A triple reuptake inhibitor for use in methods of treating a behavioral immuno-metabolic cluster condition or disorder

Abstract

Disclosed herein are methods of treating or preventing a behavioral immuno-metabolic cluster (BIMC) condition or disorder in a subject in need thereof by administering to the subject a composition comprising a triple uptake inhibitor.

Description

A TRIPLE REUPTAKE INHIBITOR FOR USE IN METHODS OF TREATING A BEHAVIORAL IMMUNO-METABOLIC CLUSTER CONDITION OR DISORDERBACKGROUND

[0001] Behavioral immuno-metabolic cluster (BIMC) refers to one or more conditions or disorders generally associated with immunometabolic dysregulation and associated behavioral or affective adaptations and disorder(s). A condition or disorder falling under the BIMC umbrella is typically characterized by alterations in biological pathways associated with homeostatic control of energy regulation that result in dysregulated immune signaling which increases inflammation. Neurobiological and behavioral adaptations to the underlying inflammation can result in clusters of symptoms that, taken together, can present as unique pathologies in individual patients. These varied presentations among patients and the often unrecognized underlying source of the pathology make BIMC disorders or conditions very difficult to properly diagnose and effectively treat. The present disclosure provides methods and compositions for the treatment of BIMC disorders or conditions.SUMMARY OF THE DISCUOSURE

[0002] The present disclosure is based, in part, on the discovery that the constellation of pathological symptoms that manifest in behavioral immuno-metabolic cluster (BIMC) conditions or disorders can be treated by administration of therapeutics which are triple reuptake inhibitors (TRI).

[0003] Disclosed herein, in some embodiments, are methods and compositions for treating or preventing a BIMC condition or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a triple reuptake inhibitor (TRI). In some embodiments, the treating or preventing comprises (a) reducing one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) symptoms of the BIMC condition or disorder in the subject; and / or (b) modulating an immune response in the subject.

[0004] In some embodiments, the subject exhibits one or more symptoms associated with a neurological condition. In some embodiments, the subject exhibits one or morepsychological symptoms associated with a neurological condition. In some embodiments, the one or more psychological symptoms is selected from the group consisting of: (a) mood reactivity; (b) low mood; (c) low self-esteem; (d) leaden paralysis; (f) fatigue; (g) malaise; (h) lethargy; (i) anhedonia; (j) rumination; (k) irritability; (1) low libido; and (m) suicidal ideation. In some embodiments, the one or more psychological symptoms is selected from the group consisting of: (a) low mood; (b) fatigue; and (c) fatigue.

[0005] In some embodiments, the subject exhibits one or more behavioral symptoms associated with a neurological condition. In some embodiments, the subject exhibits one or more behavioral symptoms selected from the group consisting of: (a) increased sleep; (b) hypersomnia; (c) binge eating not associated with the regular use of inappropriate compensatory behaviors; (d) binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa; (e) recurrent inappropriate compensatory behaviors; (f) recurrent episodes of binge eating; (g) hyperphagia; (h) self-reproach following eating; (i) distress during eating; (j) impaired impulse control; (k) low appetite; (1) hypophagia; (m) intense fear of gaining weight; and (n) body dysphoria. In some embodiments, the subject exhibits one or more behavioral symptoms selected from the group consisting of:(a) increased sleep; (b) hypersomnia; (c) recurrent episodes of binge eating; (d) hyperphagia; and (e) impaired impulse control.

[0006] In some embodiments, the subject exhibits one or more cognitive symptoms associated with a neurological condition. In some embodiments, the one or more cognitive symptoms is selected from the group consisting of: (a) impairment of memory;(b) impairment of attention; (c) impairment of concentration; (d) impairment of language; (e) impairment of learning; (f) impairment of perception; (g) impairment of reasoning; (h) executive dysfunction; (i) psychomotor impairment; (j) impaired processing speed; and (k) disorder of thought.

[0007] In some embodiments, the subject exhibits one or more symptoms associated with a metabolic condition. In some embodiments, the one or more symptoms associated with a metabolic condition is selected from the group consisting of: (a) hypertension; (b) hyperglycemia; (c) insulin resistance; (d) leptin resistance; (e) prediabetes; (f) hypercholesterolemia; (g) hypertriglyceridemia; (h) low serum levels of high-density lipoprotein (HDL); (i) abdominal obesity; (j) hyperuricemia; (k) gastrointestinal dysfunction; and (1) hepatic dysfunction.

[0008] In some embodiments, the subject exhibits one or more symptoms associated with an immune condition. In some embodiments, the one or more symptoms associated with an immune condition is selected from the group consisting of: (a) joint pain, stiffness, or swelling due to inflammation; (b) recurrent infections; (c) gastrointestinal dysregulation; (d) anemia; (e) rash; (f) cold extremities; (g) dry eyes; (h) fatigue; (i) fever; and (j) headache.

[0009] In some embodiments, the TRI is Compound 1:or a pharmaceutically acceptable salt thereof.

[0010] Disclosed herein, in some embodiments, is a method of modulating an immune response in a subject having or at risk of developing a BIMC condition or disorder, the method comprising administering to the subject a therapeutically effective amount of a TRI. In some embodiments, the TRI is Compound 1:or a pharmaceutically acceptable salt thereof. In some embodiments, modulating an immune response in the subject comprises modulating immune cell activity in the subject. In some embodiments, the immune cell activity comprises cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, antibody-dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), antigen presentation, lymph node homing, and lymph node egress. In some embodiments, modulating an immune response in the subject comprises reducing a blood level of one or more pro-inflammatory mediators associated with the BIMC condition or disorder in the subject as compared to a blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI. In some embodiments, the one or more pro-inflammatory mediators associated with the BIMC condition or disorder includes oneor more of TNFa, IFNa, sTNFR2, IL-ip, IL-IRA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, and MIF, or any combination thereof. In some embodiments, the one or more pro- inflammatory mediators associated with the BIMC condition or disorder is TNFa. In some embodiments, the blood level of the one or more pro-inflammatory mediators associated with the BIMC condition or disorder is reduced in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more following treatment with the TRI, as compared to a blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI. In some embodiments, prior to treatment, the patient has been identified as exhibiting an increased level of one or more pro-inflammatory mediators associated with the BIMC. In some embodiments, prior to treatment, the patient has been identified as exhibiting an increased level of one or more pro-inflammatory mediators associated with the BIMC. In some embodiments, the method further comprises measuring a level of one or more pro-inflammatory mediators associated with the BIMC condition or disorder prior to, concurrently with, and / or after administration of the TRI. In some embodiments, modulating an immune response in the subject comprises increasing a blood level of one or more anti-inflammatory mediators associated with the BIMC condition or disorder in the subject as compared to a blood level of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI. In some embodiments, the one or more anti-inflammatory mediators associated with the BIMC condition or disorder includes one or more of IL-10, IL-4, IL-13, TGFp, adiponectin, or any combination thereof. In some embodiments, the blood level of the one or more anti-inflammatory mediators associated with the BIMC condition or disorder is increased in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 120%, 140%, 160%, 180%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more following treatment with the TRI, as compared to a blood level of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI. In some embodiments, prior to treatment, the patient has been identified as exhibiting a decreased level of one or more anti-inflammatory mediators associated with the BIMC. In some embodiments, the method further comprises measuring a level of one or more anti-inflammatory mediators associated with the BIMC condition or disorder prior to, concurrently with, and / or after administration ofthe TRI. In some embodiments, the blood level of the one or more pro-inflammatory mediators and / or anti-inflammatory mediators is measured at least 1 hour (hr), 2 hrs, 3 hrs, 3 hrs, 4 hrs, 5 hrs, 6, hrs, 7 hrs, 8 hrs, 9, hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more, prior to and / or following treatment of the subject with the TRI. In some embodiments, the blood level of the one or more pro-inflammatory mediators and / or anti-inflammatory mediators is measured at least 1 hour (hr), 2 hrs, 3 hrs, 3 hrs, 4 hrs, 5 hrs, 6, hrs, 7 hrs, 8 hrs, 9, hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more, prior to and / or following treatment of the subject with the TRI. In some embodiments, the blood level is a whole blood level, plasma level, or serum level. In some embodiments, the immune cell is selected from the group consisting of regulatory T cell (Treg), T effector cell, T helper cell, Thl cell, Th2 cell, Thl7 cell, B cell, natural killer (NK) cell, innate lymphoid cell 1 (ILC1), ILC2 cell, ILC3 cell, monocyte, macrophage, dendritic cell, Ml macrophage, M2 macrophage, and antigen presenting cell. In some embodiments, the immune mediator is a cytokine. In some embodiments, the immune mediator is a chemokine.[Oil] Disclosed herein, in some embodiments, is a method of treating metabolic dysregulation in a subject having or at risk of developing a BIMC condition or disorder, the method comprising administering to the subject a therapeutically effective amount of a TRI. In some embodiments, the metabolic dysregulation comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) of the following symptoms: (a) hypertension; (b) hyperglycemia; (c) insulin resistance; (d) leptin resistance); (e) prediabetes; (f) hypercholesterolemia; (g) hypertriglyceridemia; (h) low serum levels of high-density lipoprotein (i) abdominal obesity; (j) hyperuricemia; (k) gastrointestinal dysregulation; and (1) hepatic dysfunction.

[0012] In some embodiments, the TRI is Compound 1:or a pharmaceutically acceptable salt thereof.

[0013] Disclosed herein, in some embodiments, is a method of treating or preventing neuroinflammation in the central nervous system of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TRI. In some embodiments, the treating or preventing comprises one or more of: (a) modulating immune cell activity in the subject; and / or (b) reducing one or more (e.g., 1, 2, 3, 4, 5, or more) symptoms of neuroinflammation associated with a BIMC condition or disorder in the subject. In some embodiments, the immune cell activity comprises cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, ROS production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, and lymph node egress. In some embodiments, the immune cell is selected from the group consisting of Treg, T effector cell, T helper cell, Thl cell, Th2 cell, Th 17 cell, B cell, NK) cell, ILC1 cell, ILC2 cell, ILC3 cell, monocyte, macrophage, dendritic cell, Ml macrophage, M2 macrophage, and antigen presenting cell. In some embodiments, the one or more symptoms of neuroinflammation associated with the BIMC condition or disorder are present and those to be treated can include one or more symptoms selected from the group consisting of mood reactivity, interpersonal rejection sensitivity (e.g., having a long-standing pattern and resulting in significant social or occupational impairment), low mood, low self-esteem, leaden paralysis, fatigue, malaise, lethargy, anhedonia, rumination, irritability, low libido, suicidal ideation, impairment of memory, impairment of attention, impairment of concentration, executive dysfunction, psychomotor impairment, impaired processing speed, disorder of thought,; insomnia; and fatigue. In some embodiments, the neuroinflammation is in the brain of the subject. In some embodiments, the neuroinflammation is a result of an aseptic insult, infection, aging, toxic metabolites, or an autoimmune response. In some embodiments, the neuroinflammation is in the spinal cord of the subject. In some embodiments, the TRI is Compound 1:or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the subject has been identified as exhibiting one or more symptoms of the BIMC condition or disorder. In some embodiments, the subject has one or more symptoms of the BIMC disorder or condition that is secondary to a primary immune disorder. In some embodiments, the method comprises identifying the presence of one or more symptoms of the BIMC condition or disorder in the subject. In some embodiments, the subject is refractory to prior treatment with one or more therapeutic agents other than the TRI to treat the BIMC condition or disorder. In some embodiments, the subject has not received any prior treatment for the BIMC condition or disorder.

[0015] In some embodiments, the therapeutically effective amount is between 1 mg per day and 30 mg per day (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg per day).DEFINITIONS

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0017] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0018] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from the group consisting of two or more of the recited elements or components.

[0019] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where a reference is made to a particular compound, that compound can be used in various embodiments of methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0020] As used herein, singular forms “a,” “and,” and “the” include plural referents unless the context clearly indicates otherwise. Thus, e.g., reference to “a compound” includes a single compound or a plurality e.g., 2 or more) of compounds.

[0021] The use of the term “comprise,” “comprises,” “comprising,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0022] As used herein, all numerical values or numerical ranges include whole integers within or encompassing such ranges and fractions of the values or the integers within or encompassing ranges unless the context clearly indicates otherwise. Thus, e.g., reference to a range of 90-100%, includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. In another example, reference to a range of 1-5,000 fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5 fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5 fold, etc., and so forth.

[0023] ‘ ‘About” a number, as used herein, refers to range including the number and ranging from 10% below that number to 10% above that number. “About” a range refers to 10% below the lower limit of the range, spanning to 10% above the upper limit of the range.

[0024] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0025] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0026] As used herein, the term “administration” refers to delivery of an agent or composition disclosed herein to a subject by any acceptable route. Non-limiting examples of acceptable administration routes include oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0027] As used herein, the term “behavioral immuno-metabolic cluster (BIMC) condition or disorder” is an umbrella category referring to any condition or disorder associated with a constellation of dysregulations in inflammatory, metabolic, and bioenergetics signaling pathways, and associated neurological and physiological disturbances. BIMC conditions and disorders are, in some embodiments, associated with a diverse array of complex neurological phenotypes presenting with one or more psychological, behavioral, and / or cognitive symptoms. For example, a subject with BIMC may exhibit one or more psychological disturbances selected from mood reactivity, interpersonal rejectionsensitivity (e.g., having a long-standing pattern and resulting in significant social or occupational impairment), low mood, low self-esteem, leaden paralysis, fatigue, malaise, lethargy, anhedonia, rumination, irritability, low libido, and suicidal ideation. Additionally or alternatively, a subject with BIMC may exhibit one ore more behavioral symptoms selected from increased sleep, hypersomnia, binge eating (e.g., binge eating not associated with regular use of inappropriate compensatory behaviors, binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa, and / or recurrent binge eating), recurrent inappropriate compensatory behaviors, hyperphagia, self-reproach following eating, distress during eating, impaired impulse control, low appetite, hypophagia, intense fear of gaining weight, and body dysphoria. Additionally or alternatively, a subject with BIMC may exhibit one or more cognitive symptoms, including but not limited to, impairment of memory, impairment of attention, impairment of concentration, impairment of language, impairment of learning, impairment, of perception, impairment of reasoning, executive dysfunction, psychomotor impairment, impaired processing speed, and disorder of thought e.g., delusions). Additionally or alternatively, a subject with BIMC may present with one or more symptoms associated with a metabolic condition, including but not limited to, hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), abdominal obesity, hyperuricemia, hepatic dysfunction, and gastrointestinal dysregulation. Additionally or alternatively, a subject with BIMC may present with one or more symptoms associated with an immune condition, such as joint pain, stiffness, or swelling due to inflammation, recurrent infections, gastrointestinal dysregulation, anemia, rash, cold extremities, dry eyes, fatigue, fever, and / or headache. In some embodiments, any one of the above symptoms of BIMC may be associated with an abnormal immune response (e.g., chronic low-grade inflammation associated with altered blood levels of immune mediators, such as cytokines and chemokines). BIMC conditions or disorders may feature complex clinical phenotypes presenting with various combinations psychological, behavioral, cognitive, immune, and metabolic dysregulations and associated symptoms and / or compensatory behaviors, such as those described above. A BIMC condition or disorder may result from a genetic predisposition to immunometabolic dysregulation and / or environmental or experiential factors that aloneor combined can produce a BIMC phenotype. In some embodiments, a BIMC condition or disorder is idiopathic.

[0028] As used herein, the term “immune mediator” refers to any endogenous biological molecule (e.g., a carbohydrate, nucleic acid, lipid, or protein) capable of modulating (e.g., increasing or decreasing) an immune response in an organism or a cell. Non-limiting examples of immune mediators include cytokines, chemokines, antibodies, immune receptors, antigens, hormones, vasoactive amines, peptides, eicosanoids, bile acids, and the like.

[0029] As used herein, the phrase “modulating an immune response” refers to any alteration in a cell of the immune system or any alteration in the activity of a cell involved in the immune response. Such modulation includes an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes that can occur within the immune system. Cells involved in the immune response include, but are not limited to, T lymphocytes (T cells), B lymphocytes (B cells), natural killer (NK) cells, innate lymphoid cells (ILCs), macrophages, eosinophils, mast cells, dendritic cells and neutrophils.

[0030] As used herein, the term “metabolic dysregulation” refers to a condition in which a subject’s metabolism, including processes such as breaking down carbohydrates, proteins, and fats in food to release energy, and converting chemicals into other substances and transporting them inside cells for energy utilization and / or storage, operates outside of the range of normal physiological function. Some symptoms of a metabolic dysregulation include high serum triglycerides, high low-density cholesterol (LDL), low high-density cholesterol (HDL), and / or high fasting insulin levels, elevated fasting plasma glucose, abdominal (central) obesity, and elevated blood pressure, among others. Metabolic dysregulation increases the risk of developing other diseases, such as cardiovascular disease. Exemplary conditions or disorders featuring metabolic dysregulation any condition or disorder falling within the umbrella of BIMC, as well as obesity, Type-1 diabetes, and Type-2 diabetes.

[0031] As used herein, the term “modulate” and variants thereof refer to decreasing or increasing the value of a parameter describing a particular system. For example, in the context of modulating immune cell activity, “modulation” can mean increasing or decreasing one or more (e.g., 1, 2, 3, 4, 5, or more) parameters of an immune cell activity,including but not limited to cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, and lymph node egress. “Modulation” can be by any amount. For example, in the context of increasing immune cell activity, the increase in immune cell activity can be by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 220%, 240%, 260%, 280%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1,000%, or more. In the context of decreasing immune cell activity, the decrease in immune cell activity can be by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more.

[0032] As used herein, the term “neuroinflammation” refers to immune and inflammatory responses of the central nervous system (CNS) during normal functioning or development, or in response to an immunological event. Diagnosis of neuroinflammation may be indicated by presentation with one or more symptoms selected from mood reactivity, interpersonal rejection sensitivity (e.g., having a long-standing pattern and resulting in low mood, leaden paralysis, fatigue, lethargy, anhedonia, rumination, irritability, low libido, impairment of memory, impairment of attention, impairment of concentration, executive dysfunction, psychomotor impairment, impaired processing speed. Symptoms of neuroinflammation can be identified using known methods, including psychological, psychomotor, and behavioral evaluation. Neuroinflammation per se can be detected in a living patient, e.g., using conventional medical neuroimaging modalities, e.g., computerized tomography (CT) scan, magnetic resonance imaging (MRI) scan, and positron emission tomography (PET) scan. For example, neuroimaging can be used for in vivo detection of blood-brain-barrier (BBB) permeability - a known biomarker of neuroinflammation. Dynamic contrast-enhanced or perfusion imaging protocols can be performed on MRI or CT scanners using intravenously injected iodine- based or gadolinium-based contrast agents. BBB permeability measurements can then be obtained using known pharmacokinetic modeling methods. Furthermore, the presence of specific immune cells in the CNS can be detected using conventional methods. For example, a patient can be infused with a labeling agent that binds to immune-cell specificmarkers. Subsequently, PET-based detection methods can be used to identify presence of specific immune cells within the CNS. Additional methods for assessing neuroinflammation in a subject includes use of micron-sized particles of iron oxide (MPIOs) functionalized with antibodies against protein markers of neuroinflammation (e.g., TNFa, IFNa, sTNFR2, IL-ip, IE-1RA, IE-6, IE-2R, IE-18, IL-12, CCL2, CRP, MIF, P-selectin, E-selectin, VCAM-1, ICAM-1). Common triggers for neuroinflammation may include an aseptic insult (e.g., tissue damage resulting from mechanical injury), bacterial or viral infection, aging, toxic metabolites, autoimmune processes, or a spontaneous or idiopathic immunological event e.g., idiopathic systemic inflammatory response syndrome; SIRS). Occurrence of any one of these events in a BIMC patient’s medical history can be supportive of a positive diagnosis of neuroinflammation .

[0033] As used herein, a “pharmaceutical composition” or “pharmaceutical preparation” is a composition or preparation having pharmacological activity or other direct effect in the mitigation, treatment, or prevention of disease, and / or a finished dosage form or formulation thereof and which is indicated for human use.

[0034] As used herein, the term “pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate, and / or that are approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0035] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., Compound 1), which salt is compatible with pharmaceutical administration. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like. Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+(where W can be a Ci-4 alkyl group), and the like.

[0036] For therapeutic use according to the methods disclosed herein, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0037] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline (PBS) solution, emulsions (e.g., such as an oil / water or water / oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0038] As used herein, the term “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.

[0039] As used herein, the terms “subject” and “patient” refer to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a particular condition, or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. In some embodiments, the subject is a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., cynomolgus monkey, rhesus monkey, and the like), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0040] As used herein, the term “therapeutically effective amount” of an agent or composition described herein (e.g., a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof) refer to a quantity sufficient to, when administered to a subject, including a mammal (e.g. , a human), effect beneficial or desired results, including effects at the cellular level, tissue level, or clinical results, and, as such, an “therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in the context of treating a BIMC condition or disorder, it is an amount of the agent or composition sufficient to achieve a treatment response as compared to the response obtained without administration of the agent or composition. The amount of a given agent or composition described herein that will correspond to such an amount will vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of conditionor disorder, the identity of the subject (e.g., age, sex, and weight) or host being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. Also, as used herein, a “therapeutically effective amount” of agent or composition of the present disclosure is an amount that results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of an agent or composition of the present disclosure may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen may be adjusted to provide the optimum therapeutic response.

[0041] ‘ ‘Treatment” and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize (z.e., not worsen), prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition; preventing spread of the disease or condition; delay or slowing the progress of the disease or condition; amelioration or palliation of the disease or condition; and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0042] As used herein, the term “triple reuptake inhibitor (TRI)” refers to an agent (e.g., small molecule) capable of inhibiting: (1) reuptake of serotonin by blocking serotonin transporter (SERT) proteins at the presynaptic terminals of serotonin-releasing neurons; (2) reuptake of noradrenaline by blocking noradrenaline transporter (NAT) proteins at thepresynaptic terminals of noradrenaline-releasing neurons; and (3) reuptake of dopamine by blocking dopamine transporter (DAT) proteins at the presynaptic terminals of dopamine-releasing neurons. The inhibition reuptake of each of serotonin, noradrenaline, and / or dopamine can independently be by any amount, such as at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Exemplary TRIs of the disclosure include, without limitation, Compound 1:or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 is a plot showing dose-dependent reduction of LPS-induced serum TNFa levels (pg / mL) in Wistar Han rats treated with vehicle (0); 3, 10, and 30 mg / kg of Compound 1; or 30 mg / kg of positive control Compound 2 (JNK inhibitor).

[0044] FIG. 2 is a bar graph showing immobility time of rats in a forced swim test. Rats were treated with vehicle (0.3% Tween 80 in distilled water), or 1 mg / kg, 3 mg / kg, or 10 mg / kg of Compound 1. Data are mean ± standard error of the mean (SEM) on 10 animals per group. * = p < 0.05 relative to vehicle control; ** = p < 0.01 relative to vehicle control; and *** = p < 0.001 relative to vehicle control, based on Dunnett’s post hoc test.

[0045] FIG. 3 is a bar graph showing immobility time of mice in a tail suspension test. Mice were treated with vehicle (HPMC), 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of Compound 1, or 30 mg / kg Duloxetine (DLX30). * = p < 0.05 relative to vehicle control.

[0046] FIGS. 4A-4D are bar graphs showing the effects of Compound 1 (1 mg / kg, 3 mg / kg, or 10 mg / kg), 10 mg / kg chlordiazepoxide (CDZ10), and vehicle control (0.3% Tween / NaCl 0.9%) on mice in an elevated plus-maze. (FIG. 4A) Effects on time spent in open arms of the elevated-plus maze. (FIG. 4B) Effects on distance traveled in open arms of the elevated-plus maze. (FIG. 4C) Effects on percentage of entries into open arms of the elevated-plus maze. (FIG. 4D) Effects on speed of travel in open arms of the elevated-plus maze.

[0047] FIG. 5A and FIG. 5B show bar graphs depicting lever pressing by adult male Sprague-Dawley rats in a progressive ratio / chow feeding choice task. (FIG. 5A) Bar graph showing mean (± SEM) of total lever presses by adult male Sprague Dawley rats (n = 31) during a 30-minute session, where **p<0.001: significant difference between Compound 1 treatments and vehicle (VEH) on lever presses. (FIG. 5B) Bar graph showing mean (+SEM) number of total lever presses during a 30-minute session, where **p<0.001: significant difference between Compound 1 dose treatments and VEH on lever presses.

[0048] FIG. 6A and FIG. 6B show bar graphs depicting chow intake by adult male Sprague-Dawley rats in a progressive ratio / chow feeding choice task. (FIG. 6A) Bar graph showing mean (± SEM) of chow intake (in grams) by adult male Sprague Dawley rats (n=31) during a 30-minute session, where **p<0.001: significant between groups effect of treatment on chow consumption between Compound 1 and vehicle (VEH). (FIG. 6B) Bar graph showing mean (+SEM) of chow intake (in grams) during a 30-minute session, where **p<0.001, *p<0.01: significant difference between groups effect of treatment on chow consumption between dose Compound 1 and VEH.

[0049] FIG. 7 is a bar graph showing mean (± SEM) of total lever presses by adult male Sprague Dawley rats (n = 31) during a 30-minute operant session, where **p<0.001: significant difference between Compound 1 treatments (n=16) and vehicle (VEH) (n=15) on lever presses.

[0050] FIG. 8A and FIG. 8B are plots showing appetite suppressant effects of Compound 1 in rats in a binge eating of chocolate test. (FIG. 8A) is a plot showing mean (+SEM) intake of chocolate over the 12 1-hour training sessions during the chocolate intake experiment. (FIG. 8B) Bar graph showing consumption of chocolate in rats treated with VEH, or 5, 10, or 20 mg / kg of Compound 1.

[0051] FIG. 9A and FIG. 9B are bar graphs showing effects of Compound 1 on sleep in rats. (FIG. 9A) Bar graph showing mean (± SEM) of latency to the first 6 continuous epochs of nonrapid eye movement sleep (NR). (FIG. 9B) Bar graph showing mean (± SEM) of latency to the first 3 continuous epochs of rapid eye movement sleep (REM).

[0052] FIGS. 10A-10C are bar graphs showing effects of Compound 1 in a five-choice serial-reaction task (5CSRTT) test in rats. FIG. 10A shows a bar graph of % of correct nose-pokes in rats trained in a 5CSRTT task as a function of administered dose ofCompound 1. (FIG. 10B) Bar graph showing premature (PREM) responses of rats in a 5CSRTT task as a function of administered dose of Compound 1. (FIG. IOC) Bar graph showing perseverative (PSV) responses of rats in a 5CSRTT task as a function of administered dose of Compound 1.DETAILED DESCRIPTION

[0053] Disclosed herein are methods and compositions for the treatment of a behavioral immuno-metabolic cluster (BIMC) condition or disorder in a human subject in need thereof with a triple reuptake inhibitor (TRI; i.e., a serotonin-norepinephrine-dopamine reuptake inhibitor). The methods include, without limitation, administering to a subject a composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.Behavioral Immuno-Metabolic Cluster

[0054] BIMC refers to one or more conditions or disorders generally characterized by immuno-metabolic dysregulation and associated behavioral or affective disorder(s). A condition or disorder falling under the BIMC umbrella typically features alterations in biological pathways associated with homeostatic control of energy regulation, dysregulated immune signaling that favors increased inflammation, and corresponding neurobiological (e.g., altered neurogenesis, neuroplasticity, and hypothalamic -pituitary- adrenal (HPA) axis activity) and neurological symptoms and adaptations. The neurological phenotype of a BIMC patient can be characterized by psychological and behavioral dysregulation and / or cognitive impairment.

[0055] Dysregulated immune signaling in BIMC can be associated with chronic increases in serum levels of one or more pro-inflammatory biomarkers, such as IL-6, TNFa, IL-ip, IFNy, IL- 18, IL- IRA, sTNFR2, CCL2, CXCL4, and CXCL7, and / or reduced levels of one or more anti-inflammatory biomarkers, such as IL-10, IL-4, IL-13, TGFp, and adiponectin. Other immunological changes associated with BIMC can include, without limitation, increased activation of inflammatory monocytes and T cells, reduced regulatory T (Treg) cell activity, and increased infiltration of peripheral immune cells into the CNS parenchyma (e.g., as a result of increased blood-brain-barrier permeability) and resulting neuroinflammation.

[0056] Disruptions to homeostatic mechanisms of energy balance and metabolic dysregulation in BIMC can lead to changes in body shape (e.g., abdominal obesity), appetite, and eating disorders. As a result, patients suffering from BIMC may experience chronic physiological symptoms including hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), hyperuricemia, hepatic dysfunction, and / or gastrointestinal dysregulation. Although the causal relationship between the various pathophysiological immune, metabolic, behavioral, and psychological changes in BIMC remains unclear, these changes can present in various combinations and with a constellation of symptom combinations that result from the underlying biological pathway(s). Thus, BIMC is a highly heterogenous indication associated with diverse endophenotypes that can be associated with various distinct genetic and / or environmental factors.

[0057] The present disclosure is based, at least in part, on the discovery that a novel TRI, Compound 1, reduces lipopolysaccharide (LPS)-induced TNFa release in rodents in vivo and exhibits antidepressant-like properties in murine and rat models of behavioral despair. Furthermore, the present disclosure demonstrates that Compound 1 reduces impulsive and compulsive behaviors and promotes wakefulness. These results indicate that Compound 1 can effectively treat multiple pathophysiological processes and symptoms underlying and / or associated with BIMC. Accordingly, the present disclosure provides methods and compositions for treatment of BIMC in patients in need thereof.Methods of TreatmentAdministration

[0058] An effective amount of a compound or composition described herein for treatment of a BIMC condition or disorder can be administered to a subject by standard methods. For example, the agent can be administered by any of a number of different routes including, e.g., oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. The most suitable route for administration in any given case will depend on the particular agent administered, thepatient, the particular disease or condition being treated, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient’s age, body weight, sex, severity of the diseases being treated, the patient’s diet, and the patient’s excretion rate.

[0059] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In some embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.Dosage

[0060] The compounds and compositions of the disclosure are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, in some embodiments. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each subject. Suitable regimes for initial administration, but are typified by an initial administration followed by repeated doses at one hour intervals or longer by a subsequent administration. Alternatively, continuous administration that is sufficient to maintain concentrations in the blood are contemplated.

[0061] The amounts of the active ingredients (e.g., compound of the disclosure or a pharmaceutically acceptable salt thereof) in the compositions, the composition formulation, and the mode of administration, are among the factors that are varied to provide an amount of the active ingredient that is effective to achieve the desired therapeutic response for each subject, without being unduly toxic to the subject. The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health,diet and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0062] In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof is administered to a subject in various dosing amounts and over various time frames. Additionally, the dose(s) of a compound is administered, in some embodiments, twice a week, weekly, every two weeks, every three weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 12 weeks, or any combination of weeks therein. Dosing cycles are also contemplated, such as, e.g., administering the compound once or twice a week for 4 weeks, followed by two weeks without therapy. Additional dosing cycles including, e.g., different combinations of the doses and weekly cycles described herein are also contemplated within the disclosure.

[0063] Therapeutically effective amounts of a composition, in some embodiments, vary and depend on the severity of the disease, the subject’s weight, and general state of the subject being treated. Administration is, in some embodiments, daily, on alternating days, weekly, twice a month, monthly, or more or less frequently, as necessary depending on the response of the disorder or condition and the subject’s tolerance to the therapy. In some embodiments, maintenance dosages over a longer period of time, such as 4, 5, 6, 7, 8, 10, or 12 weeks or longer, are needed until a desired suppression of disorder symptoms occurs, and dosages are adjusted as necessary. The progress of this therapy is easily monitored by conventional techniques and assays.

[0064] A physician having ordinary skill in the art, in some cases, readily determines and prescribes the effective amount (ED50) of the composition required. For example, the physician could start doses of the compounds employed in the composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Alternatively, a dose remains constant in some embodiments.

[0065] The compounds and pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dose” or “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some embodiments, the pharmaceutical dosage formsdescribed herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

[0066] The dosage of the compound of the disclosure or compositions comprising the compound can vary depending on multiple factors, such as, e.g., the pharmacodynamic properties of the compound, the mode of administration, age, health, or weight of the recipient, the nature and extent of the symptoms, frequency of the treatment, the type of concurrent treatment, if any, and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compound of the disclosure or a pharmaceutically acceptable salt thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the disclosure are administered to a human at a daily dosage of, e.g., between 0.05 mg and 3000 mg (measured as the solid form). Dose ranges include, for example, between 0.1-1000 mg (e.g., 0.2-950, 0.4-900, 0.6-850, 0.8-800, 1-750, 1-20, 2- 16, 2-700, 4- 650, 6-600, 8-550, 10-500, 15-450, 20-400, 30-350, 40-300, 50-250, 75- 200, or 100-150 mg). In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mg of the compound of the disclosure or a pharmaceutically acceptable salt thereof is administered, e.g., per day. A single dose or multiple doses may be administered in a 24-hour period. For example, in some embodiments, between 0.5-8 mg (e.g., 0.5, 1, 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 mg) of the compound is administered to the subject once or more than once, e.g., twice, daily.

[0067] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may be 0.005-5 (0.01-4.8, 0.02-4.6, 0.04-4.4, 0.06-4.2, 0.08-4.0, 0.1-3.8, 0.2-3.6, 0.3-3.4, 0.4-3.2, 0.5-3.0, 0.6, 2.8, 0.7-2.6, 0.8-2.4, 0.9-2.2, 1-2, 1.1-1.9, 1.2-1.8, 1.3-1.7, or 1.4-1.6) mg / kg. In exemplary, non-limiting embodiments, the dose may range from 0.005-1 mg / kg (e.g., 0.01-0.5, 0.01-0.2, or 0.01-0.1 mg / kg).Therapeutic Efficacy

[0068] A response is achieved when the subject experiences partial or total alleviation or reduction of signs or symptoms of illness following treatment with a compound or composition disclosed herein. In some embodiments, a compound or composition of the disclosure described herein is administered in an amount and for a time effective to result in reduction in one or more (e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more) symptoms associated with a BIMC condition or disorder. As is discussed herein, a subject having a BIMC condition or disorder can present with one or more psychological, behavioral, cognitive, metabolic, and / or immune symptoms. z. Assessment of treatment of psychological symptoms

[0069] Accordingly, therapeutic efficacy of a compound or composition of the disclosure in treating a BIMC condition or disorder may be confirmed, e.g., by a reduction in one or more psychological symptoms of a BIMC condition for disorder. In some embodiments, one or more psychological symptoms of a BIMC condition or disorder include, without limitation, mood reactivity, interpersonal rejection sensitivity e.g., having a longstanding pattern and resulting in significant social or occupational impairment), low mood, low self-esteem, leaden paralysis, fatigue, malaise, lethargy, anhedonia, rumination, irritability, low libido, and suicidal ideation. Diagnosis of the one or more psychological symptoms associated with a BIMC condition or disorder can be performed using known and routine methods, including subjective self-reporting and / or observation by a skilled clinician. Non-limiting examples of tests that can be used for psychological evaluation of a subject include Back Depression Inventory (BDI), Center for Epidemiologic Studies of Depression scale (CES-D), EQ-5D (tests mobility, self-care, usual activities, pain / discomfort, and anxiety / depression), Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale (MADRS), Social Problem-Solving Inventory-Revised (SPSI-RTM), Beck Hopelessness Scale, Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), Patient Health Questionnaire (PHQ-9), Reminiscence Functions Scale (RFS), Short Form Health Survey (SF-36), Social Adjustment Scale-Self Report (SAS-SR), Social Functioning Questionnaire (SFQ), Geriatric Depression Scale (GDS), and Fife Satisfaction Index (ESI). A reductionin the intensity or frequency of one or more of the above-listed symptoms or their complete resolution, as assessed by the above methods, can be indicative of the therapeutic efficacy of a compound or composition disclosed herein. ii. Assessment of treatment of behavioral symptoms

[0070] In some embodiments, therapeutic efficacy of a compound or composition of the disclosure in treating a BIMC condition or disorder may be confirmed, e.g. , by a reduction in one or more behavioral symptoms of a BIMC condition for disorder. In some embodiments, one or more behavioral symptoms of a BIMC condition or disorder include, without limitation, increased sleep, hypersomnia, binge eating (e.g., binge eating not associated with regular use of inappropriate compensatory behaviors, binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa, and / or recurrent binge eating), recurrent inappropriate compensatory behaviors, hyperphagia, self-reproach following eating, distress during eating, impaired impulse control, low appetite, hypophagia, intense fear of gaining weight, and body dysphoria. Diagnosis of the one or more behavioral symptoms associated with a BIMC condition or disorder can be performed using known and routine methods, including subjective self-reporting and / or observation by a skilled clinician. In embodiments where the behavioral symptoms relate to a sleep disorder e.g., increased sleep, hypersomnia, and insomnia), tests that can be used to diagnose the subject include those that are known in the art, such as polysomnography, multiple sleep latency test, and maintenance wakefulness test. In embodiments where the behavioral disorder relates to an eating disorder (e.g., binge eating, hyperphagia, recurrent inappropriate compensatory behaviors, self-reproach following eating, distress during eating, impaired impulse control, low appetite, hypophagia, intense fear of gaining weight, and body dysphoria), tests that can be used to diagnose the subject include, without limitation, physical examination, psychological evaluation (e.g., using diagnostic methods disclosed herein), assessment of blood sugar levels, electrolyte levels, liver and kidney functioning, urinalysis, electrocardiogram, complete blood count, comprehensive metabolic profile, serum magnesium and phosphate testing, thyroid screen, and self-diagnosis. A reduction in the intensity or frequency of one or more of the above-listed symptoms or their complete resolution, asassessed by the above methods, can be indicative of the therapeutic efficacy of a compound or composition disclosed herein.Hi. Assessment of treatment of cognitive symptoms

[0071] In some embodiments, therapeutic efficacy of a compound or composition of the disclosure in treating a BIMC condition or disorder may be confirmed, e.g. , by a reduction in one or more cognitive symptoms of a BIMC condition for disorder. In some embodiments, one or more cognitive symptoms of a BIMC condition or disorder include, without limitation, impairment of memory, impairment of attention, impairment of concentration, impairment of language, impairment of learning, impairment of perception, impairment of reasoning, executive dysfunction, psychomotor impairment, impaired processing speed, and disorder of thought e.g., delusions). Diagnosis of the one or more cognitive symptoms associated with a BIMC condition or disorder can be performed using known and routine methods, including Eight-item Informant Interview to Differentiate Aging and Dementia (AD8), Annual Wellness Visit (AWV), General Practitioner Assessment of Cognition (GPCOG), Health Risk Assessment (HRA), Memory Impairment Screen (MIS), Mini Mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA), St. Louis University Mental Status Exam (SLUMS), and Short Informant Questionnaire on Cognitive Decline in the Elderly (Short IQCODE). A reduction in the intensity or frequency of one or more of the above-listed symptoms or their complete resolution, as assessed by the above methods, can be indicative of the therapeutic efficacy of a compound or composition disclosed herein. iv. Assessment of treatment of metabolic symptoms

[0072] In some embodiments, therapeutic efficacy of a compound or composition of the disclosure in treating a BIMC condition or disorder may be confirmed, e.g. , by a reduction in one or more metabolic symptoms of a BIMC condition for disorder. In some embodiments, one or more metabolic symptoms of a BIMC condition or disorder include, without limitation, hypertension, hyperglycemia, insulin resistance, leptin resistance, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high- density lipoprotein (HDL), abdominal obesity, hyperuricemia, hepatic dysfunction, and gastrointestinal dysregulation. Diagnosis of the one or more metabolic symptomsassociated with a BIMC condition or disorder can be performed using known and routine methods, including physical examination, assessment of blood sugar and / or A1C levels, electrolyte levels, liver and kidney functioning, urinalysis, electrocardiogram, complete blood count, comprehensive metabolic profile, serum magnesium and phosphate testing, thyroid screen, blood pressure measurement, and lipid profile test. A reduction in the intensity or frequency of one or more of the above-listed symptoms or their complete resolution, as assessed by the above methods, can be indicative of the therapeutic efficacy of a compound or composition disclosed herein. v. Assessment of treatment of immune symptoms

[0073] In some embodiments, therapeutic efficacy of a compound or composition of the disclosure in treating a BIMC condition or disorder may be confirmed, e.g. , by a reduction in one or more immune symptoms of a BIMC condition for disorder. In some embodiments, one or more immune symptoms of a BIMC condition or disorder include, without limitation, inflammation, recurrent infections, gastrointestinal dysregulation, anemia, rash, cold extremities, dry eyes, fatigue, fever, and / or headache. Diagnosis of the one or more immune symptoms associated with a BIMC condition or disorder can be performed using known and routine methods, including physical examination, temperature measurement, complete blood count, and urinalysis. A reduction in the intensity or frequency of one or more of the above-listed symptoms or their complete resolution, as assessed by the above methods, can be indicative of the therapeutic efficacy of a compound or composition disclosed herein.

[0074] As discussed herein, a therapeutic response can be achieved by modulating an immune response in a subject having a BIMC condition or disorder, e.g. , by administering to the subject a compound or composition of the disclosure in a dose (e.g., an effective amount) and for a time sufficient to modulate an immune response in the subject. One way to modulate an immune response is to modulate an immune cell activity. This modulation can occur in vivo (e.g., in a human subject or animal model). The types of cells that can be modulated include T cells (e.g., peripheral T cells, cytotoxic T cells / CD8+ T cells, T helper cells / CD4+ T cells, memory T cells, regulatory T cells / Tregs, natural killer T cells / NKTs, mucosal associated invariant T cells, and gamma delta T cells), B cells (e.g., memory B cells, plasmablasts, plasma cells, follicular Bcells / B-2 cells, marginal zone B cells, B-l cells, regulatory B cells / Bregs), dendritic cells (e.g., myeloid DCs / conventional DCs, plasmacytoid DCs, or follicular DCs), granulocytes (e.g., eosinophils, mast cells, neutrophils, and basophils), monocytes, macrophages (e.g., peripheral macrophages or tissue resident macrophages), myeloid- derived suppressor cells, natural killer (NK) cells, innate lymphoid cells (e.g., ILCls, ILC2s, and ILC3s), thymocytes, and megakaryocytes.

[0075] The immune cell activities that can be modulated by administering to a subject an effective amount of a compound or composition of the disclosure described herein include activation, phagocytosis, antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, polarization, proliferation, lymph node homing, lymph node egress, recruitment, migration, differentiation, immune cell cytokine production and / or secretion, antigen presentation, maturation, and degranulation. Modulation can increase or decrease these activities.

[0076] In some embodiments, an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof is an amount sufficient to modulate (e.g., increase or decrease) one or more (e.g., 2 or more, 3 or more, 4 or more) of the following immune cell activities in the subject or cell: T cell polarization; T cell activation; dendritic cell activation; neutrophil activation; eosinophil activation; basophil activation; T cell proliferation; B cell proliferation; T cell proliferation; monocyte proliferation; macrophage proliferation; dendritic cell proliferation; NK cell proliferation; ILC proliferation, mast cell proliferation; neutrophil proliferation; eosinophil proliferation; basophil proliferation; cytotoxic T cell activation; circulating monocytes; peripheral blood hematopoietic stem cells; macrophage polarization; macrophage phagocytosis; macrophage ADCP, neutrophil phagocytosis; monocyte phagocytosis; mast cell phagocytosis; B cell phagocytosis; eosinophil phagocytosis; dendritic cell phagocytosis; macrophage activation; antigen presentation (e.g., dendritic cell, macrophage, and B cell antigen presentation); antigen presenting cell migration (e.g., dendritic cell, macrophage, and B cell migration); lymph node immune cell homing and cell egress (e.g., lymph node homing and egress of T cells, B cells, dendritic cells, or macrophages); NK cell activation; NK cell ADCC, mast cell degranulation; NK cell degranulation; ILC activation, ILC ADCC, ILC degranulation, cytotoxic T cell degranulation; neutrophil degranulation; eosinophil degranulation; basophil degranulation; neutrophil recruitment; eosinophilrecruitment; NKT cell activation; B cell activation; regulatory T cell differentiation; and dendritic cell maturation. In some embodiments, the immune response (e.g., an immune cell activity listed herein) is increased or decreased in the subject or cell at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500% or more, compared to before the administration. In some embodiments, the immune response is increased or decreased in the subject or cell between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-200%, between 100%-500%, compared to before the administration.

[0077] Prior to and / or after a compound of the disclosure or a pharmaceutically acceptable salt thereof is administered to treat a patient or contact a cell, a readout can be used to assess the effect on immune cell activity. Immune cells can be isolated from the subject using, e.g., a blood sample, lymph node biopsy, or tissue sample. Immune cell activity can also be assessed by measuring a cytokine, chemokine, or marker associated with a particular immune cell type using routine assays. In some embodiments, the cytokine or chemokine is selected from the group consisting of TNFa, IFNa, sTNFR2, IL-ip, IL-IRA, IL-6, IL-2R, IL-18, IL-12, CCL2, CRP, and MIF, or any combination thereof. In some embodiments, an increase or reduction in the blood (e.g., whole blood, plasma, or serum) levels of one or more of aforementioned cytokines or chemokines can be indicative of a therapeutically effective response in a subject treated with the compound or composition of the disclosure. In some embodiments, the blood level of the one or more cytokines or chemokines is increased or decreased in the subject at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more, compared to before the administration. In some embodiments, the blood level of the one or more cytokines or chemokines is increased or decreased in the subject between 5-20%, between 5-50%, between 10-50%, between 20-80%, between 20-70%, between 50-200%, between 100%-500%. In some embodiments, the blood level of the one or more cytokines or chemokines is decreased in a subject following treatment with a compound or composition of the disclosure. In some embodiments, the blood level of the one or more cytokines or chemokines is increased in a subject following treatment with a compound or composition of the disclosure. In some embodiments, the blood level of the one or more cytokines or chemokines is decreased in a subject following treatment with acompound or composition of the disclosure. Methods for assaying immune cell activity are known, and include, without limitation, evaluation of cell surface markers on the surface of T cells using, e.g., flow cytometry, immunohistochemistry, in situ hybridization, ELISA, western blot analysis, and other assays that allow for measurement of cellular markers.

[0078] Treatment efficacy is measured across different timeframes, in some embodiments, including, e.g., in months to years, depending on prognostic factors including the number of relapses, stage of disease, and other factors.

[0079] In some embodiments, the methods described herein include identifying a patient as having or at risk of developing a BIMC condition or disorder, as described herein. For example, a representative method includes: (a) identifying (e.g., diagnosing) a patient as having or at risk of developing a BIMC condition or disorder; (b) administering to the patient a therapeutically effective dose of a disclosed compound or composition, thereby treating the patient, in some embodiments. The method may further optionally include (c) assessing the patient for reduction in the severity or frequency of the aforementioned symptoms to determine if the composition led to a therapeutically effective reduction in the degree or frequency of one or more of the aforementioned symptoms of a BIMC condition or disorder.Selection of Subjects

[0080] Subjects that may be treated as described herein are subjects having a disease or disorder, such as, e.g., a BIMC condition or disorder described herein. For example, a subject having or at risk of developing a BIMC condition or disorder is one that may have one or more symptoms associated with BIMC, including, but not limited to behavioral dysregulation, immune dysregulation, metabolic dysregulation, and / or affective dysregulation. Non-limiting examples of behavioral dysregulation may include increased sleep, hypersomnia, interpersonal rejection sensitivity, binge eating, hyperphagia, hypophagia, compensatory behaviors, impaired impulse control, among others. Examples of immune dysregulation may include, without limitation, chronic low-grade inflammation (e.g., persistent increases in blood levels of one or more pro-inflammatory cytokines), autoimmune disease, immune dysregulation resulting from use of immunotherapy, immune dysregulation resulting from an infection (e.g., bacterial or viralinfection), among others. Metabolic dysregulation associated with BIMC may include, in some embodiments, one or more symptoms selected from hypertension, hyperglycemia, insulin resistance, leptin resistance, mitochondrial dysfunction, prediabetes, hypercholesterolemia, hypertriglyceridemia, low serum levels of high-density lipoprotein (HDL), abdominal obesity, gastrointestinal dysregulation hyperuricemia, and hepatic dysfunction. Non-limiting examples of affective dysregulation include mood reactivity, low mood, low self-esteem, anhedonia, rumination, irritability, low libido, suicidal ideation, leaden paralysis, long-standing pattern of interpersonal rejection sensitivity, self-reproach (e.g., following eating), intense fear of gaining weight, body dysphoria, among others.Triple Reuptake Inhibitor

[0081]

[0060] A triple reuptake inhibitor (TRI) is a serotonin-norepinephrine-dopamine reuptake inhibitor that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. A TRI concomitantly blocks reuptake of these neurotransmitters at the serotonin transporter (SERT), noradrenaline transporter (NAT), and dopamine transporter (DAT), respectively. Reuptake inhibition of these neurotransmitters increases their extracellular concentrations, resulting in increased serotonergic, noradrenergic, and dopaminergic neurotransmission across the central nervous system (CNS). Measuring affinity of TRI compounds disclosed herein to any one of SERT, NAT, and / or DAT may be determined by assaying the percent inhibition of these transporters from a radioligand binding assay using cells expressing human transporters. Relevant radioligand binding assays to determine affinity are well- known in the art.Compound 1

[0082] Compound 1, as depicted below, is a triple reuptake inhibitor, also known as (3,4- dichloro-phenyl) - ((S )- 3 -propyl-pyrrolidin- 3 -yl) -methanone :(Compound 1).

[0083] A method of chemically synthesizing Compound 1 is described in U.S. Patent No. 8,084,623 and U.S. Patent No. 9,527,810 which are incorporated by reference in their entirety.

[0084] In some embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0085] In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a hydrate or an anhydrate form (e.g., anhydrate, hemihydrate, monohydrate, or quarterhydrate). In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt, being in a quarterhydrate form.

[0086] In some embodiments, the pharmaceutically acceptable salt of Compound 1 isor a hydrate thereof.

[0087] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in an amorphous form. In some embodiments, Compound 1 or a pharmaceuticallyacceptable salt thereof is in a crystalline form. In some embodiments, the crystalline form is a crystalline polymorph or a hydrate thereof. In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarterhydrate (Form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (Form 2).Form 1

[0088] In some embodiments, the compound is in a crystalline quarterhydrate form (Form 1) of a hydrochloride salt of Compound 1. In some embodiments, Form 1 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu& radiation at 29 (2 Theta): 5.5+0.20°, 9.4+0.20°, 10.6+0.20°, 12.5+0.20°, 14.6+0.20°, 16.2+0.20°, 16.6+0.20°, 17.3+0.20°, 18.6+0.20°, 19.6+0.20°, 22.2+0.20°, 22.7+0.20°, 23.1+0.20°, 23.7+0.20°, and 25.3+0.20°.Form 2

[0089] In some embodiments, the compound is in a crystalline form (Form 2) of a hydrochloride salt of Compound 1. In some embodiments, Form 2 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained with a Cu&radiation at 29 (2 Theta): 5.2+0.20°, 10.5+0.20°, 12.3+0.20°, 15.3+0.20°, 15.6+0.20°, 16.0+0.20°, 17.1+0.20°, 18.8+0.20°, 23.0+0.20°, 23.9+0.20°, 27.2+0.20°, 28.2+0.20°, and 30.5+0.20°.

[0090] In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of Compound 1.

[0091] In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with physiologically compatible mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid,trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.Pharmaceutical Compositions

[0092] The compound or composition of the disclosure can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically include the agent and a pharmaceutically acceptable carrier. As used herein the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances are known. Except insofar as any conventional media or agent is incompatible with the active compound, such media can be used in the compositions of the invention. Supplementary active compounds can also be incorporated into the compositions.

[0093] A pharmaceutical composition can be formulated to be compatible with its intended route of administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0094] The pharmaceutical compositions provided herein may be presented in sustained release form. A sustained release form is a formulation which is designed to slowly release a therapeutic agent in the body over an extended period of time. A sustained release form can be formulated to sustain, for example, the compound’ s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein e.g., provide a physiologically - effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.

[0095] In some embodiments, the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a tablet.

[0096] In some embodiments, the pharmaceutical compositions provided herein comprise Compound 1 or a pharmaceutically acceptable salt thereof as the sole active agent, or in combination with other active agents.

[0097] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005.Medicaments

[0098] The disclosure provides, in some embodiments, a use of the compound and compositions described herein to make a medicament for treating a condition, disease, or disorder described herein. In some embodiments, medicaments are formulated based on the physical characteristics of the subject needing treatment and are formulated in single or multiple formulations based on the stage of the condition, disease, or disorder. Medicaments are packaged in a suitable package with appropriate labels for the distribution to hospitals and clinics in which the label is for the indication of treating a subject having a disease described herein in some embodiments. Medicaments are packaged as a single or multiple units in some embodiments. Instructions for the dosage and administration of the compositions are included with the packages as described below in some embodiments. The disclosure is further directed to medicaments comprising compound described herein and a pharmaceutically acceptable carrier.EXAMPLES

[0099] The following examples are put forth to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their invention.

[0100] In the Examples provided below, the following abbreviations are used: “PROG” refers to progressive ratio; “FR1” refers to fixed ration of one or fixed ratio 1; “SEM” refers to standard error of mean; “VEH” refers to vehicle; “ANOVA” refers to analysis of variance test; “NR” refers to non-rapid eye movement sleep; “REM” refers to rapid eye movement sleep; “p.o.” or “per os” refers to by mouth; “CAF” refers to caffeine; and “TRI” refers to triple reuptake inhibitor.Example 1: In vivo effects of a triple reuptake inhibitor on LPS-induced TNFa release in rat serum

[0101] The current study was performed to assess the effects of a triple uptake inhibitor of the present disclosure, Compound 1, on LPS-induced TNFa secretion into serum of rats. LPS is a bacterial endotoxin containing a protein and a polysaccharide, and a robust activator of the immune system. LPS induces an acute inflammatory response characterized by increased levels of the pro-inflammatory cytokine TNFa in peripheral circulation when administered in vivo. LPS-induced TNFa release has been used as a first tier acute model to test anti-inflammatory therapeutic effects of drug candidates and determine therapeutically efficacious dose ranges prior to testing in chronic inflammatory models.Animals and. drug administration

[0102] To assess the effect of Compound 1 on LPS-induced TNFa release in vivo, female Wistar Han rats (n = 8) were administered (i.p.) 1 mL / 100 g of vehicle (HPMC; TG10, pH 3.5) or Compound 1 (3 mg / kg) prior to administration of LPS. At 0 hr, LPS was injected (i.p.) at 50 pg / kg. 1.5 hr after LPS injection, animals were euthanized using CO2 inhalation and blood was withdrawn via cardiocentesis. The sera was separated and keptat -20°C until ready for TNFa measurement by ELISA. Plasma was also collected in Plasma separator tubes for pharmacokinetic (PK) analysis.Results

[0103] A dose-response assessment was performed at 1.5 hr post LPS exposure. In this context, serum TNFa level induced by LPS was 10,621 pg / mL. Pre-treatment with Compound 1 resulted in a dose-dependent reduction of TNFa level by 80.2% at 3 mg / kg, 90.7% at 10 mg / kg, and 93.5% at 30 mg / kg, respectively, all reaching statistical significance (FIG. 1). Unexpectedly, dosing at 30 mg / kg caused animals to have seizures 20 min post-administration. Thus, these animals were sacrificed immediately (70 min earlier than intended). Compound 2, a reference JNK inhibitor and positive control, led to a reduction of TNFa level by 82.8% at a dose of 30 mg / kg (FIG. 1). A summary of this data is presented in Table 1, below. Exposures of drug in plasma are presented in Table 2.Table 1: Effect of Compound 1 on LPS-induced TNFa release in rat plasma** = p < 0.01Table 2: Concentration of Compound 1 in plasma samples of Wistar Han rats after LPS challenge

[0104] In conclusion, Compound 1 inhibits LPS-induced TNFa release in the serum of rats in a dose-dependent manner. High dose at 30 mg / kg might not be well-tolerated due to seizure induction.Example 2: Effects of a triple reuptake inhibitor in rats in a forced swim test

[0105] The present study was performed to test the antidepressant- like effects of Compound 1 in the forced swim test in rats. The forced swim test relies on the principle that when placed in water, rodents will, after an initial period of vigorous activity, adopt a characteristic immobile posture, making only minimal movements necessary to stay afloat. A reduction in the time of immobility is considered indicative of potential antidepressant-like properties of a particular drug.Animals

[0106] Female adult Wistar rats weighing approximately 100- 130g were used. The animals were housed in groups of four in cages (810 cm2) with sawdust bedding. Tap water and standard laboratory chow were continuously available except during testing. The animal quarters were maintained on a 12:12 hr light-dark cycle with light onset at 6am. Room temperature (21-23°C) and humidity (55-65%) were kept constant. At the conclusion of testing, rats were euthanized by means of CO2 inhalation.Swim test

[0107] In the forced swim test, naive rats were individually placed into vertical Plexiglas cylinders (height: 40 cm; diameter: 17.5 cm) containing 16 cm of water maintained at 23- 24°C. After 15 min in the water, they were removed carefully, dried in a towel and allowed to further dry for 15 min under a heating lamp before being returned to their home cage. Twenty-four hours later, they were retested for 5 min under identical conditions and the total duration of immobility was measured. A rat was considered immobile when it remained passive floating in water in a slightly hunched but upright position, with his head just above the surface. Four rats were monitored simultaneously by automated video tracking and according to a counterbalanced protocol for both treatments and cylinders.Administration of drugs

[0108] Compound 1 was suspended in 0.3% Tween 80 in distilled water. Compound 1 was administered p.o. (gavage) 24 hr, 16 hr, and 2 hr prior to the test. The injection volume was 5 mL / kg of body weight. Doses refer to the free base of the drug.Statistical analysis

[0109] Data were analyzed with a 1-way ANOVA followed by a 1-tailed Dunnett’s post hoc tests. A p-value < 0.05 was considered significant.Results

[0110] Compound 1 significantly decreased the duration of immobility at 10 mg / kg, but not at lower doses (FIG. 2 and Table 3). These data provide in vivo evidence for antidepressant-like properties of Compound 1 following oral administration.Table 3: Effects of Compound 1 on rats in the forced swim testExample 3: Effects of a triple reuptake inhibitor in the mouse tail suspension test

[0111] The mouse tail suspension test is a well-documented animal behavior test which is sensitive to standard classes of antidepressants. The antidepressant effect of Compound 1 was examined in the mouse tail suspension model at doses ranging from 0.3 to 10 mg / kg p.o. Male A / J mice (n = 15-17) were administered Compound 1 120 minutes prior to testing. Oral administration of Compound 1 at 1, 3, and 10 mg / kg significantly decreased mobility time (p < 0.05). Duloxetine (30 mg / kg, i.p., 120 min pre-treatment), used as a positive control, shows a significant decrease in immobility time.Animals

[0112] Male A / J mice (9-10 weeks old) were housed in corncob bedding with free access to food and water. They were housed on a 12 hr light-dark cycle and maintained for at least seven days prior to testing.Administration of drugs

[0113] Compound 1 (0.3, 1, 3, and 10 mg / kg) was prepared fresh in Generic HPMC (5 mg / mL hypromellose, 4 mg / mL polysorbate- 80, and 9 mg / mL benzyl alcohol in sterile water) and acute dose was administered orally 120 minutes before testing. Duloxetine (30 mg / kg) was dissolved in sterile water and ana acute dose was administered i.p. 120 minutes before testing. After the appropriate injection-test interval elapses, the mouse was suspended by the tail attached, using adhesive tape, to a hook connected to a load cell amplifier circuit (test cubicle) that calculated the total immobility time for the six minute test period.Statistical analysis

[0114] Statistical analysis was performed by an overall analysis of variance on all dose groups. Pairwise comparisons were of immobility time (s) for each dose to vehicle were then performed using Dunnett’s test. Validation of the assay was performed by comparing the single dose of Duloxetine (positive control) to vehicle using an unpaired t-test.Results

[0115] Compound 1 (1, 2, and 10 mg / kg) significantly (p < 0.05) reduced immobility time as compared to the vehicle-treated animals (FIG. 3). The positive control Duloxetine (30 mg / kg) also exhibited a significant decrease in immobility time. These findings further demonstrate the antidepressant properties of Compound 1.Example 4: Effects of a triple reuptake inhibitor in the elevated plus-maze test in rats

[0116] This study investigated the behavioral effects of Compound 1 in the elevated plusmaze in rats. This test relies on the principle that rodents avoid open and exposed environments (open arms of the plus-maze), and prefer to spend time in protected places (closed arms of the apparatus). An increase in time spent, distance traveled, andpercentage of entries in to the open arms are considered indicative of anxiolytic-like properties of a particular drug, whereas opposite effects are considered anxiogenic-like.Animals

[0117] Adult male Sprague Dawley rats weighing approximately 200 g at the start of the experiment were used. They were housed in groups of four in MacroIon Type 3 cages (810 cm2) with sawdust bedding. The animals’ quarters were maintained on a 12:12 hr light-dark cycle with light onset at 6 am, with free access to tap water and food. Room temperature (21-23°C) and humidity (55-65%) were kept constant.Elevated plus-maze

[0118] The elevated plus-maze consisted of two open arms perpendicular to two closed arms (each arm was 10 cm wide x 50 cm long) extending from an open central area. The apparatus was constructed from grey polyvinylchloride plastic and placed 50 cm above the floor. The closed arms, opposite to one other, had a surrounding wall of height 48 cm. The apparatus was situated in a sound- attenuated observation room with controlled illumination (200 lux on the central platform of the plus-maze). The plus-maze was positioned in the middle of a closed black environment with the animal observed via a closed circuit video camera mounted vertically over the maze. Behavioral analysis was conducted using a computerized system. Rats were tested in randomized order. The test started by placing the animal on the central platform facing a closed arm. The duration of the test was 5 minutes. 70% ethanol was used to clean the apparatus prior the introduction of each animal.

[0119] Each treatment group consisted of 12 rats. Each animal was used only for a single experiment. Rats were treated with either Compound 1 at doses 1, 3 or 10 mg / kg, vehicle (0.3 % Tween - NaCl 0.9%) or 10 mg / kg chlordiazepoxide, as a positive control. Rats were isolated for 60 minutes in small cages without sawdust and water, before being placed in the plus-maze.

[0120] The parameters selected to represent anxiolytic -related behaviors were the time spent (sec) within the open arms, the distance travelled (cm) within the open arms, and the percentage of transitions between the central platform and the open arms. The measureused to quantify motor activity was the distance travelled per second (speed) within the closed arms.Administration of drugs

[0121] Compound 1 and chlordiazepoxide were suspended in 0.3% Tween / NaCl 0.9%. The compounds were administered p.o. (gavage) in an amount of 5 mL / kg body weight. Control animals received equal volume injections of vehicle. The pre-treatment time was 120 minutes for vehicle and Compound 1 and 60 minutes for chlordiazepoxide.Statistical analysis

[0122] For Compound 1, data was analyzed with a one-way analysis of variance (ANOVA), followed by a post hoc Dunnett’s test. Statistical significance was determined at ap-value of < 0.05. The effects of the positive control, chlordiazepoxide, were analyzed using an unpaired t-test.Results

[0123] Compound 1 had no effect on time spent in the open arms (FIG. 4A and Table 4), distance traveled in the open arms (FIG. 4B and Table 5), or the percentage of entries into the open arms (FIG. 4C and Table 6). Chlordiazepoxide produced a significant increase in the time spent by animals in the open arms, distance traveled in the open arms, but no clear increase in the percentage of entries into the open arms (p > 0.01). The speed in the closed arms was affected by neither Compound 1 nor chlordiazepoxide (p > 0.01) (FIG. 4D and Table 7). These findings indicate that, at the doses administered, Compound 1 did not exhibit anxiolytic-like or anxiogenic-like effects in rodents.Table 4: Time in open arms (s)indicates that the animal fell down the arena and was excluded from analysisTable 5: Distance traveled in open armsindicates that the animal fell down the arena and was excluded from analysisTable 6: Percentage of entries into open armsindicates that the animal fell down the arena and was excluded from analysisTable 7: Speed in closed arms (cm / s)indicates that the animal fell down the arena and was excluded from analysisExample 5: Assessment of appetite suppressant effects of Compound 1 using progressive ratio / chow feeding choice task in rats

[0124] A study to evaluate Compound 1 for appetite suppressant effects was conducted. The PROG / Chow feeding choice procedure was used as a test designed to evaluate the effort a rat is willing to make to eat a palatable food by pressing a lever instead of eating freely available standard food.Methods

[0125] Thirty-one (n = 31) adult male Sprague Dawley rats were used in this study. The animals were restricted to 85% of their free-feeding weight, with modest growth allowed throughout the study period. Animals were assessed using operant conditioning chambers. Animals were first introduced to the high carbohydrate pellets (“palatable food”) and trained to lever press using a continuous reinforcement schedule with a fixed ration of one (FR1 = one active lever press trigger the delivery of the palatable food) for one week. Subsequently, rats were trained on the progressive ratio schedule (progressively more lever pressures were needed to trigger the delivery of the palatable food) alone for nine weeks, at which point chow (“standard food”) was introduced (=PROG / Chow feeding choice procedure), and animals trained for another 5 weeks to acquire a steady baseline. Each session lasted 30 minutes, and rats ran in the operant chambers once a day, five days a week (Monday-Friday). Vehicle (VEH), or Compound 1 at doses of 5, 10, and 20 mg / kg were administered via oral gavage once a week (Thursday or Friday) after the training period. Treatment conditions were selected randomly. Lever presses and chow consumption (including spillage) were recorded after each operant session.Statistical analyses

[0126] Repeated measures analysis of variance test (ANOVA) and planned comparisons were used to assess the data. Factorial ANOVA was used to assess group x treatment interaction. If significant interactions were found, planned comparisons (using the overall error term) were used to assess the groups individually. Dunnett’s tests were also used toanalyze differences between drug treatments and VEH. A p-value < 0.05 was considered statistically significant for all analyses.Results

[0127] All treatment conditions showed significant decreases in standard chow intake when compared to VEH (5.0 mg / kg: [F(l,90)=15.589, p<0.001], 10.0 mg / kg [F(l,90)=159.881, p<0.001], and 20.0 mg / kg: [F(l,90)=236.567, p<0.001]), as shown in FIG. 6A. No significant difference in lever pressing was observed between VEH and the 5.0 mg / kg dose [F(l,90)=0.391, p = n.s.]. Lever pressing was significantly reduced at both the 10.0 mg / kg dose [F(l,90)=13.534, p<0.001] and the 20.0 mg / kg dose [F(l,90)=38.407, p<0.001], as shown in FIG. 5A.

[0128] The study indicates that Compound 1 demonstrates appetite-suppresant effects. The pattern of decreased lever pressing and chow intake, as shown in this study of PROG / Chow feeding choice task.High vs. Low Responders

[0129] Factorial ANOVA test conducted on lever pressing revealed a significant group x treatment interaction [F(3,90)=13.824, p<0.001 ; pp2= 0.323] and a significant interaction of the linear trend (p < 0.001). Due to this significant interaction, the high and low responder level pressing was analyzed separately. Significant treatment effects were found in both groups (high: p<0.001; low: p=0.01). High responder lever presses showed a significant linear trend (p<0.001). Planned comparisons revealed significant decreases in lever pressing at both the 10.0 mg / kg [F(l,42)=26.735, p<0.001] and 20.0 mg / kg [F(l,42)=55.797, p<0.001] doses when compared to VEH. There were no significant differences found when comparing the 5.0 mg / kg dose to VEH conditions [F(l,42)=3.372, p=n.s.] (FIG. 5B). Planned comparisons showed no significant differences when comparing any of the drug conditions to VEH (5.0 mg / kg: [F(l,45)=0.319, p=n.s.], 10.0 mg / kg: [F(l,45)=0.079, p=n.s.], 20.0g mg / kg: [F(l,45)=3.157, p=n.s.]). However, a significant quadratic trend (p=0.01) was found in the low responder group (FIG. 5B). A factorial ANOVA was also used to assess the concurrent chow intake. A significant group x treatment interaction [F(3,90)=3.191, p<0.05; r|p2= 0.099] was found (FIG. 6A), as well as an interaction of linear trend(p<0.05). This significant interaction allowed for separate analysis of the high and low responders. Significant treatment effects (p<0.001) and significant linear trend (p<0.001) were found in both high and low responders (FIG. 6B). In the high responder group, significant decreases in chow intake were found at the 5.0 mg / kg [F( 1,42)= 13.450, p<0.010], 10.0 mg / kg [F(l,42)=70.714, p<0.001], and 20.0g mg / kg [F(l,42)=100.204, p<0.001] groups when compared to VEH. Low responders also showed significant decreases in lever presses at all dose treatments (5.0 mg / kg [F(l,45)=16.976, p<0.001], 10.0 mg / kg [F(l,45)=156.918, p<0.001], 20.0 mg / kg [F(l,45)=226.122, p<0.001]) as determined by Dunnett’s test.Example 6: Assessment of appetite suppressant effects of Compound 1 in rats using a fixed ratio schedule

[0130] A second study was conducted to evaluate Compound 1 for appetite- suppressant effects. A fixed ratio 1 (FR1) schedule was used. This task is the most food-dense and appetite-dependent operant schedule, with high sensitivity to appetite-related manipulations like pre-feeding and appetite-suppressant drugs.Methods

[0131] The same adult male Sprague Dawley rats (n = 31) as used in Example 5 were used in this study. Animals trained once daily on the PROG / Chow feeding choice procedure from Monday through Thursday. On Friday, the testing day, the animals were switched from the PROG / Chow feeding choice procedure to FR1 with no prior training. Each operant session lasted 30 minutes and lever presses were recorded at the end of the run. Drug treatment and the FR1 probe occurred on the Friday after two weeks of washout period from Example 5. A dose of 20 mg / kg of Compound 1 or vehicle was administered via oral gavage on the testing day. Only the highest dose was tested in this study because, in Example 5, it produced the most robust decrease in lever pressing and chow intake compared to VEH. Treatment conditions were assigned randomly. Differences between treatment group were assessed by unpaired t-test. A p-value < 0.05 was considered statistically significant.Results

[0132] Compound 1 produced a significant decrease in lever pressing in the FR1 probe study, as measured by an unpaired t-test (t = 9.74; p<0.001). As shown in FIG. 7, there is a significant decrease at the 20 mg / kg dose when compared to the vehicle (VEH). Importantly, 6 of 16 rats that received the high drug dose pressed the lever but refrained from eating some of the pellets. After the completion of the 30-minute operant session, approximately 5-10 uneaten pellets were left in the food dishes of these animals, which is an additional marker of appetite-suppression. Accordingly, together with the results in the study of Example 5, the study demonstrates that Compound 1 exhibits appetite- suppresant properties.Example 7: Assessment of appetite-suppressant effects of Compound 1 in rats using binge-like eating of chocolate

[0133] A third study to evaluate the appetite- suppressant effects of Compound 1 was conducted using the binge-like eating of chocolate model.Methods

[0134] A new group of male Sprague-Dawley rats (n = 8; initial weight 300-325 g) was used for the binge-like eating experiment. They were pair-housed under the same conditions described in Examples 5 and 6, above, however, they were not food-restricted, and in the home cage were allowed ad libitum access to food (laboratory chow) and water. Acquisition of binge-like eating took place over the course of 12 exposure sessions. A 3- day, 1-hr habituation exposure to an empty feeding cage with a ceramic dish took place before chocolate exposure. With chocolate exposure, rats received chocolate (0.3 g fat, 0.57 g carbohydrate, and 0.073 g protein with a total of 5.34 kcal / g) on days 1, 2, 4, 6, 7, 9, 12, 14, 15, 18, 23, and 28. On exposure days, rats were placed in an empty feeding cage with a ceramic dish containing ground chocolate for 1 hr. Weight of chocolate was taken before and after each session to determine intake. These acquisition procedures led to gradually increased levels of chocolate intake across sessions (from 0.9 ± 0.3 g chocolate on the first session to 5.5 ± 0.5 g on the 12thsession (see FIG. 8A).Drug Administration

[0135] Upon completion of the 12 acquisition sessions of binge-like eating, rats continued to be exposed to chocolate sessions twice a week for 1 hr in empty feeding cages with a ceramic dish containing chocolate. One session was for maintenance of the binge-like behavior, and the second for drug treatment. These sessions took place randomly throughout the week with the maintenance session always occurring prior to the drug treatment session. Compound 1 was dissolved in 0.3 % Tween 80 in dHiO. Vehicle (VEH), or doses of 5, 10, and 20 mg / kg of Compound 1 were administered via oral gavage once a week for testing. A pre-treatment lead time of four hours was used. A within- subjects design was used in this study, with each rat receiving one treatment per week for a total of four weeks. Treatment conditions were selected randomly.Data Analysis

[0136] Repeated measures ANOVA and planned comparisons were used to assess the effect of Compound 1 on binge-like eating of chocolate.Results

[0137] The results of the binge-like eating experiment are shown in Table 8, FIGS. 8A and 8B.Table 8: Statistical analysis of binge eating experimentsPaired comparisons:• VEH vs lOmg / kg: p<.05**• VEH vs 20mg / kg: p<.05**

[0138] FIG. 8A depicts the acquisition of binge-like chocolate intake over 12 training sessions. FIG. 8B shows the suppressive effects of Compound 1 administration of bingelike eating. There was an overall significant effect of Compound 1 treatment [F(3,21) = 17.3, p<0.001]. Planned comparisons revealed that the 5 mg / kg dose did not significantly suppress chocolate intake [F(l,21) = 1.5, n.s.], but there were significant reductions in chocolate intake at the 10 [F (1,21) = 20.4, p <0.001] and 20 [F(l,21) = 4.09, p<0.001] mg / kg doses.Example 8: Assessment of effects of Compound 1 on sleep in rats

[0139] Using a counter-balanced, repeated measures design, three doses of Compound 1 (1, 3 and 10 mg / kg; p.o.) were tested for their effects on sleep / wake parameters in adult male Sprague-Dawley rats (n = 8). The results were compared with the effects on caffeine (10 mg / kg).Methods

[0140] Eight (n = 8) adult male Sprague Dawley rats were used in this study. Each rat received Compound 1 at 3 doses (1, 3 and 10 mg / kg), vehicle (purified H2O - negative control), and caffeine (10 mg / kg - positive control). Treatments were administered orally during the middle of the rats’ normal inactive period on occurrences separated by a minimum of 3 days. Sleep parameters (non-rapid eye movement sleep, NR; rapid eye movement sleep, REM) were recorded and the first 6 hours of post-dosing records were analyzed. Results were compared to vehicle, as shown in FIG. 9A and FIG. 9B.Result

[0141] Compound 1 has wake-promoting effects at 10 mg / kg (p.o.) in rats, as shown by a complete suppression of REM sleep. 3 mg / kg also significantly increased wakefulness and reduced REM sleep, but to a lesser extent.Example 9: Assessment of effects of Compound 1 on attentional performance and impulsivity in rats

[0142] The 5-choice serial reaction time task (5-CSRTT) is widely used to measure attentional performance and response control (motor impulsivity) in rodents. A strength of the test is its adaptability to task modification. Variations to stimulus duration and frequency of presentation, amongst others, have become commonly used to challenge performance in the context of attention and response control. The primary objective of these studies was to examine the effect of Compound 1 on attentional performance and on aspects of response control, defined as premature responses (PREM) and perseverative responses (PSV), measures of impulsive action, and compulsive action respectively. Two experimental manipulations were undertaken to differentially challenge performance. Specifically, (1) test Compound 1 (1, 3, 10 mg / kg) under standard test conditions of 0.75s stimulus duration (SD), 5s inter-trial interval (ITI), 100 trials, and (2) test Compound 1 (1, 3 mg / kg) against a long ITI challenge. The long ITI challenge is designed to elevate PREM and PSV responses and so provide a means to examine the effect of both test articles on measures of impulsive and compulsive action.Materials

[0143] Vehicle ControlDosage form: 0.3% Tween 80 in 0.9% SalinePretreatment time: 180 minutes

[0144] Compound 1Dosage form: Compound 1 was suspended in 0.3% Tween 80 in 0.9% saline and sonicated. Drug was administered at a volume of 5 mL / kg, oral (PO) route.Pretreatment time: 180 minutesDoses tested: Phase 1: 1, 3, 10 mg / kg; Phase 2: 1, 3 mg / kg

[0145] Subjects: 24 male Long Evans rats

[0146] Housing and Management of Test System:_Following a one-week period of familiarization to the test facility, animals were placed on a restricted diet regimen, in which they were fed approximately 20 g of standard laboratory chow once per day (corresponding to -80% of normal food consumption) following the completion of study procedures (between 16:0011 and 18:0011). Overall food intake was therefore based on food earned during 5-choice training / testing and chow at the end of each study day. On days where no training / testing occurred, the daily allotted lab chow was increased to approximately 24 g per animal. Water was available ad libitum except during the 5-choice training / testing sessions. Animals were maintained on a 12h / 12h light / dark cycle with all testing conducted during the animals’ light cycle.

[0147] 5-choice serial reaction time task: 5-choice operant chambers were housed in sound-insulated and ventilated enclosures. Chambers consisted of an aluminum enclosure (25 x 30 cm), containing a reward magazine attached to a food pellet dispenser and house light on one wall, and on the opposite wall an array of 5 square niches (2.5 x 2.5 x 2.5 cm) arranged on a curved panel and raised 2.5 cm from the grid floor. An LED was positioned at the rear of each niche. Each niche and the reward magazine also contained a photocell to detect head entry. Test chambers were controlled by software.

[0148] The 5-CSRTT schedule began with the illumination of the house light and delivery of a food pellet. A nose-poke into the magazine tray initiated the first trial which consisted of an inter-trial interval (ITI, 5 s) followed by the random illumination of one of the 5 lights for a fixed interval (stimulus duration, SD). If a nose-poke was registered in the illuminated niche before the end of either the SD, or a fixed interval after this period (limited hold, LH) a further pellet was dispensed and a Correct Trial registered. An incorrect nose poke (Incorrect Trial) or failure to respond within the allotted time (Missed Trial) resulted in a Time Out (TO) period in which the house light was extinguished for 5s. Responding into one of the five niches during the ITI (PREM response), resulted in a further TO. PSV responses were not punished by a TO.

[0149] Each session ran for either 100 trials or 60 min, depending on which session endpoint was achieved first. Animals were trained via a series of steps to final test conditions of 0.75s SD, 5s ITI, 5s limited hold. Target performance was stable performance around a threshold of 80% correct ([correct / (correct + incorrect)] *100) and <20% omissions for at least a two week period. At this point drug testing began accordingto a repeated measures design with animals receiving treatment over repeated test sessions. Test sessions were run twice weekly under the standard (5s ITI) and long ITI schedule to allow drug washout and to re-baseline subjects between cycles.

[0150] Phase 1: The effect of Compound 1 (1, 3, 10 mg / kg) or vehicle control was investigated on test performance under standard test conditions of: 0.75s SD, 5s ITI, 5s LH, 100 trials total. Treatments were administered in a randomized sequence.

[0151] Phase 2: The effect of Compound 1 (1 and 3 mg / kg) or vehicle control was investigated in a 10s ITI 5-choice schedule (10s ITI, 0.3s SD, 5s LH, 100 trials). Treatments were administered in a randomized sequence.Statistical Analyses

[0152] Primary measures of performance from the 5-CSRTT, i.e. accuracy measured either as % correct ([# correct / # correct + # incorrect] *100) or % hit ([# correct / # correct + # incorrect + # omissions] * 100), speed of responding (correct latency), incomplete trials (omissions) and total # trials are expressed as means and SEM.Results

[0153] Phase 1: Effect of Compound 1 on 5-choice task performance: Standard Conditions: Compound 1 was tested at doses 1, 3, and 10 mg / kg in all rats at each dose according to a repeated measures design. A vehicle pretreated group served as control. Main effects of treatment were found for total trials (F3,69=4.4; P<0.01), PREM responses (F3,69=5.1; P<0.01) and PSV responses (F3,69=4.6; P<0.01). These main effects reflected a dose-related decrease in PREM and PSV responses following Compound 1 pretreatment relative to vehicle control. Additionally, trial number was decreased at the 10 mg / kg dose. There were no main effects of treatment on any other task measure including accuracy. 5-CSRTT results obtained under standard test conditions (0.75 sec. stimulus duration, 5 sec. ITI, 100 trials) are shown in FIGS.10A-10C.

[0154] Phase 2: Effect of Compound 1 on 5-choice task performance: 10s ITI: Compound 1 was tested at doses 1 and 3 mg / kg in all rats at each dose according to a repeated measures design under the 10s ITI schedule. A vehicle pretreated group served as control. Increasing the ITI from 5s to 10s, and duration of the visual stimulus from 0.75s to 0.3s,reduced accuracy (% correct; 5s ITI: 83.9+1.5%; 10s ITI: 68.5+2.4%; P<0.01) and increased both PREM (5s ITI: 6.0+1.2; 10s ITI: 46.7+10.2; P<0.01) and PSV (5s ITI: 20.9+3.4; 10s ITI: 33.8+7.4; P<0.05) responses. The effect of Compound 1 on task performance under the 10s ITI schedule was evaluated against vehicle pretreatment under the same condition. There were no main effects of treatment on any measure (F2,40<2.5; NS), i.e., no effects of treatment on accuracy (% correct, % hit) or on PREM / PSV responses when all N=21 rats were included in the analysis. Subsequently the rats were sub-grouped into low impulsive (LI) and high impulsive (HI) based on the level of PREM responses made following vehicle pretreatment under the 10s ITI schedule, i.e., PREM: LI: 16.7+2.4; HI: 93.9+21.6; P<0.01). This subgrouping resulted in main effects of subgroup on PREM (Fl, 12=8.0; P=0.02), and PSV responses (Fl, 12=8.3; P=0.01), reflecting the HI rats to have significantly higher PREM and PSV responses relative to their LI counterparts. In terms of the effect of Compound 1 on task performance in these subgroups, main effects of treatment and subgroup x treatment interactions were noted for both PREM (treatment: F2, 24=6.7; P<0.01; subgroup x treatment: F2, 24=10.2; P<0.01) and PSV responses (treatment: F2,24=4.2; P=0.02; subgroup x treatment: F2,24=7.7; P<0.01). This reflected an effect of NOE- 115 at both 1 and 3 mg / kg doses to selectively reduce both PREM and PSV responses in the HI subgroup.OTHER EMBODIMENTSVarious modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the disclosure. Other embodiments are in the claims.

Claims

CLAIMS1. A method of treating or preventing a behavioral immuno-metabolic cluster (BIMC) condition or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a triple reuptake inhibitor (TRI).

2. The method of claim 1, wherein the treating or preventing comprises: a) reducing one or more symptoms of the BIMC condition or disorder in the subject; and / or b) modulating an immune response in the subject.

3. The method of claim 1 or 2, wherein the subject exhibits one or more symptoms associated with a neurological condition.

4. The method of claim 3, wherein the subject exhibits one or more psychological symptoms associated with a neurological condition.

5. The method of claim 4, wherein the one or more psychological symptoms is selected from the group consisting of: a) mood reactivity; b) low mood; c) low self-esteem; d) leaden paralysis; e) long-standing pattern of interpersonal rejection sensitivity resulting in significant social or occupational impairment; f) fatigue; g) malaise; h) lethargy; i) anhedonia; j) rumination; k) irritability; l) low libido; and m) suicidal ideation.

6. The method of any one of claims 3-5, wherein the subject exhibits one or more behavioral symptoms associated with a neurological condition.

7. The method of claim 6, wherein the subject exhibits one or more behavioral symptoms selected from the group consisting of: a) increased sleep; b) hypersomnia; c) binge eating not associated with the regular use of inappropriate compensatory behaviors; d) binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa; e) recurrent inappropriate compensatory behaviors; f) recurrent episodes of binge eating; g) hyperphagia; h) self-reproach following eating; i) distress during eating; j) impaired impulse control; k) low appetite; l) hypophagia; m) intense fear of gaining weight; and n) body dysphoria.

8. The method of any one of claims 3-7, wherein the subject exhibits one or more cognitive symptoms associated with a neurological condition.

9. The method of claim 8, wherein the one or more cognitive symptoms is selected from the group consisting of: a) impairment of memory; b) impairment of attention; c) impairment of concentration; d) impairment of language;e) impairment of learning; f) impairment of perception; g) impairment of reasoning; h) executive dysfunction; i) psychomotor impairment; j) impaired processing speed; and k) disorder of thought.

10. The method of any one of claims 1-9, wherein the subject exhibits one or more symptoms associated with a metabolic condition.

11. The method of claim 10, wherein the one or more symptoms associated with a metabolic condition is selected from the group consisting of: a) hypertension; b) hyperglycemia; c) insulin resistance; d) leptin resistance; e) prediabetes; f) hypercholesterolemia; g) hypertriglyceridemia; h) low serum levels of high-density lipoprotein (HDL); i) abdominal obesity; j) hyperuricemia; k) gastrointestinal dysregulation; and l) hepatic dysfunction.

12. The method of any one of claims 1-11, wherein the subject exhibits one or more symptoms associated with an immune condition.

13. The method of claim 12, wherein the one or more symptoms associated with an immune condition is selected from the group consisting of: a) joint pain, stiffness, or swelling due to inflammation; b) recurrent infections;c) gastrointestinal dysregulation; d) anemia; e) rash f) cold extremities; g) dry eyes; h) fatigue; i) fever; and j) headache.

14. A method of modulating an immune response in a subject having or at risk of developing a BIMC condition or disorder, the method comprising administering to the subject a therapeutically effective amount of a TRI.

15. The method of claim 14, wherein modulating an immune response in the subject comprises reducing a blood level of one or more pro-inflammatory mediators associated with the BIMC condition or disorder in the subject as compared to a blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI.

16. The method of claim 15, wherein the one or more pro-inflammatory mediators associated with the BIMC condition or disorder includes one or more of TNFa, IFNa, sTNFR2, IL-ip, IL- IRA, IL-6, IL-2R, IL- 18, IL- 12, CCL2, CRP, and MIF, or any combination thereof.

17. The method of claim 15 or 16, wherein the one or more pro-inflammatory mediators associated with the BIMC condition or disorder is TNFa.

18. The method of any one of claims 15-17, wherein the blood level of the one or more pro- inflammatory mediators associated with the BIMC condition or disorder is reduced in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more following treatment with the TRI, as compared to a blood level of the one or more pro-inflammatory mediators in the subject prior to administration of the TRI.

19. The method of any one of claims 14-18, wherein, prior to treatment, the patient has been identified as exhibiting an increased level of one or more pro-inflammatory mediators associated with the BIMC.

20. The method of any one of claims 14-19, further comprising measuring a level of one or more pro-inflammatory mediators associated with the BIMC condition or disorder prior to, concurrently with, and / or after administration of the TRI.

21. The method of any one of claims 14-20, wherein modulating an immune response in the subject comprises increasing a blood level of one or more anti-inflammatory mediators associated with the BIMC condition or disorder in the subject as compared to a blood level of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI.

22. The method of claim 21, wherein the one or more anti-inflammatory mediators associated with the BIMC condition or disorder includes one or more of IL-10, IL-4, IL-13, TGFp, adiponectin, or any combination thereof.

23. The method of claim 21 or 22, wherein the blood level of the one or more antiinflammatory mediators associated with the BIMC condition or disorder is increased in the subject by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 120%, 140%, 160%, 180%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or more following treatment with the TRI, as compared to a blood level of the one or more anti-inflammatory mediators in the subject prior to administration of the TRI.

24. The method of any one of claims 14-23, wherein, prior to treatment, the patient has been identified as exhibiting an decreased level of one or more anti-inflammatory mediators associated with the BIMC.

25. The method of any one of claims 14-24, further comprising measuring a level of one or more anti-inflammatory mediators associated with the BIMC condition or disorder prior to, concurrently with, and / or after administration of the TRI.

26. The method of any one of claims 15-25, wherein the blood level of one or more pro- inflammatory mediators or anti-inflammatory mediators is measured at least 1 hour (hr), 2 hrs, 3 hrs, 3 hrs, 4 hrs, 5 hrs, 6, hrs, 7 hrs, 8 hrs, 9, hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 23 hrs, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more, prior to and / or following treatment of the subject with the TRI.

27. The method of any one of claims 15-26, wherein the blood level is a whole blood level, plasma level, or serum level.

28. A method of modulating immune cell activity in a subject having or at risk of developing a BIMC condition or disorder, the method comprising administering to the subject a therapeutically effective amount of a TRI.

29. A method of treating metabolic dysregulation in a subject having or at risk of developing a BIMC condition or disorder, the method comprising administering to the subject a therapeutically effective amount of a TRI.

30. A method of treating or preventing neuroinflammation in the central nervous system of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a TRI.

31. The method of claim 30, wherein the treating or preventing comprises one or more of the following: a) modulating immune cell activity in the subject; and / or b) reducing one or more symptoms of the BIMC in the subject.

32. The method of claim 30 or 31, wherein the immune cell activity comprises cytokine production, migration, proliferation, recruitment, differentiation, activation, polarization, reactive oxygen species (ROS) production, degranulation, maturation, ADCC, ADCP, antigen presentation, lymph node homing, or lymph node egress.

33. The method of any one of claims 30-32, wherein the neuroinflammation is a result of an aseptic insult, infection, aging, toxic metabolites, or an autoimmune response.

34. The method of any one of claims 30-33, wherein the neuroinflammation is in the brain of the subject.

35. The method of any one of claims 30-34, wherein the neuroinflammation is in the spinal cord of the subject.

36. The method of any one of claims 1-35, wherein the TRI is Compound 1:or a pharmaceutically acceptable salt thereof.

37. The method of any one of claims 1-36, wherein the subject has been identified as exhibiting one or more symptoms of the BIMC condition or disorder.

38. The method of any one of claims 1-37, wherein the subject has one or more symptoms of the BIMC disorder or condition that is secondary to a primary immune disorder.

39. The method of any one of claims 1-38, wherein the method comprises identifying the presence of one or more symptoms of the BIMC condition or disorder in the subject.

40. The method of any one of claims 1-39, wherein the subject is refractory to prior treatment with one or more therapeutic agents other than the TRI to treat the BIMC condition or disorder.

41. The method of any one of claims 1-39, wherein the subject has not received any prior treatment for the BIMC condition or disorder.

42. The method of any one of claims 1-41, wherein the therapeutically effective amount is between 1 mg per day and 30 mg per day.

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