WO2018075481A1 - Compounds, compositions and methods for treating or preventing depression and other diseases - Google Patents

Abstract

The present invention provides compositions and methods for treating diseases or disorders using a therapeutically effective amount of a NMDA receptor antagonist and a therapeutically effective amount of a μ-opioid receptor antagonist. In certain embodiments, the NMDA receptor antagonist and the μ-opioid receptor antagonist are part of a single pharmaceutical composition.

Description

TITLE OF THE INVENTION

Compounds, Compositions and Methods for Treating or Preventing Depression And Other

Diseases CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Applications No.

62/408,983, filed October 17, 2016, and No. 62/444,552, filed January 10, 2017, all of which are incorporated herein by reference in their entireties. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR

DEVELOPMENT

This invention was made with government support under AA010121, AA012308, AA000261, AA014906, and AA012870 awarded by National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Major depressive disorder (MDD), also known as depression, is a mental disorder characterized by at least two weeks of continuously low mood, and often accompanied by low self-esteem, loss of interest in previously enjoyable activities, low energy, and unexplained pain. MDD negatively affects a person's social life, sleeping or eating habits, and general health, leading to suicide in about 2-7% of affected adults. Up to 60% of suicide victims had experienced MDD or another mood disorder. MDD patients are often treated with counseling and antidepressants, but unfortunately the efficacy of current

pharmacotherapy for depression is only modest.

The N-methyl-D-aspartate ("NMDA") receptor (also known as "NMDAR" or

"NMDA-R") is an ionotropic glutamate receptor and ion channel protein found in nerve cells. The NMDAR receptor is activated when glutamate and glycine (or D-serine) bind to it, and that activation triggers nonselective flow of cations through the cell membrane. The NMDA receptor plays key roles in synaptic plasticity and memory function.

The activity of the NMDA receptor is affected by certain psychoactive drugs, such as phencyclidine (PCP), alcohol (ethanol) and dextromethorphan (DXM). Antagonists of the NMDA receptor are used as anesthetics for animals and humans, and are often used as recreational drugs due to their hallucinogenic properties. For example, the anesthetic effects of ketamine and nitrous oxide are partially due to their antagonistic effects on NMDA receptor activity. Further, NMDA receptor antagonists often have unique effects, such as dissociation, at elevated dosages. Non-limiting examples of NMDA receptor antagonists are AP5 (also known as R-2-amino-5-phosphonopentanoate), CERC-301 (also known as MK- 0657 or 4-methylbenzyl (35',4i?)-3-fluoro-4-[(2-pyrimidinylamino)methyl]- l-piperidine carboxylate), conantokins, dextromethorphan, dexanabinol, diethyl ether, dizocilpine (also known as MK-801), ketamine, memantine, nitrous oxide, phencyclidine, xenon,

methoxetamine, agmatine and 4-chlorokynurenine (also known as AV-101 ; this is a prodrug of NMDA receptor antagonist 7-chlorokynurenic acid). Further, the following compounds are known to have weak NMDA receptor antagonism: amantadine, dextropropoxyphene, ethanol, guaifenisen, huperzine A, ibogaine, ketobemidone, methadone and tramadol.

NMDA receptor antagonists, including ketamine, 4-chlorokynurenine and CERC-301, are under development for the treatment of mood disorders, including major depressive disorder and treatment-resistant depression. In fact, ketamine is already employed for this purpose as an off-label therapy in some clinics.

However, the class of NMDA receptor antagonists is plagued with high abuse potential, and drug supplies are often misused as recreational drugs. Ketamine (known as K or Special K) is a widely abused substance, especially in southern Asia (for example, China, Taiwan, Hong Kong, Vietnam, and Cambodia). Some data suggest that ketamine is the third most commonly abused drug, after methamphetamine and MDMA. Ketamine abuse is associated with damage to the mucosa of the urinary bladder and nasal passages, as well as with cognitive, behavioral and emotional abnormalities, including persisting psychosis in some heavy users. Nitrous oxide (known as "whippets"), dextromethorphan (known as "Robo-tripping" or "skittling") and amantadine also are abused. The most highly abused NMDA receptor antagonist is ethanol, which produces significant occupancy of NMDA receptor at ethanol doses associated with heavy social drinking (>4 alcohol drinks).

There is thus a need in the art for novel compositions and methods that allow for the administration of NMDA receptor antagonists to subjects who can benefit from their pharmacological effects, while minimizing or eliminating abuse liability for these antagonists. The present invention addresses and meets this need.

BRIEF SUMMARY OF THE INVENTION

The invention provides a method of treating or preventing a disease in a subject, wherein the disease or disorder is treatable or preventable by administering a N-methyl-D- aspartate (NMDA) receptor antagonist to the subject. The invention further provides a method of preventing and/or minimizing abuse of a NMDA receptor antagonist by a subject. The invention further provides a method of treating or preventing major depressive disorder in a subject. The invention further provides a pharmaceutical composition comprising a NMDA receptor antagonist and a μ-opioid receptor antagonist, wherein the NMDA receptor antagonist and the μ-opioid receptor antagonist are present in amounts whereby:

administration of the pharmaceutical composition to a subject treats in the subject a disease or disorder that is treatable or preventable by the NMDA receptor antagonist; and the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the NMDA receptor antagonist and a therapeutically effective amount of a μ-opioid receptor antagonist.

In certain embodiments, the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

In certain embodiments, the subject has a comorbid addictive disease or disorder. In other embodiments, the subject does not have a comorbid addictive disease or disorder.

In certain embodiments, the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject

In certain embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are co-administered to the subject. In other embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are co-formulated as a pharmaceutical composition. In yet other embodiments, physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition is not possible and/or feasible. In yet other embodiments, physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition requires denaturation and/or destruction of the pharmaceutical composition. In yet other embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are independently administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In yet other embodiments, the pharmaceutical composition is administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In certain embodiments, the NMDA receptor antagonist is at least one selected from the group consisting of ketamine; R-ketamine; S-ketamine; nitrous oxide; memantine;

amantadine; racemic dextromethorphan; dextromethorphan; lanicemine; phencyclidine; dizocilpine; CERC-301 ; CGP 37849; 1-aminocylopropanecarboxylic acid; traxoprodil; Ro 25-6981 ; eliprodil; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

In certain embodiments, the μ-opioid receptor antagonist is at least one selected from the group consisting of naltrexone; naloxone; nalmefene; nalodeine; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

In certain embodiments, the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S-ketamine. In other embodiments, the μ-opioid receptor antagonist comprises at least one selected from the group consisting of naltrexone and naloxone. In yet other embodiments, the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S-ketamine, and the μ-opioid receptor antagonist comprises at least one selected from the group consisting of naltrexone and naloxone.

In certain embodiments, administering according to at least one method of the invention has at least one effect selected from the group consisting of reduced anxiety, reduced irritability, reduced anger, and reduced alcohol consumption.

In certain embodiments, the subject is a mammal. In other embodiments, the mammal is human.

In certain embodiments, the pharmaceutical composition is formulated for administration by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In other embodiments, the pharmaceutical composition is formulated for administration by nasal route. In yet other embodiments, the pharmaceutical composition is part of a kit further comprising an applicator, and an instructional material for use thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of illustrative embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, certain illustrative embodiments are shown in the drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

FIG. 1 is a graph that illustrates the finding that a combination of ketamine and naltrexone decreased depressive symptoms as measured by the MADRS in patients with MDD and AUD.

FIG. 2 is a graph that illustrates the finding that an exemplary method of the invention decreased anxiety, irritability, and/or anger symptoms.

FIGs. 3A-3C are a set of graphs that illustrate the finding that a combination of ketamine and naltrexone decreased anxiety, irritability, and anger symptoms as measured by the VAS in patients with MDD and AUD.

FIG. 4 is a graph that illustrates the finding that a combination of ketamine and naltrexone reduced alcohol craving and consumption as measured by the OCDS in patients with MDD and AUD.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates in part to the unexpected discovery that a subject in need of treatment for depression can be co-administrated an NMDA receptor antagonist and a μ- opioid receptor antagonist. In certain embodiments, the μ-opioid receptor antagonist reduces the abuse liability of the NMDA receptor antagonist. In other embodiments, the μ-opioid receptor antagonist increases the safety (i.e. , increases the maximum dose devoid of significant and/or undesirable side effects) of the NMDA receptor antagonist.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. As used herein, each of the following terms has the meaning associated with it in this section.

Generally, the nomenclature used herein and the laboratory procedures in molecular biology, pharmacology and organic chemistry are those well-known and commonly employed in the art.

Standard techniques are used for biochemical and/or biological manipulations. The techniques and procedures are generally performed according to conventional methods in the art and various general references (e.g. , Sambrook and Russell, 2012, Molecular Cloning, A Laboratory Approach, Cold Spring Harbor Press, Cold Spring Harbor, NY, and Ausubel et al. , 2002, Current Protocols in Molecular Biology, John Wiley & Sons, NY), which are provided throughout this document.

The articles "a" and "an" are used herein to refer to one or to more than one (/^'. e. , to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

"About" as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

A disease or disorder is "alleviated" if the severity or frequency of at least one sign or symptom of the disease or disorder experienced by a patient is reduced.

As used herein, the terms "analog," "analogue," or "derivative" are meant to refer to a chemical compound or molecule made from a parent compound or molecule by one or more chemical reactions. As such, an analog can be a structure having a structure similar to that of the small molecule inhibitors described herein or can be based on a scaffold of a small molecule inhibitor described herein, but differing from it in respect to certain components or structural makeup, which may have a similar or opposite action

metabolically.

As used herein, the term "binding" refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, antibodies to antigens, DNA strands to their complementary strands. Binding occurs because the shape and chemical nature of parts of the molecule surfaces are complementary. A common metaphor is the "lock-and-key" used to describe how enzymes fit around their substrate.

A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.

In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

An "effective amount" or "therapeutically effective amount" of a compound or composition is that amount of compound or composition that is sufficient to provide a beneficial effect to the subject to which the compound or composition is administered. An "effective amount" of a delivery vehicle is that amount sufficient to effectively bind or deliver a compound or composition.

The phrase "inhibit," as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and/or a protein's expression, stability, function or activity by a measurable amount or to prevent entirely. Inhibitors are compounds that, e.g. , bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function and activity, e.g. , antagonists.

As used herein, the term "MDD" refers to major depression disorder.

"Naturally occurring" as applied to an object refers to the fact that the object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man is a naturally-occurring sequence.

As used herein, the term "NMDA" refers to N-methyl-D-aspartate."

As used herein, the term "NMDAR" or "NMDA-R" refers to a NMDA receptor.

The terms "patient," "subject," "individual," and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human.

As used herein, the term "pharmaceutically acceptable carrier" means a

pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound or composition useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound or composition useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound or composition useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the language "pharmaceutically acceptable salt" or "therapeutically acceptable salt" refers to a salt of the administered compounds prepared from

pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof.

The terms "pharmaceutically effective amount" and "effective amount" or

"therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. The amount of a compound of the invention that constitutes a

"therapeutically effective amount" varies depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the terms "polypeptide," "protein" and "peptide" are used interchangeably and refer to a polymer composed of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof linked via peptide bonds. Synthetic polypeptides can be synthesized, for example, using an automated polypeptide synthesizer.

By the term "specifically binds," as used herein, is meant a molecule, such as an antibody, which recognizes and binds to another molecule or feature, but does not substantially recognize or bind other molecules or features in a sample.

A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

As used herein, "treating a disease or disorder" means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein.

As used herein, the term "treatment" or "treating" encompasses prophylaxis and/or therapy. Accordingly the compositions and methods of the present invention are not limited to therapeutic applications and can be used in prophylaxis ones. Thus "treating" or "treatment" of a state, disorder or condition includes: (i) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (ii) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (iii) relieving the disease, i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Description

Major depressive disorder (MDD) is the second leading cause of disease burden among all medical diseases in developed countries, and is projected to be the number one cause of burden of disease in the 2030' s worldwide. However, the efficacy of current pharmacotherapy for depression is only modest. The delay of weeks or months before the onset of antidepressant effects of traditional antidepressants is also problematic, particularly given the elevated risk for suicide in this population. NMDA receptor antagonists, such as ketamine and nitrous oxide, have demonstrated rapid and robust antidepressant effects in depressed patients. Several meta-analyses have reported that a single dose of ketamine is highly efficacious in the treatment of MDD, with a large effect size (odds ratio = 6.58-9.87). Ketamine has also shown rapid and robust anti- suicidal effects. However, there are major concerns of prescribing NMDA receptor antagonists, such as ( 1) abuse liability of NMDA receptor antagonists and (2) the inability to prescribe NMDA receptor antagonists to patients with comorbid addictive and depressive disorders. In fact, the NMDA receptor antagonist ketamine has been tested only in patients without comorbid addictive disorders. Since more than 40% of all depressed patients have alcohol or other addictive disorders in their lifetime, it is important to develop a safer ketamine-based treatment for patients with and without comorbid addictive disorders.

As demonstrated herein, with the objective of pursuing the therapeutic use of NMDA receptor antagonists further by reducing their abuse liability, the present invention provides methods for treating diseases, such as but not limited to depressive disorders, with the combination of at least one NMDA glutamate receptor antagonism and at least one μ-opioid receptor antagonism. As compared to the NMDA antagonist treatment alone, this combination treatment has several benefits, such as but not limited to (1) reducing NMDA antagonist's abuse liability and (2) treating comorbid addictive disorders in depressed patients.

Without wishing to be limited by any theory, NMDA receptor antagonists (such as, but not limited to, R/S-ketamine, R-ketamine, S-ketamine, and dextromethorphan) bind to the μ-opioid receptor directly. Such binding may contribute to the abuse liability of these substances, but the clinical efficacy of these drugs does not depend on μ-opioid receptor stimulation. Thus, in certain embodiments, by blocking μ-opioid receptors, μ-opioid receptor antagonists reduce the abuse liability of NMDA receptor antagonists without compromising their clinical efficacy.

In one aspect, the present invention provides a method for treating depressive disorders, such as but not limited to MDD, major depressive episode in bipolar disorder (bipolar depression), persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, and posttraumatic stress disorder. In certain embodiments, the subject suffering from the depressive disorder further suffers from an addictive disorder (i. e. , the subject has comorbid depressive disorder and addictive disorder).

In certain embodiments, the subject in need of such treatment is administered a combination of an NMDA receptor antagonist and a μ-opioid receptor antagonist. In other embodiments, the NMDA receptor antagonist and the μ-opioid receptor antagonist are coadministered to the subject. In yet other embodiments, the NMDA receptor antagonist and the μ-opioid receptor antagonist are coformulated. In yet other embodiments, the methods of the invention allow for reducing abuse potential of the NMDA receptor antagonist by the subject. In yet other embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are the only active agents administered to the subject.

Any NMDA receptor antagonist known in the art is contemplated within the present invention. Non-limiting examples of NMDA receptor antagonists useful within the methods of the invention include:

ketamine (also known as RS-ketamine, R/S-ketamine, or (i¾)-2-(2-Chlorophenyl)-2- (methylamino)cyclohexanone),

R-ketamine (also known as (i?)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone), S-ketamine (also known as esketamine, or (<S)-2-(2-Chlorophenyl)-2-(methylamino) cyclohexanone),

nitrous oxide,

memantine (also known as 3,5-dimethyladamantan- l-amine),

amantadine (also known as adamantan-1 -amine),

racemic dextromethorphan (also known as racemic (4b<S,8ai?,9iS)-3-Methoxy- l 1-methyl- 6,7,8, 8a,9, 10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene),

dextromethorphan,

lanicemine (also known as AZD6765, or (1<S)-1 -phenyl -2 -pyridin-2-ylemanamine), phencyclidine (also known as l-(l-phenylcyclohexyl)piperidine),

dizocilpine (also known as MK-801 or (5i?, 105)-(+)-5-methyl-10, l l-dihydro-5H- dibenzo [a,<f]cyclohepten-5 , 10-imine),

CERC-301 (also known as MK-0657, or 4-Methylbenzyl (3S,4R)-3-fluoro-4-[(2- pyrimidinylamino)methyl] - 1 -piperidinecarboxylate),

CGP 37849 (also known as (E,2R)-2-amino-4-methyl-5-phosphonopent-3-enoic acid), 1-aminocylopropanecarboxylic acid,

traxoprodil (also known as CP- 101,606, or (15^*,25)-l-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidino)- 1 -propanol), Ro 25-6981 (also known as (ai?, 5)-a-(4-Hydroxyphenyl)- -methyl-4-(phenylmethyl)-l- piperidinepropanol), and

eliprodil (also known as l-(4-chlorophenyl)-2-[4-[(4-fluorophenyl)methyl]piperidin-l- yl]ethanol),

any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

Any μ-opioid receptor antagonist known in the art is contemplated within the present invention. Non-limiting examples of μ-opioid receptor antagonists useful within the methods of the invention include:

naltrexone ( 17-(cyclopropylmethyl)-4,5a-epoxy- 3, 14-dihydroxymoφhinan-6-one), naloxone ((4R,4aS,7aR, 12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a, 13-hexahydro-

1 H-4, 12-methanobenzofuro [3 ,2-e] isoquinoline -7-one) ,

nalmefene ( 17-cyclopropylmethyl-4,5 a-epoxy-6-methylenemorphinan-3 , 14-diol), and nalodeine ((4R,4aR,7S,7aR, 12bS)-9-methoxy-3-prop-2-enyl-2,4,4a,7,7a, 13-hexahydro- 1H-4, 12-methanobenzofuro [3 ,2-e] isoquinoline-7-ol),

any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

The compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. The compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. A compound illustrated herein by the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof.

In certain embodiments, the compounds of the invention exist as tautomers. All tautomers are included within the scope of the compounds recited herein.

Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and

U 13

are not limited to H, H, C, C, C, CI, F, I, I, N, N, O, O, O, P, and S. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Salts

The compounds described herein may form salts with acids and/or bases, and such salts are included in the present invention. In certain embodiments, the salts are

pharmaceutically acceptable salts. The term "salts" embraces addition salts of free acids and/or bases that are useful within the methods of the invention. The term "pharmaceutically acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).

Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethane sulfonic, benzenesulfonic, pantothenic, trifluoromethane sulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylamino sulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (also known as N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Compositions

The present invention includes pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and one or more pharmaceutically active agents contemplated herein. The pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit.

In certain embodiments, the NMDA receptor antagonist and the μ-opioid receptor antagonist are coformulated in a pharmaceutical composition. In other embodiments, the NMDA receptor antagonist and the μ-opioid receptor antagonist are coformulated in a way whereby physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist is not possible and/or feasible. In yet other embodiments, separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist requires chemical purification (using extractive procedures, chromatographic separation and the like). In yet other embodiments, separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist requires denaturation and/or destruction of the pharmaceutical composition.

In certain embodiments, the pharmaceutical compositions of the invention comprise a NMDA receptor antagonist and a μ-opioid receptor antagonist, wherein the NMDA receptor antagonist and the μ-opioid receptor antagonist are present in amounts whereby:

administration of the pharmaceutical compositions to a subject treats in the subject a disease or disorder that is treatable or preventable by the NMDA receptor antagonist; and the μ- opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

In certain embodiments, the pharmaceutical compositions of the invention, or any of the active agents contemplated in the invention (separately and/or in combination), are administered to the subject in need thereof using any known and applicable route of administration, such as for example, (intra)nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In certain embodiments, the pharmaceutical compositions of the invention, or any of the active agents contemplated in the invention (separately and/or in combination), are administered to the subject in need thereof

(intra)nasally. In yet other embodiments, the pharmaceutical compositions of the invention, or any of the active agents contemplated in the invention (separately and/or in combination), are administered to the subject using a transdermal patch.

Contemplated modes of administration of compounds and/or compositions useful within the invention, including (intra)nasal delivery, are recited in the following applications, which are incorporated herein in their entireties by reference: US20040059003,

US20040138298, US20040166067, US20070287753, US20080041367, US20080153879, US20120270903, US20120277267, US20140171514, US20140256821, US20140274981, US20140275276, US20140275277, US20140275278, US20150056308, US20150196501, US20150283123, US20160000733, US20160175266, EP 1 103256, and DE102007009888.

In certain embodiments, the dose of NMD A receptor antagonist (such as, but not limited to, ketamine, R-ketamine, S-ketamine, or any mixtures thereof) administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject ranges from about 0.15 mg/kg to about 10 mg/kg. For example, the dose of NMD A receptor antagonist administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject is selected from the group consisting of about 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, and any fraction or multiple thereof.

In certain embodiments, the amount of NMD A receptor antagonist (such as, but not limited to, ketamine, R-ketamine, S-ketamine, or any mixtures thereof) administered

(intra)nasally, intravenously, intramuscularly and/or orally to the subject ranges from about 1 mg to about 200 mg. For example, the amount of NMD A receptor antagonist administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject is selected from the group consisting of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 1 10 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, and any fraction or multiple thereof.

In certain embodiments, the dose of μ-opioid receptor antagonist (such as, but not limited to, naloxone) administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject ranges from about 0.1 mg to about 5 mg. For example, the dose of NMDA receptor antagonist administered (intra)nasally to the subject is selected from the group consisting of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, and any fraction or multiple thereof.

In certain embodiments, the dose of μ-opioid receptor antagonist (such as, but not limited to, naltrexone) administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject ranges from about 10 mg to about 100 mg, or from about 10 mg to about 380 mg. For example, the dose of NMDA receptor antagonist administered intravenously and/or intramuscularly to the subject is selected from the group consisting of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, and any fraction or multiple thereof. For example, the dose of NMDA receptor antagonist administered (intra)nasally and/or orally to the subject is selected from the group consisting of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg and any fraction or multiple thereof.

In certain embodiments, the dose of μ-opioid receptor antagonist (such as, but not limited to, nalmefene) administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject ranges from about 5 mg to about 40 mg. For example, the dose of

NMDA receptor antagonist administered (intra)nasally, intravenously, intramuscularly and/or orally to the subject is selected from the group consisting of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, and any fraction or multiple thereof. Methods

The invention provides a method of treating or preventing a disease in a subject, wherein the disease or disorder is treatable or preventable by administering a N-methyl-D- aspartate (NMDA) receptor antagonist to the subject. The invention further provides a method of preventing and/or minimizing abuse of a NMDA receptor antagonist by a subject. The invention further provides a method of treating or preventing major depressive disorder in a subject.

In certain embodiments, the method comprises administering to the subject a therapeutically effective amount of the NMDA receptor antagonist and a therapeutically effective amount of a μ-opioid receptor antagonist. In certain embodiments, the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject. In other embodiments, the subject has a comorbid addictive disease or disorder.

In certain embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are co-administered to the subject. In other embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are co-formulated as a pharmaceutical composition. In yet other embodiments, physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition is not possible and/or feasible. In yet other embodiments, physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition requires denaturation and/or destruction of the pharmaceutical composition.

In certain embodiments, the NMDA receptor antagonist and μ-opioid receptor antagonist are independently administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

In certain embodiments, the pharmaceutical composition is administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

In certain embodiments, the NMDA receptor antagonist is at least one selected from the group consisting of ketamine; R-ketamine; S-ketamine; nitrous oxide; memantine; amantadine; racemic dextromethorphan; dextromethorphan; lanicemine; phencyclidine; dizocilpine; CERC-301 ; CGP 37849; 1-aminocylopropanecarboxylic acid; traxoprodil; Ro 25-6981 ; eliprodil; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

In certain embodiments, the μ-opioid receptor antagonist is at least one selected from the group consisting of naltrexone; naloxone; nalmefene; nalodeine; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

In certain embodiments, the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S-ketamine. In other embodiments, the μ-opioid receptor antagonist comprises naltrexone. In yet other embodiments, the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S-ketamine, and the μ-opioid receptor antagonist comprises naltrexone.

In certain embodiments, the administering has at least one effect selected from the group consisting of : reduced anxiety, reduced irritability, reduced anger, and reduced alcohol consumption.

In certain embodiments, the subject is a mammal. In other embodiments, the mammal is human.

Administration/Dosage/Formulations

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of a disease or disorder contemplated in the invention. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated in the invention. An effective amount of the therapeutic compound or composition necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a disease or disorder contemplated in the invention. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 and 5,000 mg/kg of body weight/per day. The pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of from ng/kg/day and 100 mg/kg/day. In certain

embodiments, the invention envisions administration of a dose which results in a

concentration of the compound of the present invention from 1 μΜ and 10 μΜ in a mammal. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/ formulating such a therapeutic compound for the treatment of a disease or disorder contemplated in the invention.

In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the

pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the compositions of the invention are administered to the patient in dosages that range from one to five times per day or more. In another embodiment, the compositions of the invention are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account.

Compounds of the invention for administration may be in the range of from about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound of the invention is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder contemplated in the invention.

Formulations may be employed in admixtures with conventional excipients, /^'. e. , pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g. , lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g. , anti-AD agents.

Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g. , sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g. , trans- and perivaginally), (intranasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein. Oral Administration

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. , polyvinylpyrrolidone, hydroxypropylcellulose or

hydroxypropylmethylcellulose); fillers (e.g. , cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. , magnesium stearate, talc, or silica); disintegrates (e.g. , sodium starch glycollate); or wetting agents (e.g. , sodium lauryl sulfate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g. , OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and

OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. , sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g. , lecithin or acacia); non-aqueous vehicles (e.g. , almond oil, oily esters or ethyl alcohol); and preservatives (e.g. , methyl or propyl p-hydroxy benzoates or sorbic acid).

The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of a disease or disorder contemplated in the invention. Using a wax/pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

Parenteral Administration

As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. , powder or granular) form for reconstitution with a suitable vehicle (e.g. , sterile pyrogen free water) prior to parenteral administration of the reconstituted composition.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a nontoxic parenterally-acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. Inhalational Administration

Routes of administration of any of the compositions of the invention include nasal, inhalational, intratracheal, intrapulmonary, intrabronchial, and inhalation.

Suitable compositions and dosage forms include, for example, dispersions, suspensions, solutions, syrups, granules, beads, powders, pellets, liquid sprays for nasal administration, dry powder or aerosolized formulations for inhalation, and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form a material that is suitable to administration to a subject. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these formulations.

A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles that comprise the active ingredient and have a diameter in the range from about 0.5 to about 7 nanometers, and in certain embodiments from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling solvent/powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. In certain embodiments, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. In certain embodiments, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (in certain embodiments having a particle size of the same order as particles comprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonary delivery may also provide the active ingredient in the form of droplets of a solution or suspension. Such formulations may be prepared, packaged, or sold as aqueous or dilute alcoholic solutions or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration in certain embodiments have an average diameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary delivery are also useful for intranasal delivery of a pharmaceutical composition of the invention.

Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may further comprise one or more of the additional ingredients described herein.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790.

Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466;

20030039688; and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/1 1879; WO 97/47285; WO 93/18755; and WO 90/1 1757.

Controlled Release Formulations and Drug Delivery Systems

In one embodiment, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material that provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

In one embodiment of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing

The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of a disease or disorder contemplated in the invention. The skilled artisan is able to determine appropriate dosages depending on these and other factors.

A suitable dose of a compound of the present invention may be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on

Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e. , a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the disease or disorder, to a level at which the improved disease is retained. In one embodiment, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.

The compounds for use in the method of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g. , about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED₅₀. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

Combination Therapies

In certain embodiments, the compounds of the invention are useful in the methods of the invention in combination with at least one additional agent useful for treating or preventing a disease or disorder contemplated herein in a mammal in need thereof. This additional agent may comprise compounds identified herein or compounds, e.g.,

commercially available compounds, known to treat, prevent or reduce the symptoms of a disease or disorder contemplated herein.

In certain embodiments, the at least one additional compound useful for treating or preventing depression comprises citalopram, escitalopram, paroxetine, fluoxetine, sertraline, femoxetine, tranylcypromine, selegiline, isocarboxzaid, phenelzine, fluvoxamine, trimipramine, amitriptyline, nortriptyline, desipramine, protriptyline, imipramine, doxepin, clominpramine, maprotiline, bupropion, nefazodone, trazodone, venlafaxine, duloxetine, desvenlafaxine, mirtazepine, and milnacipran.

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.

Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the

concentration-effect curve, isobologram curve and combination index curve, respectively. Kits

The invention includes a kit comprising at least one composition of the invention, an applicator, and an instructional material for use thereof.

The instructional material included in the kit comprises instructions for preventing or treating a disease or disorder contemplated within the invention. The instructional material recites the amount of, and frequency with which, at least one composition of the invention should be administered to the mammal. In other embodiments, the kit further comprises at least one additional agent that prevents or treats the disease or disorder contemplated within the invention.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXPERIMENTAL EXAMPLES

The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1:

A trial was designed to evaluate the safety and efficacy of the combination of an exemplary NMDA receptor antagonist (ketamine) and an exemplary opioid receptor antagonist (naltrexone) in treating major depressive disorder (MDD) and alcohol use disorder (AUD). In certain embodiments, the combination of ketamine and naltrexone is safe and effective in reducing depression, alcohol consumption, and the abuse liability of ketamine. The study is described as follows.

1. Subjects

A total of 5 depressed and recently-detoxified alcohol dependent subjects between the ages of 21-65 were recruited. Subjects were accepted into the protocol after an opportunity to review and provide voluntary written informed consent and completion of a comprehensive medical and psychiatric history, physical examination, mental status examination, and routine laboratory assessments. Patients were recruited in outpatient settings, as they met the following criteria.

Inclusion Criteria:

1. Male or female, 21-65 years old.

2. Current major depressive disorder without psychotic features by DSM-5.

3. Montgomery-Asberg Depression Rating Scale (MADRS) > 20.

4. Current alcohol use disorder by DSM-5.

5. Heavy drinking at least 3 times in the past month ("heavy drinking" defined as >5 standard drinks per day for men and >4 standard drinks per day for women).

6. Abstinence from alcohol drinking for >5 days prior to ketamine infusion.

7. Able to provide written informed consent.

Exclusion Criteria:

1. Current substance use disorder by DSM-5 in the past 3 months (except alcohol, tobacco, or cannabis).

2. Current or past history of psychotic features or psychotic disorder.

3. Current or past history of delirium or dementia.

4. Current uncontrolled hypertension (systolic BP >170 mm Hg or diastolic BP >100 mm Hg).

5. Unstable medical condition or allergy to ketamine, naltrexone, or lorazepam, as clinically determined by a physician.

6. Imminent suicidal or homicidal risk.

7. Pregnant or nursing women, positive pregnancy test, or inadequate birth control methods in women of childbearing potential.

8. Positive opioid or illicit drug screen test (except marijuana).

9. Opioid use within 10 days prior to study medication (injectable naltrexone) or risks for opioid use during the study.

10. Liver enzymes that are three times higher than the upper limit of normal

2. Research Design

One goal of the study was to test naltrexone (long-acting injectable naltrexone 380 mg only once before ketamine treatment) plus repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) for comorbid MDD and AUD.

An open-label trial included 5 patients with comorbid MDD and AUD to test safety and efficacy of naltrexone (injectable naltrexone 380 mg only once before ketamine treatment) plus repeated ketamine treatment (0.5 mg/kg; once a week for 4 weeks; a total of 4 ketamine infusions) with a follow-up of 4 weeks. This open -label trial allowed one to examine the safety and tolerability of the naltrexone plus ketamine treatment in this population. All patients received usual standard care during this trial.

3. Procedures

Table 1. Procedures involved from screening visit to visit 10

Urinalysis X

BP, Pulse, Weight X X X X X X X X X X

MADRS, QIDS-SR, HAM-A X X X X X X X X X X

C-SSRS X X X X X X X X X X

AUQ, OCDS X X X X X X X X X X

BPRS, CADSS, VAS X X X X

Concomitant Meds X X X X X X X X X

TLFB X X X X X X X X X

Breathalyzer X X X X X X X X X X

Adverse Event X X X X X X X X X

CGI X X X X X X X X X

Q-LES-Q X X X a. Day -30-0 refers to the period between signing consent and completion of screening. As such Visit 1 refers to one or multiple screening visits.

b. Informed consent was obtained prior to any study procedure.

c. Abbreviations: Structured Clinical Interview (SCID), Family History Assessment Module (FHAM), Columbia-Suicide Severity Rating Scale (C-SSRS), MGH

Antidepressant Treatment Response Questionnaire (MGH-ATRP), Montgomery- Asberg Depression Rating Scale (MADRS), Quick Inventory of Depressive

Symptomatology - Self Report (QIDS-SR), Hamilton Anxiety Rating Scale (HAM-A), Time Line Follow Back (TLFB), Clinical Global Impression (CGI), Brief Psychiatric Rating Scale (BPRS), Clinician-Administered Dissociative States Scale (CADSS), Visual Analog Scale (VAS) of Mood States, Alcohol Urges Questionnaire (AUQ), Obsessive Compulsive Drinking Scale (OCDS), Quality of life enjoyment and satisfaction survey (Q-LES-Q), Electrocardiogram (EKG), Complete Blood Count (CBC)

Initial Telephone Screening

Subject eligibility was first assessed via telephone screening and a preliminary medical record review. Telephone screening was performed by experienced research personnel adept with this process. If the subject appeared to be a likely candidate for inclusion in this protocol, he or she was invited to a screening visit for study eligibility. Screening Visit At the screening visit, the research team explained the overall study plan to potential subjects and went over the consent form. Subjects had an initial screening evaluation that included psychiatric history, medical history, mental status examination, physical examination, and laboratory assessment. Other detailed procedures are described in Table 1. If the examination and test results were acceptable and the subject met the inclusion / exclusion criteria, the subject was invited to the baseline visit.

Injectable Naltrexone Visit

The subject received injectable naltrexone between the screening visit and the first ketamine infusion session (2-6 days prior to the first ketamine infusion preferred).

Table 2. Four ketamine administration sessions (Days 0, 7, 14, 21)

a. If breathalyzer was positive for alcohol, ketamine infusion session was cancelled and rescheduled.

b. After the subject received study medication, he or she received lunch and was medically cleared before leaving.

c. If necessary, intravenous lorazepam (ativan) at 1 mg was available to reduce the

behavioral effects of ketamine. This was determined by a research physician.

d. Abbreviations: T-60, 60 minutes before intranasal ketamine/placebo administration.

Follow-up after first Infusion (Day #1)

The first follow-up session occurred the next day (Day # 1) after first infusion. This 24-hour evaluation after infusion was done only once after the "first" infusion. There were no 24-hour evaluation after 2ⁿ , 3^Γ , 4 infusions.

Four follow-up sessions (Day #28, 35, 42, 49)

A total of 4 weekly follow-up sessions were performed on Day #28, 35, 42, and 49. After the study, participants were provided with psychiatric and/or substance abuse treatment referrals to continue treatment at their discretion.

4. Measures

Medical Assessments :

Physical examination (including vital sign determination) and clinical laboratories were completed at the first visit. Urine toxicology screen and breathalyzer were performed on the morning of each infusion day, and the results were determined before proceeding with the infusions. The subject did not receive ketamine on the day if urine toxicology results were positive for any illicit drugs (except marijuana) or if his/her breathalyzer was positive for alcohol. A pregnancy test was also administered to all reproductive age females enrolled in the study prior to participation.

Psychiatric Assessments:

Ratings were performed by trained research assistants. Administration of clinical measures was supervised by the primary investigator. Each of the psychiatric assessment instruments is briefly described below.

1. Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a

standardized instrument to ascertain depressed mood and neurovegetative signs and symptoms of a major depressive episode.

2. Quick Inventory of Depressive Symptomatology- Self Report (QIDS-SR): The QIDS- SR is a patient-rated depression instrument.

3. Hamilton Anxiety Rating Scale (HAM- A): The HAM-A is a standardized instrument to evaluate anxiety severity.

4. Clinical Global Impressions Scale (CGI): The CGI is a widely-used instrument which assesses overall severity of illness on a 1 to 7 point scale with 1 indicating "normal, not at all ill" and 7 indicating "among the most extremely ill patients." It also assesses global improvement on a l-to-7 point scale with 1 indicating "very much improved," 4 indicating "no change" and 7 indicating "very much worse."

5. Brief Psychotic Rating Scale (BPRS): The BPRS is a standardized instrument that contains scales assessing psychotic symptoms including positive and negative symptoms, activation and emotional distress.

6. Clinician-Administered Dissociative States Scale (CADSS): The CADSS has self and interviewer-administered items including 5 subscales, generated a priori, evaluating dissociation including altered environmental perception, time perception, spatial/body perception, derealization and memory impairment.

7. Visual Analog Scale (VAS) of Mood States: The VAS includes scales for anxiety, drowsiness, high irritability, anger and sadness. The scales are 100 mm lines marked by subjects at a point corresponding to the apparent intensity of the feeling state (0 = none, to 100 = most ever).

8. Time Line Follow Back (TLFB): The TLFB is a standardized measure utilized for collecting information on daily alcohol use as well as other substance use.

9. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS has both

lifetime/recent and since last visit versions. The "Lifetime/Recent" version gathers information on lifetime history of suicidality and recent suicidal ideation/self-injurious behavior. The "Since Last Visit" version of the C-SSRS asks about any suicidal thoughts or behaviors the subject has exhibited since the last time administered the C- SSRS.

10. Alcohol Urges Questionnaire (AUQ): The AUQ measures drinking urges with 8 items to assess acute alcohol cravings.

11. Obsessive Compulsive Drinking Scale (OCDS): The OCDS is a self-report measure of craving which consists of two subscales that measure obsessions and compulsions associated with craving for alcohol.

12. Quality of life enjoyment and satisfaction survey (Q-LES-Q): The Q-LES-Q is a self- report measure of quality of life.

5. Selected Findings

Primary outcome was clinical response in symptoms of MDD as measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at Day 21 (visit 7, T+240 minutes). Response was defined as a > 50% improvement from baseline in MADRS score.

Combination of ketamine and naltrexone decreased depressive symptoms

FIG. 1 illustrates the finding that the combination treatment (ketamine plus naltrexone) decreased depressive symptoms as measured by the MADRS in 5 patients with MDD and AUD. After the combination treatment, all subjects had a robust clinical response and sustained antidepressant effects as follows:

1) Primary outcome (clinical response in symptoms of MDD as measured by the MADRS; response defined as a > 50% improvement from baseline in MADRS score): subjects (100% clinical response);

2) Secondary outcome (remission in symptoms of MDD as measured by the MADRS; remission defined as a MADRS score < 9): 3/5 subjects (60% remission rate).

Repeated ketamine infusions produced sustained antidepressant effects. Combination of ketamine and naltrexone decreased anxiety, irritability, and anger symptoms

FIG. 2 illustrates the finding that the combination treatment (ketamine plus naltrexone) decreased anxiety, irritability, and anger symptoms as measured by the VAS in a patient with MDD and AUD. After first ketamine infusion, the subject had a robust clinical response. Repeated ketamine infusions produced sustained treatment effects.

FIGs. 3A-3C further illustrate the finding that the combination treatment (ketamine plus naltrexone) decreased anxiety, irritability, and anger symptoms as measured by the VAS in five patients with MDD and AUD.

1) Anxiety

Subject 2 0 0 No irritability

Subject 3 0 0 No irritability

Subject 4 5 2 Improved

Subject 5 5 0 Improved

3) Anger

VAS-Anger score

Day 0 Day 21 Improvement (pre-treatment) (post-treatment)

Subject 1 8 0 Improved

Subject 2 0 0 No anger

Subject 3 0 0 No anger

Subject 4 3 2 Improved

Subject 5 1 0 Improved

Ketamine and naltrexone reduced alcohol consumption

The subject had 6 heavy drinking days ('heavy drinking' defined as >5 standard drinks per day for men) in the past 30 days prior to the combination treatment. However, the subject was able to abstain from alcohol during the active phase of the combination treatment (from the first ketamine infusion to the 4^th ketamine infusion). This finding support the potential utility of ketamine for the treatment of comorbid MDD and AUD.

FIG. 4 further illustrates the finding that the combination treatment (ketamine plus naltrexone) decreased alcohol craving and consumption as measured by the OCDS in patients with MDD and AUD. During the combination treatment, four subjects reported lower alcohol craving and consumption, while one subject reported higher alcohol craving and consumption. Repeated ketamine infusions produced sustained treatment effects. This finding supports the potential utility of ketamine plus naltrexone for the treatment of comorbid MDD and AUD.

Safety and toler ability

In this pilot trial, ketamine [as well as the combination treatment (ketamine plus naltrexone)] was safe and well tolerated in the patient with MDD and AUD. Ketamine infusions did not cause any active side effects at the completion of the test day (4 hours after infusion).

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A method of treating or preventing a disease in a subject, wherein the disease or disorder is treatable or preventable by administering a N-methyl-D-aspartate (NMDA) receptor antagonist to the subject, the method comprising administering to the subject a therapeutically effective amount of the NMDA receptor antagonist and a therapeutically effective amount of a μ-opioid receptor antagonist.

2. The method of claim 1, wherein the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

3. A method of preventing and/or minimizing abuse of a NMDA receptor antagonist by a subject, the method comprising administering to the subject a therapeutically effective amount of the NMDA receptor antagonist and a therapeutically effective amount of a μ- opioid receptor antagonist.

4. The method of any of claims 1-3, wherein the subject has or does not have a comorbid addictive disease or disorder.

5. The method of any of claims 1-4, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are co-administered to the subject.

6. The method of any of claims 1-5, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are co-formulated as a pharmaceutical composition.

7. The method of claim 6, wherein physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition is not possible and/or feasible.

8. The method of any of claims 6-7, wherein physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition requires denaturation and/or destruction of the pharmaceutical composition.

9. The method of any of claims 1-8, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are independently administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

10. The method of any of claims 6-9, wherein the pharmaceutical composition is administered to the subject by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

1 1. The method of any of claims 1-10, wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine; R-ketamine; S-ketamine; nitrous oxide; memantine; amantadine; racemic dextromethorphan; dextromethorphan; lanicemine;

phencyclidine; dizocilpine; CERC-301; CGP 37849; 1-aminocylopropanecarboxylic acid; traxoprodil; Ro 25-6981 ; eliprodil; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

12. The method of any of claims 1-1 1, wherein the μ-opioid receptor antagonist is at least one selected from the group consisting of naltrexone; naloxone; nalmefene; nalodeine; any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

13. The method of any of claims 1- 12, wherein the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S-ketamine, and wherein the μ-opioid receptor antagonist comprises at least one selected from the group consisting of naltrexone and naloxone.

14. The method of any of claims 1-13, wherein the subject is a mammal.

15. The method of claim 14, wherein the mammal is human.

16. A method of treating or preventing major depressive disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a NMDA receptor antagonist and a therapeutically effective amount of a μ-opioid receptor antagonist.

17. The method of claim 16, wherein the subject has or does not have a comorbid addictive disease or disorder.

18. The method of any of claims 16-17, wherein the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

19. The method of any of claims 16-18, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are co-administered to the subject.

20. The method of any of claims 16-19, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are co-formulated as a pharmaceutical composition.

21. The method of claim 20, wherein physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition is not possible and/or feasible.

22. The method of any of claims 20-21, wherein physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition requires denaturation and/or destruction of the pharmaceutical composition.

23. The method of any of claims 16-22, wherein the NMDA receptor antagonist and μ- opioid receptor antagonist are independently administered by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

24. The method of any of claims 20-23, wherein the pharmaceutical composition is administered by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

25. The method of any of claims 16-24, wherein the NMDA receptor antagonist is at least one selected from the group consisting of ketamine, R-ketamine, S-ketamine, nitrous oxide, memantine, amantadine, racemic dextromethorphan, dextromethorphan, lanicemine, phencyclidine, dizocilpine, CERC-301, CGP 37849, 1-aminocylopropanecarboxylic acid, traxoprodil, Ro 25-6981, eliprodil, any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

26. The method of any of claims 16-25, wherein the μ-opioid receptor antagonist is at least one selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, any salt, solvate, enantiomer, tautomer and geometric isomer thereof, or any mixtures thereof.

27. The method of any of claims 16-26, wherein the NMDA receptor antagonist comprises at least one selected from the group consisting of ketamine, R-ketamine and S- ketamine, and wherein the he μ-opioid receptor antagonist comprises naltrexone.

28. The method of any of claims 16-27, wherein the administering has at least one effect selected from the group consisting of reduced anxiety, reduced irritability, reduced anger, and reduced alcohol consumption.

29. The method of any of claims 16-28, wherein the subject is a mammal.

30. The method of claim 29, wherein the mammal is human.

31. A pharmaceutical composition comprising a NMDA receptor antagonist and a μ- opioid receptor antagonist, wherein the NMDA receptor antagonist and the μ-opioid receptor antagonist are present in amounts whereby: administration of the pharmaceutical composition to a subject treats in the subject a disease or disorder that is treatable or preventable by the NMDA receptor antagonist; and the μ-opioid receptor antagonist prevents and/or minimizes abuse of the NMDA receptor antagonist by the subject.

32. The pharmaceutical composition of claim 31, wherein physical separation of the NMDA receptor antagonist and the μ-opioid receptor antagonist in the pharmaceutical composition is not possible and/or feasible.

33. The pharmaceutical composition of any of claims 31-32, which is formulated for administration by a route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.

34. The pharmaceutical composition of any of claims 31-33, which is formulated for administration by nasal route.

35. The pharmaceutical composition of any of claims 31-34, which is part of a kit further comprising an applicator, and an instructional material for use thereof.