CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63/143,556, filed on January 29, 2021, and U.S. Application No. 63/236,061, filed on August 23, 2021, the contents of both of which are incorporated herein by reference in their entireties.

BACKGROUND

[0001] Anxiety disorders such as generalized anxiety disorder (GAD), seasonal affective disorder (SAD), depression, and panic disorder are the most common mental health concern in the United States today. See, e.g., Bystritsky, A. (2006) Molecular Psychiatry 11(9): 805- 814; Buigues and Vallego (1987) The Journal of Clinical Psychiatry 48(2): 55-59; Blanco et al. (2003) Depression and Anxiety 18(1): 29-40. Over 19% of adults in the United States have an anxiety disorder, and approximately 7% of children aged 3-17 experience issues with anxiety each year. Most people develop symptoms before age 21. Anxiety disorders are a group of related conditions with unique symptoms; however, all anxiety disorders have one thing in common: persistent, excessive fear or worry in situations that are not threatening. Typically, individuals experience one or more of the following symptoms: feelings of apprehension or dread, feeling tense or jumpy, restlessness or irritability, anticipating the worst and being watchful for signs of danger, pounding or racing heart and shortness of breath, sweating, tremors, twitches, headaches, fatigue, insomnia, upset stomach, frequent urination, and diarrhea.

[0002] Depression is among the most disabling of all medical disorders, with a lifetime prevalence of approximately 17%. It frequently appears early in life, can run a chronic course, and can adversely affect the prognosis of other medical illnesses, such as coronary vascular disease, diabetes, and osteoporosis. Depression is characterized by a depressed mood, and markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, and suicidal ideation or suicidal attempts. Depression can vary in severity from mild to very severe. It is most often episodic but can be recurrent or chronic. Some people have only a single episode, with a full return to premorbid function. Failures of first treatments are common and, more than 50 percent of those who initially suffer a single major depressive episode eventually develop another.

[0003] Current treatment options for depression include monotherapy or combination therapy with various classes of drugs such as, for example, serotonin specific reuptake inhibitors (SSRIs), serotonin noradrenergic reuptake inhibitors (SNRIs), norepinephrinedopamine reuptake inhibitors (NDRIs), mono-amine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), anti-psychotics, “natural products” (e.g, Kava-Kava, St. John's Wort), dietary supplement (e.g, s-adenosylmethionine), and others. Unfortunately, in the clinic, 40-50% of depressed patients who are initially prescribed antidepressant therapy do not experience a timely remission of depression symptoms. This group typifies level 1 treatment-resistant depression, which is characterized by a failure to demonstrate an “adequate” response to an “adequate” treatment trial (that is, sufficient intensity of treatment for sufficient duration). Moreover, about approximately 30% of depressed patients remain partially or totally treatment-resistant to at least two antidepressant treatments including combination treatments. TRD is characterized with low remission rates and partial response to treatment, often requiring a changing combination of several drugs to improve short- or medium-term response. Some TRD patients resort to Transcranial Magnetic Stimulation (TMS), which enhances response in about 30% of subjects, and Electroconvulsive Therapy (ECT), which produces response in about 50% of TRD patients with relapse probability increasing with time and reaching approximately 50% within a year. Both TMS and ECT require concurrent continuous use of “maintenance” anti-depressant medication. More recently, ketamine has been used as an anti-depressant treatment. The FDA approved esketamine treatment has a rapid response that is particularly useful for acutely suicidal patients, although clinical trials of esketamine have shown a minimal improvement in depression rating scales compared to placebo.

[0004] The vast majority of antidepressants manipulate monoamine neurotransmitters, particularly serotonin and norepinephrine, and, sometimes, dopamine. However, newer research has suggested a role for the inhibitory neurotransmitter GABA (gamma- aminobutyric acid) in treating both anxiety and depression. See, e.g, Matveychuk et al. (2013) Journal of Neural Transmission 120(6): 987-996.

[0005] Accordingly, there remains a need for compositions and methods for treating psychological disorders such as severe anxiety disorders, and, in particular, for treating generalized anxiety disorder, panic disorder, seasonal affective disorder, and treatmentresistant depression. These needs and others are met by the present invention. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to methods for treating psychological disorders such as, for example, severe anxiety disorders (e.g., generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder (SAD), depression, treatment-resistant depression, depression with severe anxiety, and bipolar disorder with severe anxiety) and obsessive-compulsive disorder (OCD) using phenylethylidenehydrazine (PEH) or a pharmaceutically acceptable salt or prodrug thereof, a GABA transaminase enzyme inhibitor, in combination with an antidepressant, compositions comprising PEH or a salt or prodrug thereof and an antidepressant, and methods of making and using same. Without wishing to be bound by theory, the disclosed methods introduce a treatment that potentiates levels of monoamine neurotransmitters, as well as GABA levels, which beneficially enhances the effectiveness of anti-depressant therapy, while also simultaneously treating concomitant anxiety symptoms.

[0007] Thus, disclosed are methods for treating a psychological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of phenylethylidenehydrazine (PEH) or a pharmaceutically acceptable salt thereof, and an antidepressant.

[0008] Also disclosed are methods for treating a psychological disorder in a subject, the method comprising administering to the subject an effective amount of PEH or a pharmaceutically acceptable salt thereof, and a 5HTIA receptor agonist.

[0009] Also disclosed are methods for treating treatment-resistant depression in a human subject in need thereof, the method comprising orally administering to the subject an effective amount of PEH or a pharmaceutically acceptable salt thereof, and an antidepressant, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step.

[0010] Also disclosed are methods for treating treatment-resistant depression in a human subject in need thereof, the method comprising orally administering to the subject an effective amount of PEH or a pharmaceutically acceptable salt thereof, and a 5HTIA receptor agonist, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step.

[0011] Also disclosed are pharmaceutical compositions comprising PEH or a pharmaceutically acceptable salt thereof, an antidepressant, and a pharmaceutically acceptable carrier, wherein at least one of PEH or the pharmaceutically acceptable salt thereof and the antidepressant is present in a therapeutically effective amount, or wherein PEH or the pharmaceutically acceptable salt thereof and the antidepressant are together present in a therapeutically effective amount.

[0012] Also disclosed are pharmaceutical compositions comprising PEH or a pharmaceutically acceptable salt thereof, a 5HTIA receptor agonist, and a pharmaceutically acceptable carrier, wherein at least one of PEH or the pharmaceutically acceptable salt thereof and the 5HTIA receptor agonist is present in a therapeutically effective amount, or wherein PEH or the pharmaceutically acceptable salt thereof and the 5HTIA receptor agonist are together present in a therapeutically effective amount.

[0013] Also disclosed are kits comprising PEH or a pharmaceutically acceptable salt thereof, and an antidepressant, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder.

[0014] Also disclosed are kits comprising PEH or a pharmaceutically acceptable salt thereof, and a 5HTIA receptor agonist, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder.

[0015] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention. [0017] FIG. 1 shows representative data illustrating the average systolic blood pressure (SBP) increase observed when taking a variety of drugs with 40 mg of tyramine taken with a meal.

[0018] FIG. 2 shows representative data illustrating that a postural drop in SBP is highly correlated with TCP plasma concentration.

[0019] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

[0020] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0021] Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0022] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. [0023] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. DEFINITIONS

[0024] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an antidepressant,” “a psychological disorder,” or “a subject” includes mixtures of two or more such antidepressants, psychological disorders, or subjects, and the like.

[0025] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0026] Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0027] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0028] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0029] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0030] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0031] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0032] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g, a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g, cats, dogs, etc.), livestock (e.g, cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g, mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0033] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed. [0034] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. [0035] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0036] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0037] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0038] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0039] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0040] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14 ^th edition), the Physicians' Desk Reference (64 ^th edition), and The Pharmacological Basis of Therapeutics (12 ^th edition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g, doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0041] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0042] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g, PEH) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0043] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

B. METHODS FOR TREATING A PSYCHOLOGICAL DISORDER

[0044] Phenelzine (PLZ) is a potent irreversible, non-selective monoamine oxidase inhibitor (MAOI). It is used clinically for the treatment of a number of psychiatric disorders, including major depression (McGrath, et al. 1986), atypical depression (Paykel, et al. 1982), and social anxiety disorder (Liebowitz, et al. 1988). Interestingly, PLZ is also an inhibitor of y-aminobutyric acid (GABA) and alanine (ALA), presumably due to its inhibition of GABA transaminase and ALA transaminase, respectively ((Popov and Matthies (1969) J Neurochem 16(3): 899-907; Paslawski, et al. (1995) Prog Brain Res 106: 181-186). It has been suggested that a metabolite of PLZ formed by the action of monoamine oxidase (MAO) is primarily responsible for these beneficial effects, since PLZ-induced increases in GABA and ALA can be abolished by pre-treating the animals with another MAO inhibitor (Popov and Matthies (1969; Todd and Baker (1995) J Affect Disord 35: 125-129; MacKenzie, et al. (2009) “Neurochemical and neuroprotective aspects of phenelzine and its active metabolite [3- phenylethylidenehydrazine,” University of Alberta, Dissertation). This metabolite has since been identified as PEH (MacKenzie (2009)).

[0045] The structures of PLZ and PEH, and prodrugs thereof, are shown below.

PLZ Prodrug PEH Prodrug

[0046] As would be understood by one of ordinary skill in the art, the disclosed prodrugs would be present with a counterion. Exemplary counterions are well-known by those of ordinary skill in the art, and include, but are not limited to, halogen, acetate, alginate, ascorbate, benzoate, carbonate, cinnamate, citrate, diphosphate, fumarate, gluconate, lactate, laurate, malate, maleate, mesylate, myristate, nitrate, palmitate, phosphate, propionate, sorbate, succinate, sulfate, tartrate, and a conjugate base of a phenolic acid. Thus, in various aspects, a PLZ prodrug and a PEH prodrug can be present as follows:

PLZ Prodrug PEH Prodrug in which X is a counterion, such as, for example, halogen, acetate, alginate, ascorbate, benzoate, carbonate, cinnamate, citrate, diphosphate, fumarate, gluconate, lactate, laurate, malate, maleate, mesylate, myristate, nitrate, palmitate, phosphate, propionate, sorbate, succinate, sulfate, tartrate, and a conjugate base of a phenolic acid.

[0047] Although PEH and PLZ share many pharmacological properties, an important distinction is that PEH is only a weak and transient inhibitor of MAO-A and MAO-B (Paslawski, et al. (2001) Drug Dev Res 54: 35-39; MacKenzie, et al. (2008) BioorgMed Chem 16(17): 8254-8263). A major drawback to clinical use of PLZ is a potential interaction with tyramine-containing foods such as aged cheeses and meats, overripe fruits and vegetables, and fermented beverages. By irreversibly inhibiting MAO-A in the gut, PLZ prevents the metabolism of dietary tyramine, a sympathomimetic agent, which can then enter the bloodstream and cause unpleasant symptoms ranging from headache to hypertensive crisis. Notably, because PEH is a poor inhibitor of MAO-A, it should not be associated with this adverse effect.

[0048] Without wishing to be bound by theory, it is expected that the combination of PEH or a pharmaceutically acceptable salt or prodrug thereof and an antidepressant such as, for example, a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), or a 5HTIA receptor agonist, can beneficially be useful for treating psychological disorders via two distinct mechanisms (e.g. , potentiation of both GABA and serotonin), and, in some aspects, can result in a synergistic effect. This combination is advantageous in that neither of these drugs is suspected of having long-term side effects, leading to addiction, or generating tolerance. Further, as detailed above, administration of PEH, specifically, avoids the negative interactions triggered by tyramine-rich foods, while also still maintaining the beneficial effects on GABA.

[0049] Thus, in one aspect, disclosed are methods for treating a psychological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of PEH or a pharmaceutically acceptable salt thereof, and an antidepressant. In a further aspect, the pharmaceutically acceptable salt is a compound having a structure: wherein X is a counterion. Exemplary counterions include, but are not limited to, halogen, acetate, alginate, ascorbate, benzoate, carbonate, cinnamate, citrate, diphosphate, fumarate, gluconate, lactate, laurate, malate, maleate, mesylate, myristate, nitrate, palmitate, phosphate, propionate, sorbate, succinate, sulfate, tartrate, and a conjugate base of a phenolic acid. In a still further aspect, the pharmaceutically acceptable salt is a Lewis acid-base adduct. In yet a further aspect, the Lewis acid-base adduct is a compound having a structure represented by a formula: wherein X’ is a residue of a Lewis acid such as, for example, a non-Bronsted acid. Examples of residues of Lewis acids include, but are not limited to, -BF3 and -A1CL.

[0050] In one aspect, disclosed are methods for treating a psychological disorder in a subject, the method comprising administering to the subject an effect amount of a compound having a structure: and an antidepressant. In one aspect, disclosed are methods for treating a psychological disorder in a subject, the method comprising administering to the subject an effective amount of the compound and a 5HTIA receptor agonist.

[0051] In one aspect, disclosed are methods for treating a psychological disorder in a subject, the method comprising administering to the subject an effective amount of PEH and an antidepressant. In one aspect, disclosed are methods for treating a psychological disorder in a subject, the method comprising administering to the subject an effective amount of PEH and a 5HTIA receptor agonist.

[0052] In one aspect, disclosed are methods for treating treatment-resistant depression in a human subject, the method comprising orally administering to the subject an effective amount of a compound having a structure: and an antidepressant, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step. In one aspect, disclosed are methods for treating treatment-resistant depression in a human subject, the method comprising orally administering to the subject an effective amount of the compound and a 5HTIA receptor agonist, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step.

[0053] In one aspect, disclosed are methods for treating treatment-resistant depression in a human subject, the method comprising orally administering to the subject an effective amount of PEH and an antidepressant, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step. In one aspect, disclosed are methods for treating treatment-resistant depression in a human subject, the method comprising orally administering to the subject an effective amount of PEH and a 5HTIA receptor agonist, wherein the subject has not responded to at least one adequate antidepressant treatment prior to the administering step.

[0054]

[0055] In some aspects, the method comprises administering a pharmaceutical composition comprising an effective amount of the compound. In a further aspect, the method comprises administering a pharmaceutical composition comprising an effective amount of the compound and the antidepressant. In a still further aspect, the method comprises administering a pharmaceutical composition comprising an effective amount of the compound and a 5HTIA receptor agonist.

[0056] In some aspects, the method comprises administering a pharmaceutical composition comprising an effective amount of PEH. In a further aspect, the method comprises administering a pharmaceutical composition comprising an effective amount of PEH and the antidepressant. In a still further aspect, the method comprises administering a pharmaceutical composition comprising an effective amount of PEH and a 5HTIA receptor agonist.

[0057] In some aspects, the method comprises administering a single dose of the compound. In a further aspect, the method comprises administering multiple doses of the compound.

[0058] In some aspects, the method comprises administering a single dose of PEH. In a further aspect, the method comprises administering multiple doses of PEH.

[0059] In some aspects, a single administration of the compound is sufficient to alleviate symptoms of the psychological disorder for a period of at least 4 hours, at least 6 hours, at least 8 hours, or at least 10 hours.

[0060] In some aspects, a single administration of PEH is sufficient to alleviate symptoms of the psychological disorder for a period of at least 4 hours, at least 6 hours, at least 8 hours, or at least 10 hours.

[0061] In some aspects, the compound and the antidepressant are administered sequentially. In a further aspect, the compound is administered prior to administration of the antidepressant. In a still further aspect, the compound is administered subsequent to administration of the antidepressant. [0062] In some aspects, PEH and the antidepressant are administered sequentially. In a further aspect, PEH is administered prior to administration of the antidepressant. In a still further aspect, PEH is administered subsequent to administration of the antidepressant.

[0063] In some aspects, the compound and the antidepressant are administered simultaneously.

[0064] In some aspects, PEH and the antidepressant are administered simultaneously.

[0065] To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a psychiatric disorder, such as depression.

[0066] Thus, in some aspects, the subject is a mammal. In a further aspect, the mammal is a human.

[0067] In some aspects, the subject has been diagnosed as having the psychological disorder prior to the administering step. In a further aspect, the subject has not been diagnosed as having a seizure disorder, a developmental disorder, a neurological disorder, a behavioral disorder, or addiction prior to the administering step. In a still further aspect, the subject has not been diagnosed as having a disorder associated with depression (i.e., a disorder that is a comorbidity with depression) such as, for example, addiction, a substance use disorder (e.g., alcohol use disorder, nicotine use disorder), a personality disorder (e.g, borderline personality disorder), post-traumatic stress disorder, and obsessive-compulsive disorder.

[0068] In some aspects, the method further comprises identifying a subject in need of treatment of a psychological disorder.

[0069] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of an infection or condition, such as a psychiatric disorder.

[0070] In some aspects, the compound and the antidepressant are together present in an effective amount. In a further aspect, the compound and the antidepressant are each present in individually effective amounts. In a still further aspect, the compound is present in an individually effective amount. In yet a further aspect, the antidepressant is present in an individually effective amount.

[0071] In some aspects, PEH and the antidepressant are together present in an effective amount. In a further aspect, PEH and the antidepressant are each present in individually effective amounts. In a still further aspect, PEH is present in an individually effective amount. In yet a further aspect, the antidepressant is present in an individually effective amount.

[0072] In some aspects, the effective amount is a prophylactically effective amount. In a further aspect, the effective amount is a therapeutically effective amount.

[0073] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 1000 mg, preferably from about 20 mg to about 800 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. [0074] In some aspects, the compound is formulated as an oral dosage form. In a further aspect, the antidepressant is formulated as an oral dosage form. In a still further aspect, the compound and the antidepressant are administered as a single dosage form. In yet a further aspect, the compound and the antidepressant are orally administered as a single dosage form. [0075] In some aspects, PEH is formulated as an oral dosage form. In a further aspect, the antidepressant is formulated as an oral dosage form. In a still further aspect, PEH and the antidepressant are administered as a single dosage form. In yet a further aspect, PEH and the antidepressant are orally administered as a single dosage form. [0076] In some aspects, the compound is administered at a dose of from about 0.5 mg/kg/day to about 3 mg/kg/day, about 0.5 mg/kg/day to about 2.5 mg/kg/day, about 0.5 mg/kg/day to about 2 mg/kg/day, about 0.5 mg/kg/day to about 1.5 mg/kg/day, about 0.5 mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 3 mg/kg/day, about 1.5 mg/kg/day to about 3 mg/kg/day, about 2 mg/kg/day to about 3 mg/kg/day, about 2.5 mg/kg/day to about 3 mg/kg/day, about 1 mg/kg/day to about 2.5 mg/kg/day, or about 1.5 mg/kg/day to about 2 mg/kg/day.

[0077] In some aspects, PEH is administered at a dose of from about 0.5 mg/kg/day to about 3 mg/kg/day, about 0.5 mg/kg/day to about 2.5 mg/kg/day, about 0.5 mg/kg/day to about 2 mg/kg/day, about 0.5 mg/kg/day to about 1.5 mg/kg/day, about 0.5 mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 3 mg/kg/day, about 1.5 mg/kg/day to about 3 mg/kg/day, about 2 mg/kg/day to about 3 mg/kg/day, about 2.5 mg/kg/day to about 3 mg/kg/day, about 1 mg/kg/day to about 2.5 mg/kg/day, or about 1.5 mg/kg/day to about 2 mg/kg/day.

[0078] In some aspects, the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), or buspirone.

[0079] Thus, in various aspects, the antidepressant is a SSRI. Examples of SSRIs include, but are not limited to, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine.

[0080] In various aspects, the antidepressant is a SNRI. Examples of SNRIs include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine.

[0081] In various aspects, the antidepressant is a TCA. Examples of TCAs include, but are not limited to, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine.

[0082] In various aspects, the antidepressant is a 5HTIA receptor agonist . Examples of 5HTIA receptor agonists include, but are not limited to, buspirone, trazodone, nefazodone, vortioxetine, flibanserin, etappirone, lesopitron, alnespirone, repinotan, and gepirone. In a further aspect, the 5HTIA receptor agonist is buspirone.

[0083] In some aspects, the psychological disorder is a severe anxiety disorder. Examples of severe anxiety disorders include, but are not limited to generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder (SAD), depression, depression with severe anxiety, and bipolar disorder with severe anxiety. [0084] In some aspects, the psychological disorder is obsessive-compulsive disorder (OCD).

[0085] In some aspects, the psychological disorder is depression. In a further aspect, depression is treatment-resistant depression.

[0086] In some aspects, the subject has not responded to at least one adequate antidepressant treatment prior to the administering step. Examples of adequate antidepressant treatments include, but are not limited to, administration of bupropion, a monoamine oxidase inhibitor, a SNRI, a SSRI, a TCA, nefazodone, trazodone, pramipexole, mirtazapine, or vortioxetin. In a further aspect, the adequate treatment comprises administration of an agent selected from the group consisting of a SSRI, a SNRI, a TCA, a MAOI, and a 5HTIA receptor agonist.

[0087] In some aspects, the subject has not responded to at least two adequate antidepressant treatments prior to the administering step. In a further aspect, the two adequate antidepressant treatments comprise treatments with agents from two different classes of antidepressants.

C. PHARMACEUTICAL COMPOSITIONS COMPRISING PEH AND AN ANTIDEPRESSANT

[0088] In one aspect, disclosed are pharmaceutical compositions comprising a compound having a structure: an antidepressant, and a pharmaceutically acceptable carrier, wherein at least one of the compound and the antidepressant is present in a therapeutically effective amount, or wherein the compound and the antidepressant are together present in a therapeutically effective amount. In one aspect, disclosed are pharmaceutical compositions comprising the compound, a 5HTIA receptor agonist, and a pharmaceutically acceptable carrier, wherein at least one of the compound and the 5HTIA receptor agonist is present in a therapeutically effective amount, or wherein the compound and the 5HTIA receptor agonist are together present in a therapeutically effective amount.

[0089] In one aspect, disclosed are pharmaceutical compositions comprising [3- phenylethylidenehydrazine (PEH), an antidepressant, and a pharmaceutically acceptable carrier, wherein at least one of PEH and the antidepressant is present in a therapeutically effective amount, or wherein PEH and the antidepressant are together present in a therapeutically effective amount.

[0090] In some aspects, the composition is formulated as an oral dosage form. In some aspects, the composition is formulated as a single oral dosage form.

[0091] In some aspects, the compound is present in a therapeutically effective amount. In some aspects, the antidepressant is present in a therapeutically effective amount. In a still further aspect, the compound and the antidepressant are together present in a therapeutically effective amount.

[0092] In some aspects, PEH is present in a therapeutically effective amount. In some aspects, the antidepressant is present in a therapeutically effective amount. In a still further aspect, PEH and the antidepressant are together present in a therapeutically effective amount. [0093] In some aspects, the antidepressant is a SSRI, a SNRI, a TCA, or a 5HTIA receptor agonist.

[0094] Thus, in various aspects, the antidepressant is a SSRI. Examples of SSRIs include, but are not limited to, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine.

[0095] In various aspects, the antidepressant is a SNRI. Examples of SNRIs include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine.

[0096] In various aspects, the antidepressant is a TCA. Examples of TCAs include, but are not limited to, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine.

[0097] In various aspects, the antidepressant is a 5HTIA receptor agonist. Examples of 5HTIA receptor agonists include, but are not limited to, buspirone, trazodone, nefazodone, vortioxetine, flibanserin, etappirone, lesopitron, alnespirone, repinotan, and gepirone. In a further aspect, the 5HTIA receptor agonist is buspirone.

[0098] The pharmaceutical compositions comprise the compounds in a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The compounds can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

[0099] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0100] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0101] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form should be sterile and should be effectively fluid for easy syringability. The pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0102] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0103] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0104] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0105] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0106] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0107] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. [0108] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

D. ADDITIONAL METHODS OF USING THE COMPOSITIONS

[0109] Provided are methods of using of a disclosed composition or medicament. In one aspect, the method of use is directed to the treatment of a disorder. In a further aspect, the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. [0110] The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

1. MANUFACTURE OF A MEDICAMENT

[0111] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a psychological disorder in a mammal, the method comprising combining a therapeutically effective amount of PEH and an antidepressant with a pharmaceutically acceptable carrier or diluent.

[0112] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of a psychological disorder, such as treatment resistant depression and other psychological disorders disclosed herein. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the disorder.

[0113] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining PEH, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with an antidepressant and a pharmaceutically acceptable carrier or diluent.

2. USE OF COMPOUNDS AND COMPOSITIONS

[0114] Also provided are the uses of the disclosed compounds and compositions. Thus, in one aspect, the invention relates to the uses of combination treatments for treating psychological disorders.

[0115] In a further aspect, the invention relates to the use of PEH and an antidepressant in the manufacture of a medicament for the treatment of a psychological disorder such as, for example, a severe anxiety disorder (e.g. , generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder (SAD), depression, treatment-resistant depression, depression with severe anxiety, and bipolar disorder with severe anxiety) or obsessive-compulsive disorder (OCD).

[0116] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of PEH and an antidepressant, and a pharmaceutically acceptable carrier, for use as a medicament.

[0117] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of PEH and an antidepressant, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of PEH and an antidepressant.

[0118] In various aspects, the use relates to the treatment of a psychological disorder in a vertebrate animal. In a further aspect, the use relates to the treatment of a psychological disorder in a human subject.

[0119] In a further aspect, the use is the treatment of a psychological disorder, for example, a severe anxiety disorder (e.g. , generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder (SAD), depression, treatment-resistant depression, depression with severe anxiety, and bipolar disorder with severe anxiety) or obsessive-compulsive disorder (OCD).

[0120] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or composition of a medicament for the treatment of a psychological disorder in a mammal.

[0121] In a further aspect, the invention relates to the use of a disclosed compound or composition in the manufacture of a medicament for the treatment of a psychological disorder such as, for example, a severe anxiety disorder (e.g., generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder (SAD), depression, treatment-resistant depression, depression with severe anxiety, and bipolar disorder with severe anxiety) or obsessive-compulsive disorder (OCD).

3. KITS

[0122] In one aspect, disclosed are kits comprising a compound having a structure: and an antidepressant, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder. In one aspect, disclosed are kits comprising the compound and a 5HTIA receptor agonist, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder. [0123] In one aspect, disclosed are kits comprising PEH and an antidepressant, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder. In one aspect, disclosed are kits comprising PEH and a 5HTIA receptor agonist, and one or more of: (a) a device for delivering a medicament orally; and (b) instructions for treating a psychological disorder.

[0124] In some aspects, the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), or buspirone.

[0125] Thus, in various aspects, the antidepressant is a SSRI. Examples of SSRIs include, but are not limited to, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vortioxetine. [0126] In various aspects, the antidepressant is a SNRI. Examples of SNRIs include, but are not limited to, desvenlafaxine, duloxetine, levomilnacipran, and venlafaxine.

[0127] In various aspects, the antidepressant is a TCA. Examples of TCAs include, but are not limited to, amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine.

[0128] In various aspects, the antidepressant is a 5HTIA receptor agonist. Examples of 5HTIA receptor agonists include, but are not limited to, buspirone, trazodone, nefazodone, vortioxetine, flibanserin, etappirone, lesopitron, alnespirone, repinotan, and gepirone. In a further aspect, the 5HTIA receptor agonist is buspirone.

[0129] In some aspects, the psychological disorder is a severe anxiety disorder. Examples of severe anxiety disorders include, but are not limited to generalized anxiety disorder (GAD), panic disorder, seasonal affective disorder, depression, depression with severe anxiety, and bipolar disorder with severe anxiety.

[0130] In some aspects, the psychological disorder is obsessive-compulsive disorder (OCD).

[0131] In some aspects, the psychological disorder is depression. In a further aspect, depression is treatment-resistant depression.

[0132] In some aspects, the compound and the antidepressant are co-packaged. In some aspects, the compound and the antidepressant are co-formulated.

[0133] In some aspects, PEH and the antidepressant are co-packaged. In some aspects, PEH and the antidepressant are co-formulated.

[0134] In some aspects, the compound and the antidepressant are administered sequentially. In some aspects, the compound and the antidepressant are administered simultaneously.

[0135] In some aspects, PEH and the antidepressant are administered sequentially. In some aspects, PEH and the antidepressant are administered simultaneously.

[0136] In some aspects, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the antidepressant. In a further aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of PEH and the antidepressant. In a still further aspect, the effective amount is a therapeutically effective amount. In yet a further aspect, the effective amount is a prophylactically effective amount. [0137] In some aspects, each dose of the compound and the antidepressant are coformulated. In a still further aspect, each dose of the compound and the antidepressant are copackaged.

[0138] In some aspects, each dose of PEH and the antidepressant are co-formulated. In a still further aspect, each dose of PEH and the antidepressant are co-packaged.

[0139] In some aspects, each dose of the compound and the antidepressant are administered sequentially. In a still further aspect, each dose of the compound and the antidepressant are administered simultaneously.

[0140] In some aspects, each dose of PEH and the antidepressant are administered sequentially. In a still further aspect, each dose of PEH and the antidepressant are administered simultaneously.

[0141] In some aspects, the dosage forms are formulated for oral administration, inhalation, topical administration, and/or parenteral administration. In a still further aspect, the dosage form for the compound is formulated for oral administration and the dosage form for the antidepressant is formulated for parental administration. In yet a further aspect, the dosage form for the compound is formulated for parental administration and the dosage form for the antidepressant is formulated for oral administration. In an even further aspect, the dosage form for the compound is formulated for topical administration and the dosage form for the antidepressant is formulated for parental administration. In a still further aspect, the dosage form for the compound is formulated for parental administration and the dosage form for the antidepressant is formulated for topical administration. In yet a further aspect, the dosage form for the compound is formulated for oral administration and the dosage form for the antidepressant is formulated for inhalation. In an even further aspect, the dosage form for the compound is formulated for inhalation and the dosage form for the antidepressant is formulated for oral administration. In a still further aspect, the dosage form for the compound is formulated for topical administration and the dosage form for the antidepressant is formulated for inhalation. In a yet further aspect, the dosage form for the compound is formulated for inhalation and the dosage form for the antidepressant is formulated for topical administration.

[0142] In various aspects, the dosage form for PEH is formulated for oral administration and the dosage form for the antidepressant is formulated for parental administration. In yet a further aspect, the dosage form for PEH is formulated for parental administration and the dosage form for the antidepressant is formulated for oral administration. In an even further aspect, the dosage form for PEH is formulated for topical administration and the dosage form for the antidepressant is formulated for parental administration. In a still further aspect, the dosage form for PEH is formulated for parental administration and the dosage form for the antidepressant is formulated for topical administration. In yet a further aspect, the dosage form for PEH is formulated for oral administration and the dosage form for the antidepressant is formulated for inhalation. In an even further aspect, the dosage form for PEH is formulated for inhalation and the dosage form for the antidepressant is formulated for oral administration. In a still further aspect, the dosage form for PEH is formulated for topical administration and the dosage form for the antidepressant is formulated for inhalation. In a yet further aspect, the dosage form for PEH is formulated for inhalation and the dosage form for the antidepressant is formulated for topical administration.

[0143] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

4. SUBJECTS

[0001] In various aspects, the subject of the herein disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0002] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a psychological disorder prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a. DOSAGE

[0003] Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LDso (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. Polypeptides or other compounds that exhibit large therapeutic indices are preferred.

[0004] Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agents used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (that is, the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g, at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.

[0005] The formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human. Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment. The dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.

[0006] In various aspects, the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response. Although individual needs may vary, the determination of optimal ranges for effective amounts of formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA). In general, the dosage required to provide an effective amount of a formulation, which can be adjusted by one skilled in the art, will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY). b. ROUTES OF ADMINISTRATION

[0007] Also provided are routes of administering the disclosed compounds and compositions. The compounds and compositions of the present invention can be administered by direct therapy using systemic administration and/or local administration. In various aspects, the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient. In various aspects, an individual patient's therapy may be customized, e.g, the type of agent used, the routes of administration, and the frequency of administration can be personalized. Alternatively, therapy may be performed using a standard course of treatment, e.g. , using pre-selected agents and pre-selected routes of administration and frequency of administration.

[0008] Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g, intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g, administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g. , ear drops), syrups, suspensions and emulsions; rectal administration, e.g, a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g, nasal sprays). [0009] In various aspects, the modes of administration described above may be combined in any order.

[0010] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0011] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.

[0144] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other aspects of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.