg/kg, oral 27.0 ± 2.4 ^a Ketamine 10 mg/kg, intraperitoneal injection 22.9 ± 3.5 ^{a a} p＜0.05 compared with vehicle (one-way ANOVA with Dunnett post hoc test) Example 3. Efficacy of alotralan in the learned helplessness model in rats

Aladolan was evaluated in the learned helplessness model in rats, which assesses loss of control over behavior in response to adverse situations and in response to antidepressant treatment (Willner 2015). In this model, rats are first exposed to an inescapable foot shock to induce helplessness and then show a subsequent inability to learn to avoid an escapable foot shock (active avoidance). Treatment with existing antidepressant drugs (usually administered in a sub-chronic regimen) reduces the number of escape failures in helpless rats.

Adult male Wistar rats (186-262 g; n=16-17 per group) were randomly assigned to 6 different groups. On day 1, five groups of animals received inescapable foot shocks every 15 seconds for 1 hour through an electrified stainless steel grid floor to induce helplessness. The remaining group did not receive inescapable foot shocks and served as a non-helpless control. On day 1, approximately 6 hours after induction of helplessness, rats were orally administered vehicle, tricyclic antidepressant imipramine (32 mg/kg), or arotaran (1, 3, or 10 mg/kg). Treatment continued on days 2 to 5, with all subjects receiving test agent or vehicle twice daily (AM and PM). Active avoidance testing was performed 60 minutes after dosing on the morning of days 3, 4, and 5. All rats were tested in a 2-compartment active avoidance chamber, where a foot shock was delivered upon presentation of a light cue. The testing session began with 5 minutes of free exploration, followed by 30 stimulus-shock trials over 15 minutes. Each trial lasted 30 seconds, with an initial 24-second rest period, followed by a 6-second presentation of a light cue, during which a foot shock was delivered during the last 3 seconds. Crossing the opposite compartment to avoid the shock within 3 seconds before presentation of the light cue was considered an active avoidance. Failure to avoid complete delivery of the foot shock (i.e., failure to cross during the 3-second presentation of the shock) was considered an escape failure. During the 24-second rest period, crossings to the opposite compartment of the shuttle box were recorded as inter-trial interval (ITI) crossings. Escape failures and ITI crossings were analyzed by two-way repeated measures ANOVA with treatment as the main factor and testing session (i.e., day) as the repeated measure. Significant ANOVA results were followed by Dunnett's post hoc analysis to measure the effect of treatment during each testing session compared with vehicle-treated helpless rats.

Arandolan 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 rats treated with imipramine (Table 2). Group Day 3 (mean ± SEM) Day 4 (mean ± SEM) Day 5 (mean ± SEM) Non-helpless/carrier 5 ± 1 4 ± 2 4 ± 2 Helpless/Carrier 15 ± 2 19 ± 3 19 ± 3 Helplessness/ Aladalan 1 mg/kg, orally twice daily 15 ± 2 19 ± 3 18 ± 3 Helplessness/ Aladalan 3 mg/kg, orally twice daily 12 ± 2 17 ± 3 17 ± 3 Helplessness/ Aladalan 10 mg/kg, orally twice daily 9 ± 2 8 ± 3 ^a 9 ± 3 ^a Helpless/ Imipramine 32 mg/kg, orally twice daily 3 ± 1 3 ± 2 ^a 2 ± 1 ^{a a} p＜0.05 compared with no help/vehicle

Analysis of ITI crossings tested on days 3, 4, and 5 showed no significant differences in ITI crossings in non-helpless rats compared to helpless controls (Table 3). Treatment with 10 mg/kg aloferol significantly increased ITI crossings on day 5 compared to helpless vehicle-treated controls, but had no effect on ITI crossings on days 3 and 4. This result suggests that the interpretation of the antidepressant-like effects of aloferol on day 4 is not confounded by the effects of locomotor activity. Table 3 Group Day 3 (mean ± SEM) Day 4 (mean ± SEM) Day 5 (mean ± SEM) Non-helpless/carrier 13 ± 2 11 ± 2 12 ± 2 Helpless/Carrier 10 ± 2 9 ± 3 9 ± 3 Helplessness/ Aladalan 1 mg/kg, orally twice daily 9 ± 2 8 ± 3 6 ± 1 Helplessness/ Aladalan 3 mg/kg, orally twice daily 10 ± 2 6 ± 2 4 ± 1 Helplessness/ Aladalan 10 mg/kg, orally twice daily 11 ± 2 14 ± 3 18 ± 4a Helpless/ Imipramine 32 mg/kg, orally twice daily 17 ± 2 12 ± 2 15 ± 2 ^a p＜0.05 compared with no help/vehicle

The results showed that alotarol showed antidepressant-like activity in the rat learned helplessness model. Example 4. A Phase 2/3 , multicenter, randomized, double-blind, placebo-controlled trial of the safety and efficacy of flexible doses of alotarol as an adjunctive therapy for the treatment of severe depression in adults

This was a Phase 2/3, multicenter, randomized, double-blind, placebo-controlled, flexible-dosing trial designed to evaluate the safety and efficacy of alodraman (50 to 75 mg/day) as an adjunct to assigned open-label antidepressant therapy (ADT) in individuals with MDD who had demonstrated an inadequate response to a prior 8-week trial of the same assigned open-label ADT.

The population will include individuals aged 18 to 65 years (inclusive) with a primary diagnosis of MDD at the time of informed consent and 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 duration of the current MDE must be ≥ 8 weeks. In addition, individuals must have a reported history of current MDE that is inadequate to at least 1 and no more than 3 adequate ADTs. Individuals must also have a 17-item Hamilton Depression Rating Scale (HAM-D ₁₇ ) total score of ≥ 18 at screening and baseline visits.

The primary objective of this study is to compare the efficacy of alodraman (50 to 75 mg/day) versus placebo as an adjunct to prescribed open-label ADT in individuals with MDD who have been shown to be inadequately responsive to a prior 8-week trial of the same prescribed open-label ADT. The primary efficacy will be assessed by the change in MADRS total score from the end of Period A (Week 8 Visit) to the end of Period B (Week 14 Visit). Specifically, efficacy will also be assessed by the change in CGIS from the end of Period A (Week 8 Visit) to the end of Period B (Week 14 Visit). Citations American Psychiatric Association practice guideline for treatment of patients with major depressive disorder, third edition [online]. Available from URL: http://www.psy chiatryonline.com/pracGuide/pracGuideTopic_7.aspx [Accessed 2022 Jul 17]. 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. Food and Drug Administration (US). 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 (US). 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 (US). Patient-Focused Drug Development: Collecting Comprehensive and Representative Input; Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders (June 2020) (“FDA 2020”). Guy W. ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW Publication No. ADM 76-338). Rockville, MD, US Department of Health, Education, and Welfare, 1976:218-22. Heffernan MLR, Herman LW, Brown S, Jones PG, Shao L, Hewitt MC, Campbell JE, Dedic N, Hopkins SC, Koblan KS, and Xie L. Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia. ACS Med. Chem. Lett. 2022, 13, 92-98. 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.

Various publications are cited throughout this application. The contents disclosed in these publications are incorporated by reference into this application in their entirety to more fully describe the prior art to which the contents of this disclosure belong. It is obvious to those skilled in the art that various modifications and changes can be made to this disclosure without departing from the scope or spirit of this disclosure. Other specific aspects of this disclosure are also apparent to those skilled in the art after considering the specification and implementation of this disclosure. The specification and implementation are to be regarded as illustrative only, and the true scope and spirit of this disclosure are shown in the attached patent application scope.

without

without

without

Claims (33)

A method for adjunctive treatment of MDD (major depressive disorder) in a human subject in need thereof, wherein the human subject has demonstrated an inadequate response to an antidepressant therapy, the method comprising administering the antidepressant therapy and a therapeutically effective amount of ulotaront or a pharmaceutically acceptable salt thereof to the subject. The method of claim 1, wherein an inadequate response is defined as a decrease in the severity of depressive symptoms of less than 50% as assessed by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) after at least 8 weeks of antidepressant treatment. The method of claim 1, wherein the antidepressant therapy comprises SSRI (Selective Serotonin Reuptake Inhibitors) or SNRI (Serotonin-norepinephrine Reuptake Inhibitor). The method of claim 1, wherein the antidepressant therapy comprises: a) an SSRI selected from escitalopram 10 to 20 mg/day, fluoxetine 20 to 60 mg/day, paroxetine 25 to 62.5 mg/day, and sertraline 50 to 200 mg/day; or b) an SNRI selected from duloxetine 30 to 60 mg/day and venlafaxine 37.5 to 225 mg/day. The method of claim 1, wherein: a) the individual has a major depressive episode (MDE); b) the individual has a history of current MDE that is inadequately responsive to at least 1 and no more than 3 adequate antidepressant therapies (ADT); and c) the individual has a 17-item Hamilton Depression Rating Scale (HAM-D ₁₇ ) total score of ≥ 18. As in claim 1, where inadequate response is defined as after at least 8 weeks of antidepressant therapy: a) (i) a decrease in the total score of the HAM-D17 (17-item Hamilton Depression Rating Scale) of < 50%; or (ii) a total score of HAM-D17 ≥ 14; b) a score of ≥ 3 on the CGI-C (Clinical Global Impression – Change) scale; and c) a decrease in the MADRS of < 50%. As in claim 1, where inadequate response is defined as a decrease in the total score of the HAM-D17 (17-item Hamilton Depression Rating Scale) by <50% after at least 8 weeks of antidepressant therapy; b) a total score of HAM-D17 ≥ 14; c) a score of ≥ 3 on the CGI-C (Clinical Global Impression – Change) scale; and d) a decrease in the total score of the MADRS by <50%. The method of any of claims 1 to 7, wherein an inadequate response is defined as a decrease in the MADRS total score of < 50% and > 25%. The method of claim 1, wherein the individual suffers from anxiety. The method of claim 1, comprising administering alodrat or a pharmaceutically acceptable salt thereof, and improving the depressive symptoms of the subject for a therapeutic effect 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. The method of claim 1, wherein the therapeutically effective amount comprises from 25 to 100 mg of alodolant or a pharmaceutically acceptable salt thereof, based on the weight of the free form of alodolant. The method of claim 1, wherein the therapeutically effective amount comprises 50 or 75 mg of alodolant or a pharmaceutically acceptable salt thereof, based on the weight of the free form of alodolant. The method of claim 1, wherein the individual has demonstrated an inadequate response to antidepressant therapy for at least eight weeks. The method of claim 1, comprising administering alotelan or a pharmaceutically acceptable salt thereof for a period of at least six weeks. The method of claim 1, wherein the method produces relief from depression. The method of claim 1, wherein the method produces remission of depression as defined in DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). The method of claim 1, wherein the method improves the individual's total MADRS score. The method of claim 1, wherein the method increases the reduction in the individual's MADRS total score by ≥ 1, ≥ 2, ≥ 3, or ≥ 4 points compared to antidepressant therapy alone. The method of claim 1, wherein the method improves the individual's CGI-S (Clinical Global Impression – Severity) score by ≥ 2, ≥ 3, or ≥ 4 points. The method of claim 1, wherein the method produces a clinically significant improvement in the individual's MADRS (Montgomery Asberg Depression Rating Scale) total score and CGI-S (Clinical Global Impression – Severity) score. The method of claim 1, wherein the method improves the individual's FAST (Functional Assessment Short Test) score. The method of claim 1, wherein the method improves the individual's PGI-S (Patient Global Impression – Severity) score. The method of claim 1, wherein the method improves the individual's SF-36 (36-Item Short-form Survey) score. The method of claim 1, wherein the method improves the individual's HAM-A (Hamilton Anxiety Rating Scale) total score. The method of claim 1, wherein the method improves the individual's HAM-D17 (17-item Hamilton Depression Rating Scale) total score. The method of claim 1, wherein the method produces a CGI-C (Clinical Global Impression – Change) score of 1 or 2 (very improved or very improved). The method of claim 1, wherein the method reduces the individual's total MADRS score by ≥ 50%. The method of claim 1, wherein the method reduces the individual's total MADRS score to ≤ 10. The method of claim 1, wherein the method reduces the individual's MADRS total score to ≤ 10 and reduces the individual's MADRS total score by ≥ 50%. The method of claim 1, wherein the method does not cause a clinically significant worsening in the individual's: a) abnormal involuntary movements as measured by AIMS (Abnormal Involuntary Movement Scale); b) akathisia as measured by BARS (Barnes Akathisia Rating Scale); c) sexual function as measured by CSFQ-14 (Changes in Sexual Functioning Questionnaire, Short Form); d) suicidal tendencies as measured by C-SSRS (Columbia-Suicide Severity Rating Scale); e) Parkinsonism as measured by SAS (Simpson Angus Scale); f) Sleep quality as measured by PSQI (Pittsburgh Sleep Quality Index); or g) A combination of any two or more of (a) to (f). The method of claim 1, wherein the method does not cause clinically significant sedation, weight gain, metabolic syndrome symptoms of diabetes and hyperlipidemia, or movement disorders. The method of claim 1, further comprising monitoring the following symptoms: i) CNS (central nervous system) stimulation including agitation, restlessness and/or insomnia; ii) depression including listlessness, drowsiness and/or shallow breathing; or iii) impaired muscle coordination, effects on heart rate and/or changes in pupil size. As in claim 1, where under-response is defined as a decrease in the MADRS total score of ≤ 25%.