(AMPAR-PAM)-NMDA receptor antagonist combination therapy for treating psychiatric conditions and disorders

Abstract

The pharmaceutical composition comprises the following components: (i) an AMPA receptor positive allosteric modulator (PAM) (e.g., an ampakine or a biarylpropylsulfonamide); and (ii) an NMDA receptor antagonist, e.g., ketamine or an analog thereof. Also described herein is a method for treating a psychiatric disorder or condition (e.g., depression, anxiety, substance use disorder, obsessive-compulsive disorder and related disorders, or a neurocognitive disorder), comprising administering a pharmacologic effective amount of components (i) and (ii) to a subject having a psychiatric disorder, wherein components (i) and (ii) may be administered to the subject as a single pharmaceutical composition in which the therapeutic compounds (i) and (ii) are present in a pharmacologic effective amount, or components (i) and (ii) are administered to the subject in separate doses within 48 hours or 24 hours of each other.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 309,271, filed February 11, 2022, the contents of which are incorporated by reference herein in their entirety.

[0002] The present invention relates generally to the treatment of various psychiatric conditions and disorders by administering an AMPA receptor positive allosteric modulator (PAM) in combination with an NMDA receptor antagonist, and more particularly to the treatment of depression (e.g., major depressive disorder), anxiety, bipolar disorder, mood disorders, obsessive-compulsive disorder, drug addiction, and neurocognitive disorders. [Background technology]

[0003] Approximately one-third of patients with major depressive disorder (MDD) are unable to achieve remission of their symptoms even after multiple treatments with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) (Rush et al. N. Engl. J. Med., 354(12), 1231-1242, 2006). This high prevalence of treatment-resistant depression (TRD) highlights the need for new, more effective pharmacotherapies for depression that would target novel mechanisms and / or patient populations. In recent years, ketamine, a drug long used as a dissociative anesthetic, has attracted much attention for its secondary use as a fast-acting antidepressant with robust efficacy in patients with TRD (Zarate et al., Arch. Gen. Psychiatry, 63(8), 856-864 2006; Berman et al., Biol. Psychiatry, 47(4), 351-354, 2000). The drug's antidepressant effects are also notable in that they persist for days or weeks after a single dose. Importantly, the S-enantiomer of ketamine (S-ket) has recently been approved by the U.S. Food and Drug Administration for the treatment of depression.

[0004] Unfortunately, the strong dissociative anesthetic effects of ketamine, S-ket, and other NMDA receptor antagonists make these drugs attractive to recreational drug users. Given the serious potential for abuse of NMDA receptor antagonist drugs, such drugs are generally available only under limited and strictly controlled conditions and under the supervision of medical providers who specialize in the treatment of psychoactive disorders. Thus, there would be significant advantages in a method of treating depression or other psychiatric disorders (e.g., anxiety, bipolar disorder, mood disorders, obsessive-compulsive disorder, drug dependence, and neurocognitive disorders) by administration of an NMDA receptor antagonist, provided that the NMDA receptor antagonist does not induce dissociative anesthetic effects in the patient and at the same time is in a dose that effectively treats the patient for the psychiatric disorder. Furthermore, a treatment method using an NMDA receptor antagonist with a reduced risk of abuse and overall risk would provide the advantage of no longer requiring such limited and controlled conditions. Finally, a method for increasing the durability of the therapeutic effect resulting from administration of an NMDA receptor antagonist would reduce the frequency of administration of treatment, increasing convenience and reducing risks. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Rush et al. N. Engl. J. Med., 354(12), 1231-1242, 2006 [Non-Patent Document 2] Zarate et al., Arch. Gen. Psychiatry, 63(8), 856-864 2006; Berman et al., Biol. Psychiatry, 47(4), 351-354, 2000 [Non-Patent Document 3] SE Ward et al., Br. J. Pharmacol., 160(2), 181-190, May 2010 [Non-Patent Document 4] SE Tomek et al., Pharmaceuticals, 6(2), 251-268, 2013 [Non-Patent Document 5] Berge et al.., 66 J. Pharm. Sci. 1-19 (1977) [Non-Patent Document 6] "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Pa., (1995) [Non-Patent Document 7] Dillon et al., 2009, Behavioral Brain Research 204, 67-76 Summary of the Invention

[0006] In one embodiment, the present disclosure relates to a pharmaceutical composition that provides the positive therapeutic effect of NMDA receptor antagonists for psychiatric disorders, but at a lower dose, thus reducing the ability of NMDA receptor antagonists to induce dissociative anesthetic effects, thereby substantially reducing the potential for abuse and improving the safety of its use. Furthermore, the present invention enhances the duration of therapeutic effects resulting from administration of NMDA receptor antagonists, thus reducing the frequency of administration of treatment, increasing convenience and reducing risk to patients. More specifically, the pharmaceutical composition comprises or exclusively contains the following components: (i) a positive allosteric modulator (PAM) of the AMPA receptor (i.e., an "AMPAR-PAM" compound); and (ii) an NMDA receptor antagonist compound. The pharmaceutical composition typically further comprises (iii) a pharma-ceutically acceptable carrier.

[0007] In another aspect, the present disclosure is directed to a method of treating a psychiatric disorder in a subject by administering to the subject a pharmacologic effective amount of an AMPAR-PAM compound (therapeutic compound (i)) and an NMDA receptor antagonist compound (therapeutic compound (ii)) in combination therapy. It has been unexpectedly found herein that the presence of an AMPAR-PAM compound advantageously modulates the activity of an NMDA receptor antagonist by retaining and even synergistically enhancing its beneficial effects in treating a psychiatric condition. In some embodiments, the subject is administered a single pharmaceutical composition in which the therapeutic compounds (i) and (ii) are present in a pharmacologic effective amount to treat the psychiatric disorder. In other embodiments, the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within a time frame short enough for component (i) to effectively modulate the function of component (ii). For example, the therapeutic compounds (i) and (ii) may be administered to the subject in separate doses within 48 hours or 24 hours of each other. In particular, in some embodiments, component (i) and component (ii) are administered to a subject in amounts that are sub-therapeutic when administered alone, but that, when administered in combination as a single pharmaceutical composition or in separate administrations within a suitable time frame of each other, provide a synergistic effect to treat the psychiatric disorder. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] In a first aspect, the present disclosure is directed to a pharmaceutical composition comprising or exclusively containing the following components: (i) an AMPA receptor positive allosteric modulator (PAM), also referred to herein as an "AMPAR-PAM compound", and (ii) an NMDA receptor antagonist, also referred to herein as an "NMDAR ant compound". Typically, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier. In particular, component (i) may be referred to as "compound (i)" or "therapeutic compound (i)", and similarly, component (ii) may be referred to as "compound (ii)" or "therapeutic compound (ii)".

[0009] The AMPAR-PAM compound of component (i) may be any of the AMPAR-PAM compounds known in the art. Most of the AMPAR-PAM compounds are known, for example, as described in SE Ward et al., Br. J. Pharmacol., 160(2), 181-190, May 2010, the contents of which are incorporated herein by reference. As is known, AMPAR-PAM compounds function as positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The term "AMPA receptor" is used herein interchangeably with the term "AMPAR". AMPARs are members of the ionotropic glutamate receptor class, which are ligand-gated ion channels activated by the neurotransmitter glutamate. These receptors are known to mediate many of the fast synaptic neurotransmissions that occur in the central nervous system.

[0010] In a first series of embodiments, the AMPAR-PAM compounds are ampakines. As is well known, some ampakines contain a benzamide-based structure, often with a phenyl ring fused to another ring. An early example of such a compound is aniracetam. Some ampakines are identified as "CX" compounds, with "CX" followed by a series of numbers, e.g., "CX-516."

[0011] Many of the CX ampakines have structures within the following general structure:

[0012] [ka]

[0013] (wherein ring A (shown fused to the phenyl ring and optionally present) is typically a 5- or 6-membered carbocyclic or heterocyclic ring, and ring B is an N-containing ring typically containing 4 or 5 ring carbon atoms). Any one or more hydrogen atoms on ring A and / or ring B may be independently replaced with a hydrocarbon group typically containing 1-10 carbon atoms and optionally one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some cases, ring B is also fused to the phenyl ring to form at least a tricyclic ring system, such as:

[0014] [ka]

[0015] (In the formula, R a is typically a hydrocarbon group containing 1-6 carbon atoms and may be fused with ring B to provide a tetracyclic ring system. Some examples of ampakines according to formulas (1) and (1a) include CX-516 (amparex), CX-546, CX-554, CX-614, CX-691 (phalampatol), CX-717, CX-1632 (tulampatol), CX-1739, ORG-26576, ORG-24448, CX-701, CX-929, CX-1501, CX-1796, CX-1837, CX-1846, CX-1942, CX-2007, CX-2076, and S-70340. Any pharma- ceutically acceptable salts of any of the above ampakines may also be used as known in the art.

[0016] In another set of embodiments, the AMPAR-PAM compounds may alternatively have an arylpropylsulfonamide structure, or, more particularly, a biarylpropylsulfonamide structure. Such AMPAR-PAM compounds may have a structure within any of the following general structures:

[0017] [ka]

[0018] (In the formula, R b R is a hydrocarbon group typically containing 1 to 12 carbon atoms and optionally one or more heteroatoms selected from nitrogen, oxygen, and sulfur. b may be, or may include, for example, a linear or branched alkyl or alkylene group, a cycloalkyl group, a heterocycloalkyl group, an aromatic group, or a heteroaromatic group. In some embodiments, R b is a nitrile (CN) group. Furthermore, one or both of the benzene rings shown in formula (2) or (2a) may be replaced with a heteroaryl group, such as a pyridine, pyrimidine, or thiophene ring, respectively. Some examples of arylpropylsulfonamide and biarylpropylsulfonamide compounds according to formula (2) and (2a) include LY-451395 (mibanpatol), LY-450108, LY-404187, LY-503430, PF-04958242 (BIIB-104; pesampatol), LY-392098, LY-451646, PF-04778574, CMPDA, CMPDB, and (R,R)-PIMSD. In some embodiments, component (i) is or comprises a biarylpropylsulfonamide, which may be or comprise PF-04958242 (BIIB-104; pesampatol). Any pharmaceutically acceptable salt of any of the above arylpropylsulfonamides may also be used as known in the art.

[0019] In another series of embodiments, the AMPAR-PAM compound may alternatively have a benzothiadiazide structure. The benzothiadiazide may be selected from, for example, BIIR-777, cyclothiazide, diazoxide, hydrochlorothiazide (HCTZ), IDRA-21, and S-18986.

[0020] In another series of embodiments, the AMPAR-PAM compound may alternatively have a racetam structure.The racetam may be selected from, for example, piracetam, aniracetam, phenylpiracetam, oxiracetam, pramiracetam, seletracetam, levetiracetam, coluracetam, fasoracetam, brivaracetam, methylphenylpiracetam, dimiracetam, nebracetam, rolziracetam, and nefiracetam.In some embodiments, the racetam is more particularly selected from piracetam, aniracetam, or a combination thereof.

[0021] In another series of embodiments, the AMPAR-PAM compound may alternatively be selected from PEPA, PF-04701475, GVS-111, and TAK-653.

[0022] The NMDAR antagonist compound of component (ii) may be any compound known in the art. Most of the NMDAR antagonist compounds are known, for example, as described in SE Tomek et al., Pharmaceuticals, 6(2), 251-268, 2013, the contents of which are incorporated herein by reference. As is well known, NMDA receptor antagonist compounds function to inhibit (i.e. antagonize) N-methyl-D-aspartate receptor (NMDAR), which is a receptor for glutamate and a common excitatory neurotransmitter in the brain. Due to this ability, NMDAR antagonist compounds are commonly used as anesthetics. NMDAR antagonist compounds are also known to induce dissociative or hallucinogenic effects depending on the dosage.

[0023] In one series of embodiments, the NMDAR antagonist compounds are arylcyclohexylamines. Many of the arylcyclohexylamines have a structure that falls within the following general structure:

[0024] [ka]

[0025] In the above formula (3), R 1 and R 2 H and R a are independently selected from R a , H, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, and C 3~10 cycloalkyl; R a optionally contains (i.e., optionally includes) one or more heteroatoms selected from O, N, S, and halogen; R 1 and R 2 are optionally linked together to form an N-containing ring; R 3 , R 4 , R 5 , R 6 , and R 7 is H, halogen, R b , CF3, -OR b , -C(O)R b , -C(O)O(R b ), -C(O)NR b 2. -OC(O)R b , -NR b 2, -NR b C(O)R b , -NR b C(O)NR b -, -NO2, -CN, -OP(=O)O2R b 2, -SR b , -S(O)R b , -SO2R b , and -SO2NR b 2 are independently selected from R b , H, C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~7 Independently selected from cycloalkyl, aryl, and heteroaryl, any of which are optionally substituted with halogen atoms. The dashed double bond in formula (3) indicates the optional presence of a keto group. The term "containing" or "comprising" refers to the optional presence of one or more heteroatoms, and includes any one or more heteroatoms that are not R aor other groups disclosed elsewhere in this application. In one case, the term "containing" or "comprising" refers to one or two hydrogen atoms on a carbon atom being replaced with a heteroatom or a heteroatom-containing group (e.g., two hydrogen atoms on a carbon atom being replaced with oxygen atoms to form a carbonyl group; or a hydrogen atom being replaced with a fluorine atom, a hydroxy group, an amino group, or a thiol group). In another case, the term "containing" or "comprising" refers to the interruption of a carbon-carbon bond in a hydrocarbon group by a heteroatom or a heteroatom-containing group (e.g., an oxygen atom interrupts an n-butyl group to provide a diethyl ether group, or an -NH- group interrupts an ethyl group to provide a -CH2-NH-CH3 group, or an oxygen atom interrupts a cyclobutyl group to provide a tetrahydrofuranyl group). In some embodiments, the alkyl, alkenyl, alkynyl, or cycloalkyl group does not contain a heteroatom. Any pharma- ceutically acceptable salts of any of the above arylcyclohexylamine compounds may also be used as known in the art.

[0026] In some embodiments, the NMDAR antagonist compound is an arylcyclohexylamine having the following general structure:

[0027] [ka]

[0028] (In the formula, R 1 and R 2 H and R a are independently selected from R a , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 Alkynyl, and C 3~5 cycloalkyl; R a optionally contains (i.e., optionally includes) one or more heteroatoms selected from O, N, S, and halogen; R1 and R 2 are optionally linked together to form an N-containing ring; R 3 , R 4 , R 5 , R 6 , and R 7 is H, halogen, R b , CF3, -OR b , -C(O)R b , -C(O)O(R b ), -C(O)NR b 2. -OC(O)R b , -NR b 2, -NR b C(O)R b , -NR b C(O)NR b -, -NO2, -CN, -SR b , -S(O)R b , -SO2R b , and -SO2NR b 2 are independently selected from R b , H, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, and C 3~5 cycloalkyl, any of which is optionally substituted with a halogen atom.) Any pharma- ceutically acceptable salts of any of the above arylcyclohexylamine compounds may be used as known in the art.

[0029] In some embodiments, the NMDAR antagonist compound is an arylcyclohexylamine having the following general structure:

[0030] [ka]

[0031] (In the formula, R 1 and R 2 H and R a are independently selected from R a , H, C 1~3 Alkyl, aryl, propargyl, and C3~5 cycloalkyl; R a optionally contains (i.e., optionally comprises) one or more heteroatoms selected from O, N, S, and F; R 1 and R 2 are optionally linked together to form a piperidine, pyrrolidine, or morpholine ring; R 3 , R 4 , R 5 , R 6 , and R 7 is H, halogen, R b , CF3, -OR b , -OC(O)R b , -NR b 2, -NO2, -CN; R b , H, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, and C 3~5 cycloalkyl, any of which is optionally substituted with a fluorine atom.) Any pharma- ceutically acceptable salts of any of the above arylcyclohexylamine compounds may be used as known in the art.

[0032] Some examples of arylcyclohexylamine compounds useful as component (ii) include ketamine, R-ketamine, S-ketamine, S-norketamine, N-ethylnorketamine, N-propylnorketamine, memantine, amantadine, phencyclidine (PCP), rolicyclidine (PCPy), PCM, PCPr, tenocyclidine (TCP), tiletamine, 2-oxo-PCP, 2-oxo-PCE, gacyclidine, 3-MeO-PCP, 3-OH-PCP, 4-MeO-PCP, deschloroketamine, 2-fluoro-deschloroketamine, ethicyclidine (PCE), 3-MeO-PCE, 4-MeO-PCE, 3-OH-PCE, methoxetamine, methoxymethamine, methoxypropamine, methoxyisopropamine, and hydroxetamine. In certain embodiments, component (ii) is or comprises ketamine or an analog thereof, such as any of the ketamine analogs provided above, in certain embodiments, component (ii) is selected from ketamine, R-ketamine, S-ketamine, and S-norketamine, or component (ii) is more particularly selected from ketamine, R-ketamine, and S-ketamine.

[0033] In some embodiments, component (ii) is selected from at least one of the following compounds:

[0034] [ka]

[0035] or component (ii) is more specifically

[0036] [ka]

[0037] It is.

[0038] In some embodiments, the NMDAR antagonist compound is not arylcyclohexylamine, but belongs to another molecular scaffold known to inhibit NMDAR instead.Examples of such compounds include 8A-PDHQ, dextromethorphan, dextromethorphan-OD3, dextrorphan, dextralorphan, PD-137889, neramexane, memantine, NEFA, dizocilpine, lanicemine, diphenidine, ephenidine, isopropylphenidine, methoxyphenidine, fluorolintane, xenon, krypton, nitrous oxide, etoxadrol, dexoxadrol, ibogaine, and noribogaine.In certain embodiments, the NMDAR antagonist compound is selected from dextromethorphan and dextromethorphan-OD3.

[0039] In some embodiments, the NMDAR antagonist compound selectively blocks or negatively modulates the NMDA receptor that contains GluN2B (GRIN2B) subunit.Examples of such compounds include MIJ821, lisrenemdaz, eliprodil, ifenprodil, besonprodil, traxoprodil, radiprodil, BMS-986169, BMS-986163, Ro 25-6981, Ro 04-5595, TCN 237, TCS 46b, and Co 101244.

[0040] In some embodiments, with respect to any of the possibilities provided above with respect to component (ii), the composition further comprises a third compound (component iii) selected from quinidine and bupropion. In some embodiments, component (ii) is selected from dextromethorphan and dextromethorphan-OD3, and the composition further comprises a third compound (component iii) selected from quinidine and bupropion.

[0041] In some embodiments, the NMDAR antagonist compound is

[0042] [ka]

[0043] [ka]

[0044] is selected from.

[0045] In some embodiments, the NMDAR antagonist compound is

[0046] [ka]

[0047] is selected from.

[0048] In some embodiments, the NMDAR antagonist compound has the structure:

[0049] [ka]

[0050] where D represents a deuterium-enriched H site.

[0051] In some embodiments, each D represents a deuterium-enriched H site and the level of deuterium at each deuterium-enriched H site of the compound is between 0.02% and 100%. In some embodiments, each D represents a deuterium-enriched H site and the level of deuterium at each deuterium-enriched H site of the compound is between 20% and 100%, between 50% and 100%, between 70% and 100%, between 90% and 100%, between 97% and 100%, or between 99% and 100%.

[0052] In some embodiments, the NMDAR antagonist compound is

[0053] [ka]

[0054] is selected from.

[0055] In some embodiments, the NMDAR antagonist compound is

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] is selected from.

[0061] In some embodiments, the NMDAR antagonist compound is

[0062] [ka]

[0063] is selected from.

[0064] In some embodiments, the NMDAR antagonist compound is

[0065] [ka]

[0066] is selected from.

[0067] In some embodiments, the NMDAR antagonist compound is

[0068] [ka]

[0069] or a pharma- ceutically acceptable salt or ester thereof, and / or specific S- or R-isomers thereof.

[0070] In some embodiments, the NMDAR antagonist compound is

[0071] [ka]

[0072] or a pharma- ceutically acceptable salt or ester thereof, and / or specific S- or R-isomers thereof.

[0073] In another embodiment, the NMDAR antagonist compound is an enantiomeric compound selected from:

[0074] [ka]

[0075] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the NMDAR antagonist compound is an isolated, substantially enantiomerically pure compound selected from any of the above compounds, wherein the enantiomeric compound is present in an enantiomeric mixture having at least 90%, at least 95%, or at least 99% of the enantiomeric compound.

[0077] In another embodiment, the NMDAR antagonist compound is

[0078] [ka]

[0079] is selected from.

[0080] In some embodiments, the NMDAR antagonist compound is

[0081] [ka]

[0082] or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, the NMDAR antagonist compound is

[0084] [ka]

[0085] [ka]

[0086] or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments, the NMDAR antagonist compound is selected from the following compounds:

[0088] [ka]

[0089] In particular, any one or more of the aforementioned NMDAR antagonistic compounds described above may be combined with any one or more of the AMPAR-PAM compounds described above.All such combinations are considered herein.At the same time, one or more combinations may be excluded from pharmaceutical composition.

[0090] In some embodiments, the optical purity of the AMPAR-PAM or NMDAR antagonist compound is greater than 5%, greater than 25%, greater than 50%, greater than 75%, greater than 90%, greater than 95%, greater than 97%, greater than 98%, or greater than 99%.

[0091] The present disclosure is also directed to a pharmaceutical composition containing the following components: (i) a positive allosteric modulator (PAM) of an AMPA receptor or a pharma- ceutically acceptable salt thereof; and (ii) (2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one or a pharma- ceutically acceptable salt thereof. Component (i) may be any of the compounds described throughout this disclosure with respect to component (i). In some embodiments, component (i) is PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dose unit of the composition contains between about 0.05 mg and about 1 mg of PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dose unit of the composition contains between about 0.1 mg and about 0.5 mg of PF-04958242 (BIIB-104; pesampatol). In further or separate embodiments, each dosage unit of the composition contains between about 10 mg and about 100 mg of component (ii). In further or separate embodiments, each dosage unit of the composition contains between about 20 mg and about 40 mg of component (ii). In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier, as fully described above.

[0092] "C 1~10The term "alkyl" as used herein refers to a linear or branched saturated hydrocarbon group (alkyl group) containing 1 to 10 carbon atoms. For any embodiment disclosed in this disclosure, C 1~10 Alkyl is C 2~10 Alkyl group, C 3~10 Alkyl group, C 2~10 Alkyl group, C 5~10 Alkyl group, C 6~10 Alkyl group, C 1~8 Alkyl group, C 2~8 Alkyl group, C 3~8 Alkyl group, C 4~8 Alkyl group, C 5~8 Alkyl group, C 6~8 Alkyl group, C 1~6 Alkyl group, C 2~6 Alkyl group, C 3~6 Alkyl group, C 4~6 Alkyl group, C 1~4 Alkyl group, C 2~4 Alkyl group, C 1~3 Alkyl group or C 1~2More specifically, the alkyl group may be selected. Some examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Some examples of branched alkyl groups include isopropyl (2-propyl), isobutyl (2-methylprop-1-yl), sec-butyl (2-butyl), t-butyl (1,1-dimethylethyl-1-yl), 2-pentyl, 3-pentyl, 2-methylbutyl-1-yl, isopentyl (3-methylbutyl-1-yl), 1,2-dimethylprop-1-yl, 1,1-dimethylprop-1-yl, neopentyl (2,2-dimethylprop-1-yl), 2-hexyl, 3-hexyl, 2-methylprop-1-yl, 1,2-dimethylprop-1-yl, 1,1-dimethylprop-1-yl, neopentyl (2,2-dimethylprop-1-yl), ... The alkyl groups include 1,1-dimethylbutyl-1-yl, 3-methylpent-1-yl, isohexyl (4-methylpent-1-yl), 1,1-dimethylbutyl-1-yl, 1,2-dimethylbutyl-1-yl, 2,2-dimethylbutyl-1-yl, 2,3-dimethylbutyl-1-yl, 3,3-dimethylbutyl-1-yl, 1,1,2-trimethylprop-1-yl, 1,2,2-trimethylprop-1-yl, and many branched alkyl groups containing 7 to 10 carbon atoms, the suffix "1-yl" indicating the point of attachment of the group. The alkyl groups may or may not contain one or more heteroatoms as discussed above.

[0093] "C 2~10 The term "alkenyl" as used herein refers to straight-chain, branched, or cyclic (C) alkyl groups containing 1 to 10 carbon atoms and at least one carbon-carbon double bond. 3~7 For any embodiment disclosed in this disclosure, C 2~10 The alkenyl group is C 3~10 Alkenyl group, C 4~10 Alkenyl group, C 5~10 Alkenyl group, C 6~10 Alkenyl group, C 2~8 Alkenyl group, C 3~8 Alkenyl group, C 4~8Alkenyl group, C 5~8 Alkenyl group, C 6~8 Alkenyl group, C 2~6 Alkenyl group, C 3~6 Alkenyl group, C 4~6 Alkenyl group, C 2~4 Alkenyl group, or C 2~3 The alkenyl group may be more specifically selected. 2~10 Some examples of alkenyl groups include vinyl, propen-1-yl (allyl), 3-buten-1-yl (CH2=CH-CH2-CH2-), 2-buten-1-yl (CH2-CH=CH-CH2-), butadienyl, 4-penten-1-yl, 3-penten-1-yl, 2-penten-1-yl, 2,4-pentadiene-1-yl, 5-hexen-1-yl, 4-hexen-1-yl, 3-hexen-1-yl, 3,5-hexadiene-1-yl, 1,3,5-hexatriene-1-yl, and 6-hepten-1-yl. 2~10 Some examples of alkenyl groups include 2-propen-2-yl, 3-buten-2-yl, 3-buten-3-yl, 4-penten-2-yl, 4-penten-3-yl, 3-penten-2-yl, 3-penten-3-yl, 2,4-pentadiene-3-yl, and many of the C6, C7, C8, C9, and C10 alkyl groups. 10 There is a branched alkenyl group. C 3~7 In the case of cycloalkenyl groups, the groups include aliphatic but not aromatic groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl). The alkenyl group may or may not contain one or more heteroatoms as discussed above.

[0094] "C 2~10 The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing 1 to 10 carbon atoms and at least one carbon-carbon triple bond. 2~10 The alkynyl group is C 3~10 Alkynyl group, C4~10 Alkynyl group, C 5~10 Alkynyl group, C 6~10 Alkynyl group, C 2~8 Alkynyl group, C 3~8 Alkynyl group, C 4~8 Alkynyl group, C 5~8 Alkynyl group, C 6~8 Alkynyl group, C 2~6 Alkynyl group, C 3~6 Alkynyl group, C 4~6 Alkynyl group, C 2~4 Alkynyl group or C 2~3 The alkynyl group may be more specifically selected. 2~10 Some examples of alkynyl groups include ethynyl, propargyl, 2-butynyl, 3-butynyl, and 4-pentynyl. Alkynyl groups may or may not contain one or more heteroatoms as discussed above.

[0095] "C 3~7 The term "cycloalkyl" as used in this disclosure refers to a cyclic hydrocarbon group containing from 3 to 7 carbon atoms. 3~10 The term "cycloalkyl" as used in this disclosure refers to a cyclic hydrocarbon group containing from 3 to 10 carbon atoms. 3~7 Some examples of cycloalkyl groups include cyclopropyl, 1-methylenecyclopropyl (i.e., with the presence of a methylene linker), 2-methylcycloprop-1-yl, 2,3-dimethylcycloprop-1-yl, cyclobutyl, 1-methylenecyclobutyl, 2-methylcyclobut-1-yl, 2,4-dimethylcyclobut-1-yl, cyclopentyl, 1-methylenecyclopentyl, 2-methylcyclopent-1-yl, 2,5-dimethylcyclopent-1-yl, 3,4-dimethylcyclopent-1-yl, cyclohexyl, 1-methylenecyclohexyl, 2-methylcyclohex-1-yl, 2,6-dimethylcyclohex-1-yl, 3,5-dimethylcyclohex-1-yl, and cycloheptyl. In some embodiments, C 3~7A cycloalkyl group is carbocyclic. In another embodiment, C 3~7 A cycloalkyl group may also include (i.e., contain) one or more heteroatoms (e.g., N, O, and / or S) in the ring, in which case the hydrocarbon group is C 3~7 C is a heterocycloalkyl group. 3~7 Some examples of heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydrofuranyl, and dioxolanyl. The term "cycloalkyl" as used herein also includes bicyclic ring systems in which one or both rings are cycloalkyl, such as decalinyl. The term "cycloalkyl" is also intended to include acyclic groups, such as groups containing a cycloalkyl ring bonded to an alkyl group (unless otherwise specified), in which case the group may be further defined as an alkyl-cycloalkyl group or a cycloalkyl-alkyl group, such as methyl-cyclohexyl (tolyl). Cycloalkyl groups may or may not contain one or more heteroatoms as discussed above.

[0096] The term "aryl" as used in this disclosure refers to an aromatic polycarbocyclic hydrocarbon group. The aryl group may be monocyclic or bicyclic. Some examples of monocyclic aryl groups include phenyl and tolyl groups. Some examples of bicyclic aryl groups include naphthalene, indanyl, and indenyl groups.

[0097] The term "heteroaryl" as used in this disclosure refers to an aromatic polyheterocyclic hydrocarbon group. Heteroaryl groups can be monocyclic or bicyclic. Some examples of monocyclic heteroaryl groups include pyridinyl, pyrazinyl, pyrrolyl, pyrimidinyl, and thienyl groups. Some examples of bicyclic heteroaryl groups include indolyl and purinyl groups.

[0098] The compounds disclosed herein may contain at least one asymmetric center. These centers are designated by the symbols "R" or "S" depending on the configuration of the substituents around the chiral atom. Unless otherwise indicated in the structural formula, it should be understood that the present invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d- and 1-isomers, and mixtures thereof, for any compound disclosed in this disclosure. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products and then separating them, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of the enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Starting compounds of a particular stereochemistry may be commercially available or may be made and separated by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. Additionally, any of the compounds disclosed herein may exist as tautomers; all tautomeric isomers are contemplated in the present disclosure. Additionally, any of the compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharma- ceutically acceptable solvents, such as water, ethanol, and the like.

[0099] In some embodiments, the compounds disclosed herein are enriched in a particular enantiomer relative to the corresponding opposite enantiomer of the compound, such that the mixture may not be racemic. In such cases, it is understood that the subject mixture of isomers is in enantiomeric excess and has an optical purity greater than 0%. The enantiomeric excess or optical purity of the isomeric mixture may be, for example, greater than 0%, greater than 5%, greater than 25%, greater than 50%, greater than 75%, greater than 90%, greater than 95%, greater than 97%, greater than 98%, or greater than 99%. The enantiomeric excess or optical purity of the isomeric mixture may be, for example, 5-100%, 25-100%, 50-100%, 75-100%, 90-100%, 95-100%, 97-100%, 98-100%, or 99-100%. Thus, for example, the compounds disclosed herein can be S enantiomers of the compounds substantially free of the R enantiomer, or R enantiomers substantially free of the S enantiomer. Furthermore, when the named compounds contain more than one chiral center, the scope of the disclosure also includes compositions that contain mixtures of various ratios between the diastereomers, as well as compositions that contain one or more diastereomers that are substantially free of one or more of the other diastereomers. By "substantially free" it is meant that the composition contains less than 50%, less than 25%, less than 15%, less than 10%, less than 8%, less than 5%, less than 3%, less than 2%, or less than 1% of the minor enantiomer or diastereomer.

[0100] For clarity, in the context of this disclosure, chemical structures of compounds depicted with a particular stereochemical orientation at any particular chiral center defined by the wedge and dash notation are intended to represent the depicted stereoisomer of the compound in substantially pure form or a mixture that is enriched in the stereoisomer having the depicted stereochemical orientation at the defined chiral center over the stereoisomer having the opposite orientation at the chiral center.

[0101] Any of the compounds disclosed herein may be in the form of their pharmaceutically acceptable salts. The phrase "pharmaceutically acceptable salts" as used herein refers to salts of the compounds disclosed herein that are safe and effective for pharmaceutical use in mammals and retain the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds disclosed herein. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Certain compounds disclosed herein can form pharma-ceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review of pharma- ceutically acceptable salts, see Berge et al., 66 J. Pharm. Sci. 1-19 (1977), incorporated herein by reference.

[0102] The compounds disclosed herein may also include one or more isotopes of the atoms present in the compounds disclosed herein. Isotopes include atoms having the same atomic number but different masses. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include fluorine, ... 13 C and 14 There is C.

[0103] In another aspect, the present invention is directed to a pharmaceutical composition comprising the above-mentioned components (i) and (ii) dispersed in a pharma- ceutically acceptable carrier, i.e., a vehicle or excipient. The components are dispersed in the pharma- ceutically acceptable carrier by mixing in solid form with a solid carrier, or by dissolving or emulsifying in a liquid carrier. The pharmaceutical composition may also be formulated or not with one or more additional active ingredients or adjuvants that improve the overall effectiveness of the pharmaceutical composition.

[0104] Components (i) and (ii) and carriers may be formulated into pharmaceutical compositions and dosage forms according to methods well known in the art. The pharmaceutical compositions of the present invention may be formulated for administration in liquid or solid form. In different embodiments, the pharmaceutical preparations may be formulated for oral administration (e.g., as tablets, capsules, powders, granules, pastes, solutions, suspensions, solutions, or syrups); for parenteral administration (e.g., by subcutaneous, intramuscular, or intravenous injection provided by a sterile solution or suspension); for topical application (e.g., as creams, ointments, or sprays); for sublingual or buccal administration; for ophthalmic administration; for transdermal administration; or for nasal administration.

[0105] Pharmaceutical compositions suitable for oral administration may be presented as individual dosage units, such as pills, tablets, sugar-coated tablets, or capsules, or as powders or granules, or as solutions or suspensions. The active ingredient may also be presented as a bolus or paste. Tablets may contain the active ingredient compound and suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and melting agents. Gelatin capsules may contain the active ingredient compound and powder carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents may be used to prepare compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask unpleasant tastes and protect the tablet from the atmosphere, or enteric-coated to selectively disintegrate in the digestive tract. For oral administration, for example in the form of a tablet or capsule dosage unit, the active drug component may be combined with an oral non-toxic pharma- ceutically acceptable inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0106] For oral administration in liquid dosage forms, the oral drug components may be combined with any oral non-toxic pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharma- ceutically acceptable fats and oils, alcohols, or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions, and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Liquid dosage forms for oral administration may contain colorants and flavorings to enhance patient acceptance.

[0107] For parenteral administration, suitable compositions may include aqueous and non-aqueous sterile solutions. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and buffer substances, if necessary. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. The compositions may be presented in unit-dose or multi-dose containers, such as sealed vials and ampoules, or may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as water, prior to use. For transdermal administration, gels, patches, or sprays, for example, may be considered. Compositions or formulations suitable for pulmonary administration, for example by nasal inhalation, include fine dusts or mists which can be generated using a metered dose pressurized aerosol, nebulizer or insufflator. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

[0108] Any of the compounds disclosed in this disclosure or combinations thereof may also be administered in the form of liposome delivery system, for example, small unilamellar vesicles, large unilamellar vesicles, or multilamellar vesicles.Liposomes, which are well known in the art, can be formed from various phospholipids, for example, cholesterol, stearylamine, or phosphatidylcholine.The compound may also be administered as a component of tissue-targeting emulsion.

[0109] Any of the compounds disclosed in this disclosure or combinations thereof may also be combined with targetable drug carriers, such as soluble polymers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide, polyhydroxyethylaspartamide, and polyethylene oxide-polylysine, substituted with palmitoyl residues. The compounds may also be combined with biodegradable polymers of the type useful in achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked hydrogels or amphiphilic block copolymers.

[0110] The pharmaceutical compositions disclosed herein may, in some embodiments, provide immediate release, delayed release, sustained release, or modified release profiles. In some embodiments, pharmaceutical compositions with different drug release profiles may be combined to produce a biphasic or triphasic release profile. For example, the pharmaceutical compositions may provide immediate and sustained release profiles. In some embodiments, the pharmaceutical compositions may provide sustained and delayed release profiles. Such compositions may be provided as pulsatile formulations, multi-layer tablets, or capsules containing tablets, beads, granules, and the like. The pharmaceutical compositions herein may also provide abuse-deterrent properties by techniques known in the art, for example, by creating tablets that are difficult to crush or dissolve in water. The present invention further includes the pharmaceutical compositions described herein in combination with packaging materials, including instructions for use of the compositions for the uses described herein. In some embodiments, any of the compounds disclosed in this disclosure may alternatively be in the form of a prodrug.

[0111] The phrase "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms within the scope of sound medical judgment that are suitable for administration to a subject. The phrase "pharmacologically acceptable carrier" as used herein refers to a pharma- ceutically acceptable vehicle, such as a liquid or solid filler, diluent, carrier, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), solvent, or encapsulating material, that serves to carry a therapeutic composition to a subject for administration. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically safe for the subject. Any of the carriers known in the art may be suitable herein depending on the mode of administration.

[0112] Some examples of materials that can serve as pharma- ceutically acceptable excipients, particularly for liquid forms, include water; isotonic saline; pH buffers; sugars (e.g., lactose, glucose, sucrose, and oligosaccharides such as sucrose, trehalose, lactose, or dextran); and antibacterial agents. Other excipients more typically used in solid dosage forms may also include, for example, starches (e.g., corn and potato starches); cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); gelatin; talc; waxes; oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols (e.g., ethylene glycol, propylene glycol, and polyethylene glycol); polyols (e.g., glycerin, sorbitol, and mannitol); esters (e.g., ethyl oleate and ethyl laurate); agar; and other non-toxic compatible substances used in pharmaceutical formulations. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Other suitable excipients can be found in standard pharmaceutical texts, such as "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Pa., (1995).

[0113] In some embodiments, the carrier further comprises a molecular or microscopic (e.g., micro- or nano-scale) subcarrier in which the pharmaceutical composition or its components are loaded and / or conjugated to the surface of the subcarrier. The subcarrier may be, for example, composed of a biocompatible and biodegradable polymer, for example, based on a polyhydroxy acid biopolyester or polysaccharide. The overall structure of the subcarrier may be, for example, a micelle, a liposome, a dendrimer, a nanoparticle, or a porous scaffold. These and many other types of subcarriers are well known in the art. The subcarrier may function to protect the pharmaceutical composition or its components during transport, for example while in the bloodstream or while passing through the digestive tract. The subcarrier may also function, if applicable, to release the pharmaceutical composition or its components closer to the target cells where there is less opportunity for degradation. The subcarrier may also be functionalized with one or more targeting agents, if applicable, that selectively target a class of cells to be treated with the pharmaceutical composition or its components. The targeting agent may be, for example, an antibody, an antibody fragment, siRNA, or a small molecule receptor binding agent.

[0114] In another aspect, the present invention is directed to a method for treating a psychiatric disorder by administering a pharmacologic effective amount of components (i) and (ii) to a subject having the psychiatric disorder. As further discussed below, components (i) and (ii) may be administered together at the same time or separately at different times, provided that the time between administration of components (i) and (ii) allows component (i) to modulate the effect of component (ii) in the subject and / or vice versa. The term "psychiatric disorder" includes any harmful or unwanted mental condition, and is therefore intended to include any of the known mental conditions, psychiatric disorders, and psychiatric conditions, such as those classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM5). The mode of administration may be any of the modes of administration described above. The typical mode of administration for the present invention may be oral or intravenous injection.

[0115] In the method of treatment, components (i) and (ii) are administered to a subject (patient) in a therapeutically effective amount. The patient is typically a human, but in some cases may be a non-human mammal, such as a dog, cat, primate, or cow. The therapeutically effective amount of each component is an amount that results in the alleviation of one or more symptoms of the psychiatric disorder or condition being treated. The therapeutically effective amount for each component can be easily determined, for example, during preclinical and clinical trials, according to methods familiar to physicians and clinicians. As is well known in the art, the dosage of the active ingredient depends not only on the type of psychiatric disorder or condition being treated, but also on the method of administration, the size of the patient, and potential side effects. Dosing depends on the severity and responsiveness of the psychiatric disorder or condition being treated, and the course of treatment may last from several days to several months, or until an acceptable alleviation of one or more symptoms of the psychiatric disorder or condition is achieved. The optimal dosing schedule may be calculated from measurements of drug accumulation in the patient's body. The administering physician can determine the optimal dosage, dosing methodology, and repeat administration rate.

[0116] More specifically, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, such as any of compounds (i) and (ii) as described above, or a combination thereof, effective to reduce or inhibit the systemic manifestation of a mental condition or disorder. An effective amount can function to reduce, for example: depression, anxiety, OCD, substance dependence, personality disorder, sadness or lethargy, depressed mood, anxious or sad feelings, reduced interest in all or nearly all activities, significantly increased or decreased appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, lack of concentration, or recurrent thoughts of death or suicide. An effective amount can also function to provide a desired pharmacological and / or physiological effect, such as reducing, inhibiting, or reversing one or more of the underlying pathophysiological mechanisms, the underlying neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate levels or GABA levels or signaling, modulating synaptic connectivity or neurogenesis in certain brain regions, or a combination thereof.

[0117] The term "therapeutic index" used in reference to any compound and its associated therapeutic effects and side effects refers to the ratio of the dose of said compound required to induce a particular negative side effect to the dose of said compound required to induce a desired therapeutic effect.For example, in the case of racemic ketamine, antidepressant therapeutic effects and dissociative side effects occur at similar doses, and therefore the therapeutic index of this compound in this context is about 1:1.In contrast, the compounds or combinations of components (i) and (ii) disclosed herein may have an improved therapeutic index, for example, about 3:1, and a 3-fold higher dose is required to induce dissociative side effects relative to the dose required for antidepressant therapeutic effects.

[0118] The term "about" or "approximately" as used herein indicates an acceptable error range for a particular value as determined by one of ordinary skill in the art, and will depend in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" may mean within 3 standard deviations or more than 3 standard deviations, as per the practice in the art. Alternatively, "about" may mean within a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term may mean within an order of magnitude, e.g., within 5-fold or within 2-fold of a value. "About" and "approximately" are used interchangeably herein.

[0119] In different embodiments, depending on the various factors discussed above, suitable dosages of components (i) and / or (ii) or combinations thereof may be independently and precisely at least, e.g., 1 mg or less, 2 mg or less, 3 mg or less, 4 mg or less, 5 mg or less, 6 mg or less, 7 mg or less, 8 mg or less, 9 mg or less, 10 mg or less, 15 mg or less, 20 mg or less per kg, or per 50 kg, 60 kg, or 70 kg adult. , 25 mg or less, 30 mg or less, 40 mg or less, 50 mg or less, 100 mg or less, 200 mg or less, 300 mg or less, 400 mg or less, 500 mg or less, 600 mg or less, 700 mg or less, 800 mg or less, 900 mg or less, 1000 mg or less, 1200 mg or less, or 1500 mg or less, or a dosage within a range determined by any of the exemplary dosage amounts set forth above. Depending on these and other factors, any of the above components (i) and (ii) are independently administered at the indicated dosages by any suitable schedule, for example, once, twice, or three times a day, or once every two days, or once every three days, or once a week, or once every other week, twice a week, once a month, twice a month, or three times a month, for a total treatment period of up to, for example, 1, 2, 3, 4, or 5 days, or 1, 2, 3, 4, 5, 6 months, a year, or longer. Alternatively, the indicated dosages may be administered every 2 or 3 days, or once a week. Alternatively, or in addition, the composition is administered until a desired change is demonstrated.

[0120] In some embodiments, the method comprises treating a mental or psychiatric disorder or condition by administering to a subject in need thereof about 0.01 mg to about 400 mg of compound (i) and / or compound (ii), or a combination thereof, wherein compounds (i) and (ii) may be administered separately or in the form of a pharmaceutical composition comprising both compounds (i) and (ii) as described above. In some embodiments, the dosage of compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof may vary, e.g., from about 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 15 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg , 20 to 100 mg, 20 to 50 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, and example doses are, for example, about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, and 400 mg.

[0121] In some embodiments, a dosage may comprise an amount of compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof in the range of, for example, about 1 mg to 200 mg, about 1 mg to 100 mg, about 1 mg to 50 mg, about 1 mg to 40 mg, about 1 mg to 30 mg, about 1 mg to 20 mg, about 1 mg to 15 mg, about 0.01 mg to 10 mg, about 0.1 mg to 15 mg, about 0.15 mg to 12.5 mg, or about 0.2 mg to 10 mg; specific examples of dosages include 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1500 mg, 1000 mg, 1500 mg, 1000 mg, 1500 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 1000 mg, 15 ... The dosage may be 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1.5mg, 1.0mg, 1.75mg, 2mg, 2.5mg, 2.75mg, 3mg, 3.5mg, 3.75mg, 4mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 10mg, 11mg, 12mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, and 200mg.

[0122] In some embodiments, component (i) is or comprises a biarylpropylsulfonamide, which may be or comprise PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dose unit of the composition contains between about 0.05 mg and about 1 mg of PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dose unit of the composition contains between about 0.1 mg and about 0.5 mg of PF-04958242 (BIIB-104; pesampatol).

[0123] Dosages of compound (i) and / or compound (ii) or combinations thereof or pharma- ceutically acceptable salts thereof may be administered to a patient in need thereof, for example, daily, every other day, once every third day, twice, three or four times, once a week, or once a month. In some embodiments, dosages are, for example, about 1-400 mg / day, or about 1-300 mg / day, or about 1-250 mg / day, or about 1-200 mg / day, e.g., 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 25 mg / day, 20 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0124] In some embodiments, a pharmaceutical composition for parenteral or inhaled use, e.g., a spray or mist, of the pharmaceutical composition of the present invention or a pharma- ceutical acceptable salt thereof, contains a concentration of compound (i), compound (ii), or a combination thereof, from about 0.005 mg / mL to about 500 mg / mL. In some embodiments, the composition comprises compound (i) and / or compound (ii), or a combination thereof, or a pharma- ceutically acceptable salt thereof, in a concentration of, for example, about 0.05 mg / mL to about 50 mg / mL, about 0.05 mg / mL to about 100 mg / mL, about 0.005 mg / mL to about 500 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 25 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.05 mg / mL to about 5 mg / mL, or about 0.05 mg / mL to about 1 mg / mL.

[0125] In some embodiments, the pharmaceutical composition comprises a compound disclosed herein or a pharma- ceutically acceptable salt thereof, or a combination thereof, for example, in a concentration of about 0.05 mg / mL to about 15 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.25 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 7 mg / mL, about 1 mg / mL to about 10 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to 25 mg / mL, about 5 mg / mL to 50 mg / mL, or about 10 mg / mL to 100 mg / mL. In some embodiments, the pharmaceutical composition is formulated, for example, in a total volume of about 10 mL, about 20 mL, about 25 mL, about 50 mL, about 100 mL, about 200 mL, about 250 mL, or about 500 mL.

[0126] Typically, the dosage may be administered to the subject daily, every other day, once every 3 days, twice, three times or four times, twice a week, once a week, twice a month or once a month. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning or once in the evening. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharmaceutically acceptable salt thereof is administered to the subject once in the morning and once in the evening. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharmaceutically acceptable salt thereof is administered to the subject three times a day (e.g., at breakfast, lunch and dinner), for example, at a dose of about 50 mg / administration (e.g., 150 mg / day).

[0127] In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 25 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 50 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 75 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 100 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 150 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 200 mg / day in one or more doses. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a subject at a dose of 250 mg / day in one or more doses.

[0128] In some embodiments, the dosage of compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is 0.01-100 mg / kg, 0.5-50 mg / kg, 0.5-10 mg / kg, or 25-50 mg / kg, once, twice, three or four times a day. For example, in some embodiments, the dosage of compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is 0.1 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg, once, twice, three or four times a day. In some embodiments, the subject is administered a total daily dose of 0.01 mg to 500 mg of compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof, once, twice, three or four times a day. In some embodiments, the total amount of compound (i) and / or compound (ii) or combinations thereof or pharma- ceutically acceptable salts thereof administered to a subject in a 24-hour period is, for example, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg, or within a range determined by any two of the foregoing values. In some embodiments, a subject may be started at a low dose and the dosage increased. In some embodiments, a subject may be started at a high dose and the dosage decreased.

[0129] In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof may be administered at specified intervals. For example, during treatment, the patient may be administered compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof at intervals of, for example, 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.

[0130] In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a patient under the supervision of a health care provider. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a patient under the supervision of a health care provider in a clinic that specializes in the delivery of psychostimulant treatments. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered to a patient under the supervision of a health care provider in a dose intended to induce a hallucinatory experience in the subject. In some embodiments, administration to a patient under the supervision of a health care provider is performed periodically, for example, every 3 days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year, so as to maintain a therapeutic effect in the patient. In some embodiments, compound (i) and / or compound (ii) or a combination thereof or a pharma- ceutically acceptable salt thereof is administered by the patient himself / herself at home or away from the supervision of a health care provider. In some embodiments, self-administration is performed periodically to maintain therapeutic efficacy in the patient, for example, daily, every other day, every third day, twice weekly, once weekly, twice monthly, or once monthly.

[0131] In one set of embodiments, the pharmaceutical composition containing components (i) and (ii) is mixed or co-administered with one or more other therapeutic agents outside the scope of components (i) and (ii), which may function to beneficially modulate the activity of components (i) or (ii), or may act independently in the treatment of a psychiatric disorder or condition, and do not adversely interact or interfere with the activity of components (i) or (ii). The co-administered therapeutic agents may be selected from conventional therapeutic agents known in the art to be useful in the treatment of a psychiatric disorder or condition, for example, either SSRIs (e.g., citalopram, escitalopram, or fluoxetine) or non-SSRIs (e.g., gabapentin or bupropion) for treating depression or anxiety. However, in some embodiments, one or more of any of the above co-administered therapeutic agents are excluded, or the co-administered therapeutic agents are entirely excluded, i.e., the pharmaceutical composition or treatment method may include or use only components (i) and (ii), optionally in a pharma- ceutically acceptable carrier. In the first case, co-administration may be achieved by including mixing components (i) and (ii) with one or more other therapeutic agents in the same pharmaceutical composition to be administered. In the second case, co-administration may be achieved by administering components (i) and (ii) separately with one or more other therapeutic agents, i.e., at the same time or at different times. In certain embodiments, GABA receptor modulators or antagonists and / or 5-HT2A receptor modulator agonists (e.g., tryptamines, ergolines, phenethylamines, or amphetamines) or antagonists are included or excluded from any of the pharmaceutical compositions or treatment embodiments disclosed in the present disclosure.

[0132] In a first embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in a single pharmaceutical composition in which the therapeutic compounds (i) and (ii) are present in a pharma- ceutically effective amount. In a second embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 7, 6, 5, 4, 3, or 48 hours of each other, with the term "within" referring to a time at or below a specified time (exact or approximate), but including a minimum time between the several doses, e.g., at least 1, 2, 5, 10, 20, 30, or 60 minutes. In a third embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 36 hours of each other. In a fourth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 24 hours of each other. In a fifth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 18 hours of each other. In a sixth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 12 hours of each other. In a seventh embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 6 hours of each other. In an eighth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 4 hours of each other. In a ninth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 3 hours of each other. In a tenth embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 2 hours of each other. In an eleventh embodiment, the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 1 hour of each other. In other embodiments, therapeutic compounds (i) and (ii) are administered in separate doses within a range of various times bounded by any two of the exemplary time periods provided above (e.g., 1-48 hours, 2-48 hours, 1-24 hours, 2-24 hours, 1-12 hours, or 2-12 hours), or within a range of various times having a minimum of 1, 2, 5, 10, 20, 30, or 60 minutes and any of the time periods disclosed above (e.g., 30 minutes to 24 hours or 30 minutes to 12 hours). In some embodiments, therapeutic compound (i) is administered prior to therapeutic compound (ii).In other embodiments, the therapeutic compound (ii) is administered prior to the therapeutic compound (i).

[0133] In some embodiments, the therapeutic compound (ii) is administered once or multiple times until a sufficient therapeutic response is achieved, for example, by any of the dosages or dosing regimens described above, and then the therapeutic compound (i) is administered once or multiple times to prolong or maintain the therapeutic response (by any of the dosages or dosing regimens described above). In some embodiments, the therapeutic compound (i) is administered daily or twice daily after a sufficient therapeutic response is achieved by administration of compound (ii). In other embodiments, the therapeutic compounds (i) and (ii) are administered to the subject as a single pharmaceutical composition in which the therapeutic compounds (i) and (ii) are present in a pharmacologic effective amount, once or multiple times until a sufficient therapeutic response is achieved, and then the therapeutic compound (i) is administered once or multiple times to prolong or maintain the therapeutic response. For any of the foregoing embodiments, the therapeutic response may be a >50% (greater than 50%) decrease in score on the Hamilton Depression Rating Scale or the Montgomery Asberg Depression Rating Scale.

[0134] In some embodiments, the therapeutic compounds (i) and (ii) are administered to a subject in amounts that are sub-therapeutic when administered alone, but that provide a synergistic effect to treat a psychiatric disorder when administered in combination as a single pharmaceutical composition or in separate administrations within 7, 6, 5, 4, 3, or 48 hours of each other, or within any of the other time periods previously described above. The sub-therapeutic dose will vary depending on the compound administered and the psychiatric condition or disorder being treated, and may be selected for each compound independently from any of the doses disclosed anywhere within the scope of this disclosure. The term "synergistic effect" refers to a positive effect in the treatment of a psychiatric condition or disorder, which positive effect is greater than the expected additive effect that each compound would be expected or known to provide when administered alone.

[0135] In some embodiments of the method, component (i) is a biarylpropylsulfonamide, which may be at least one of LY-451395 (mibanpatol), LY-404187, LY-503430, PF-04958242 (BIIB-104; pesampatol), LY-392098, LY-450108, LY-451646, PF-04778574, CMPDA, CMPDB, and (R,R)-PIMSD, or more particularly at least one of LY-451395 (mibanpatol), LY-404187, LY-503430, and PF-04958242 (BIIB-104; pesampatol), or more particularly PF-04958242 (BIIB-104; pesampatol). In some embodiments, PF-04958242 is administered and each dose of PF-04958242 is from about 0.05 mg to about 1 mg or from about 0.1 mg to about 0.5 mg.

[0136] In some embodiments of the method, component (ii) is selected from at least one of ketamine, R-ketamine, S-ketamine, S-norketamine, N-ethylnorketamine, N-propylnorketamine, memantine, amantadine, phencyclidine (PCP), rolicyclidine (PCPy), PCM, PCPr, tenocyclidine (TCP), tiletamine, 2-oxo-PCP, 2-oxo-PCE, gacyclidine, 3-MeO-PCP, 3-OH-PCP, 4-MeO-PCP, deschloroketamine, 2-fluoro-deschloroketamine, ethicyclidine (PCE), 3-MeO-PCE, 4-MeO-PCE, 3-OH-PCE, methoxetamine, methoxymethamine, methoxypropamine, methoxyisopropamine, and hydroxetamine. In more particular embodiments, component (ii) is selected from ketamine, R-ketamine, S-ketamine, and S-norketamine, or more particularly selected from ketamine, R-ketamine, and S-ketamine, or component (ii) may be or include ketamine or an analogue thereof.

[0137] In some embodiments of the method, component (ii) is

[0138] [ka]

[0139] or more particularly, component (ii) is selected from at least one of

[0140] [ka]

[0141] is or includes:

[0142] In some embodiments of the method, component (ii) is selected from at least one of 8A-PDHQ, dextromethorphan, dextromethorphan-OD3, dextrorphan, dextralorphan, dextromethadone (REL-1017), PD-137889, neramexane, memantine, NEFA, dizocilpine, lanicemine, diphenidine, ephenidine, isopropylphenidine, methoxyphenidine, fluorolintane, xenon, krypton, nitrous oxide, etoxadrol, dexoxadrol, ibogaine, and noribogaine, or more particularly selected from dextromethorphan and dextromethorphan-OD3. In further embodiments, the subject may be administered a pharma- ceutically effective amount of a third compound, component (iii), selected from quinidine and bupropion.

[0143] In some embodiments of the method, component (ii) is a compound that selectively blocks or negatively modulates NMDA receptors containing the GluN2B (GRIN2B) subunit. In more specific embodiments, component (ii) is selected from at least one of MIJ821, lisrenemdaz, eliprodil, ifenprodil, besonprodil, traxoprodil, radiprodil, BMS-986169, BMS-986163, Ro 25-6981, Ro 04-5595, TCN 237, TCS 46b, and Co 101244.

[0144] In some embodiments of the method, the subject (as previously described above) is administered a pharmaceutical composition containing the following components: (i) an AMPA receptor positive allosteric modulator (PAM) or a pharma- ceutically acceptable salt thereof; and (ii) (2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one or a pharma- ceutically acceptable salt thereof. Component (i) may be any of the compounds described throughout this disclosure with respect to component (i). In some embodiments, component (i) is PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dose unit of the composition contains between about 0.05 mg and about 1 mg of PF-04958242 (BIIB-104; pesampatol). In some embodiments, each dosage unit of the composition contains between about 0.1 mg and about 0.5 mg of PF-04958242 (BIIB-104; pesampatol). In further or separate embodiments, each dosage unit of the composition contains between about 10 mg and about 100 mg of component (ii). In further or separate embodiments, each dosage unit of the composition contains between about 20 mg and about 40 mg of component (ii). In some embodiments, the composition further comprises a pharma- ceutically acceptable carrier as fully described above. In some embodiments, the therapeutic compounds (i) and (ii) are administered to the subject as a single pharmaceutical composition in which the therapeutic compounds (i) and (ii) are present in a pharma- ceutically effective amount. In other embodiments, the therapeutic compounds (i) and (ii) are administered separately, e.g., within 7 days, 6 days, 5 days, 4 days, 3 days, or 48 hours of each other, as previously described above. In some embodiments, the therapeutic compound (i) is administered prior to the therapeutic compound (ii). In other embodiments, the therapeutic compound (ii) is administered prior to the therapeutic compound (i).

[0145] The mental / psychiatric condition or disorder to be treated may be any condition or disorder known in the art, for example, as described in the DSM-5 manual. The mental / psychiatric condition or disorder may generally be in the form of, for example, depression, bipolar disorder, substance abuse disorder (e.g., drug dependency, or more specifically, opioid abuse disorder), anxiety, obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, eating behavior disorders and eating disorders, borderline personality disorder, attention deficit / hyperactivity disorder, autism spectrum disorder, neurocognitive disorders (e.g., Alzheimer's disease, mild or moderate cognitive impairment, and Parkinson's disease), or treatment-resistant diseases or disorders. Any of the above-mentioned pharmaceutical compositions comprising any of the above-mentioned combinations of compounds (i) and (ii) in any of the above-mentioned dosages or dosage regimens may be used to treat any one or more of the mental / psychiatric conditions or disorders described in the present disclosure.

[0146] In a first series of embodiments, the mental / psychiatric condition or disorder treated by using any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or includes depression. The depressive condition or disorder may be, for example, major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and / or a depressive disorder caused by or associated with another medical (optionally non-psychiatric) condition. The depression may also be refractory depression, for example, a patient suffering from a depressive disorder that is unresponsive and / or has not responded to at least one or at least two other antidepressant compounds or an adequate course of therapy. As used herein, the term "depressive disorder" may include refractory depression.

[0147] In a second set of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or comprises bipolar disorder, which may be, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and / or bipolar disorder and related disorders caused by another medical (optionally non-psychiatric) condition.

[0148] In a third series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or comprises an anxiety disorder, which may be, for example, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and / or anxiety disorder caused by another medical (optionally non-psychiatric) condition.

[0149] In a fourth series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or includes a substance abuse, substance dependence, or related disorder. The substance may be any substance that can be abused to achieve a psychoactive response, particularly an addictive substance. The substance may be, for example, an opioid (e.g., heroin, oxycodone, or fentanyl), alcohol, cannabinoids (in isolated form or as the cannabis plant), inhalants, sedatives, hypnotics, anxiolytics, stimulants (e.g., amphetamine or methamphetamine), nicotine (in isolated form or as the tobacco plant), and / or caffeine. In some embodiments, the method of treatment reduces or prevents craving for the abused substance and / or promotes cessation or withdrawal from the use of the substance.

[0150] In a fifth series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or includes obsessive-compulsive disorder (OCD) or related disorders. Some examples of OCD and related disorders include obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), epidermolysis (skin-picking) disorder, substance / medication-induced obsessive-compulsive disorder and related disorders, and obsessive-compulsive disorder and related disorders due to another medical condition.

[0151] In a sixth series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or includes trauma and stressor-related disorders. Some examples of such disorders include reactive attachment disorder, disinhibited social interaction disorder, post-traumatic stress disorder, acute stress disorder, and adjustment disorder.

[0152] In a seventh series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or comprises an eating disorder. Some examples of eating disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder.

[0153] In an eighth series of embodiments, the mental / psychiatric condition or disorder treated by using any of the above-mentioned pharmaceutical compositions and dosages thereof is in the form of or includes neurocognitive disorder.Some examples of neurocognitive disorder include delirium, mild cognitive impairment, moderate cognitive impairment, severe neurocognitive disorder, mild neurocognitive disorder, mild or advanced Alzheimer's disease, severe or mild frontotemporal neurocognitive disorder, severe or mild neurocognitive disorder with Lewy bodies, severe or mild vascular neurocognitive disorder, severe or mild neurocognitive disorder caused by traumatic brain injury, substance / medication-induced severe or mild neurocognitive disorder, severe or mild neurocognitive disorder caused by HIV infection, severe or mild neurocognitive disorder caused by prion disease, mild or advanced Parkinson's disease, mild or advanced Huntington's disease, severe or mild neurocognitive disorder caused by another medical condition, and severe or mild neurocognitive disorder caused by multiple etiologies.

[0154] In a ninth series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is or includes a neurodevelopmental disorder. Some examples of neurodevelopmental disorders include autism, autism spectrum disorder, attention deficit / hyperactivity disorder, stereotypic movement disorder, tic disorder, Tourette's disorder, persistent (chronic) motor or vocal tic disorder, and episodic tic disorder.

[0155] In a tenth series of embodiments, the mental / psychiatric condition or disorder treated by the use of any of the above-mentioned pharmaceutical compositions and dosages thereof is or includes a personality disorder. Some examples of personality disorders include borderline personality disorder, paranoid personality disorder (e.g., paranoia), schizoid personality disorder (e.g., schizophrenia), schizotypal personality disorder, antisocial personality disorder, narcissistic personality disorder, and avoidant personality disorder.

[0156] In some embodiments, the above-described methods of treating using any combination of compounds (i) and (ii) result in the improvement of any one or more of the above-listed psychiatric conditions or disorders. In some embodiments, the methods may also provide improvement in at least one symptom selected from any of the following: sadness, lethargy, or fatigue, depressed mood, inability to feel emotions, anxious and anxious feelings, fear, tension, feelings of restlessness, decreased interest in all or nearly all activities, difficulty initiating activities, significantly increased or decreased appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about oneself, others or the world, feelings of helplessness, lack of concentration or distractibility, recurrent thoughts of death or suicide, feelings of guilt, memory complaints, difficulty experiencing positive emotions, feelings of detachment from people, hyperarousal, risk-taking behaviors, avoidance of thoughts about stressful or traumatic events, various pains and aches, rumination and obsessions, compulsive behaviors, disturbing intrusive thoughts, addictive drug use, feelings of guilt associated with drug use, and withdrawal symptoms resulting from drug use.

[0157] In some embodiments, patients are treated with any of the pharmaceutical compositions and dosages thereof described above to produce one or more of the following improvements: (i) a 50% or greater improvement (relative to baseline) based on at least one assessment test selected from MADRS, HDRS, QIDS, HAM-D6, and adjusted HRDS17; (ii) a 50% or greater improvement relative to baseline in a score on the Ruminative Response Scale; (iii) a 50% or greater improvement relative to baseline in a score on the Snaith Hamilton Anhedonia Pleasure Scale; (iv) a 50% or greater improvement relative to baseline in a score on the Karolinska Sleepiness Scale; (v) a 50% or greater improvement relative to baseline in a score on the Digit Symbol Substitution Test; (vi) a 50% or greater improvement relative to baseline in a score on the Prolonged Grief Disorder-13; (vii) a 50% or greater improvement relative to baseline in a HAM-A score; (viii) a 50% or greater improvement relative to baseline in a Liebowitz Social Anxiety Scale; (ix) a 50% or greater improvement relative to baseline in a score on the Yale-Brown Obsessive Compulsive Disorder-13. (x) a 50% or greater improvement over baseline in a score on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5); or (xi) a 50% or greater improvement over baseline in a score on a scale selected from the group consisting of Conners' Adult ADHD Rating Scale-Investigator Rated, AAQOL-29, and a cognitive test (e.g., CogState or CANTAB).

[0158] Examples are provided below for purposes of illustrating the present invention and to describe the best mode of the invention at the time of its disclosure, however the scope of the present invention is in no way limited by the examples provided herein. EXAMPLES

[0159] Example 1 A study of the safety and efficacy of a combination containing an AMPAR-PAM and an NMDA receptor antagonist in adults with neuropsychiatric disorders A study is conducted to evaluate the safety and efficacy of a combination comprising an AMPAR-PAM compound and an NMDA receptor antagonist (NMDAR-ant) compound in adults with psychiatric disorders. The subjects are diagnosed with depressive disorders. The subjects are first assessed (e.g., MADRS, HDRS, QIDS, HAM-D6, and adjusted HRDS17) and undergo behavioral therapy, e.g., cognitive tasks or other behavioral training or therapy on the previous day.

[0160] After evaluation and behavioral therapy, subjects will be assigned to one of the following groups:

[0161] AMPAR-PAM compound + placebo

[0162] NMDAR antagonist + placebo

[0163] AMPAR-PAM compound + NMDAR antagonist compound

[0164] Subjects will receive treatment with the combination or with each individual component either 1-3 times per week for 2-6 weeks or daily for 2-6 weeks. Maintenance therapy may be used less frequently after response. The following combinations will be evaluated:

[0165] AMPAR-PAM compounds (e.g., mibanpatol, LY-451395, BIIB-104, PF-04958242, tulanpatol, CX-156, CS-1632, CX-691, or faranpatol) and NMDA receptor antagonists (e.g., compound 18R, ketamine, R-ketamine, S-ketamine, N-ethylnorketamine, N-propylnorketamine, memantine, amantadine, phencyclidine (PCP), rolicyclidine (PCPy), PCM, P In combination with CPr, tenocyclidine (TCP), tiletamine, 2-oxo-PCP, 2-oxo-PCE, gacyclidine, 3-MeO-PCP, 3-OH-PCP, 4-MeO-PCP, deschloroketamine, 2-fluoro-deschloroketamine, eticyclidine (PCE), 3-MeO-PCE, 4-MeO-PCE, 3-OH-PCE, methoxetamine, methoxymethamine, methoxypropamine, methoxyisopropamine, hydroxetamine, or 8A-PDHQ.

[0166] After the above treatment, subject is evaluated based on at least one of the following assessment tests: MADRS, HDRS, QIDS, HAM-D6 and adjusted HRDS17.Some level of improvement is observed for all tested combinations, and at least 50% improvement is observed for at least some of tested combinations.The combination of AMPAR-PAM and NMDAR antagonist shows significant durability, efficacy and / or potency compared with the combination of each component and placebo.

[0167] Randomized withdrawal designs may also be used to assess retention:

[0168] Patients / subjects who respond to the combination (e.g., those with a 50% or greater response to acute treatment) are blinded and randomized to continue treatment or to receive a placebo. Patients / subjects are then monitored over time to assess time to relapse or other negative outcomes (e.g., a certain percentage of exacerbation). Maintenance therapy with the combination provides better durability of response than placebo. Alternatively, subjects are first treated with one or more doses of an NMDAR antagonist (e.g., compound 18R), and subjects who respond to this treatment (e.g., those with a 50% or greater response to acute treatment, e.g., a reduction in MADRS score) are blinded and randomized to receive treatment with an AMPAR-PAM (e.g., BIIB-104, e.g., at a dose of 0.1-0.5 mg per dose) or a placebo, either daily or intermittently (e.g., 1-3 times per week). Patients / subjects are then monitored over time to assess time to relapse or other negative outcomes (e.g., a certain percentage of exacerbation). Maintenance therapy with AMPAR-PAM provides superior durability of initial response to NMDAR antagonists compared with placebo.

[0169] Example 2 Combinatorial activity in the forced swimming test in rats. The disclosed combination of AMPAR-PAM (e.g., BIIB-104) and NMDAR-ants (e.g., compound 18R) induces antidepressant-like effects in the forced swim test (FST) in rats with a pretreatment time of 23.5 hours. In particular, combination treatment with the two compounds reduces immobility time compared to vehicle control, indicating an antidepressant-like effect. These effects on immobility are observed 23.5 hours after a single dose of the combination, at which point most or all of the drug has been removed from the systemic circulation, suggesting that the combination has both rapid and long-lasting antidepressant-like effects. Furthermore, the minimum effective dose of each component when administered together as a combination treatment is lower than when each compound is administered alone. In other words, the components of the combination reinforce each other, resulting in a stronger antidepressant-like effect in this rat model.

[0170] Animals. Male Sprague Dawley rats aged 8-10 weeks are used in the experiments. Animals are housed in groups of two under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, with a 12-h light / dark cycle and food and water available ad libitum. All efforts are made to minimize suffering.

[0171] Drugs and Drug Administration. Test compounds, vehicle, and the positive control desipramine are administered subcutaneously (sc) and doses are calculated based on the free base. A pharmacologically inactive vehicle is used. All compounds are administered in a volume of 5 mL / kg. Test compounds (in each case the AMPAR-PAM+NMDAR-ant combination, or either compound alone) and vehicle are administered 0.5 hours after the start of the training swim (swim 1) and 23.5 hours before the test swim (swim 2). Desipramine is administered three times at a dose of 20 mg / kg each time, 23.5 hours, 5 hours, and 1 hour before the test swim (swim 2).

[0172] Forced Swim Test (FST). Animals are randomized based on body weight to ensure that variation between groups is minimal and does not exceed ±20% of the mean body weight across groups. Group size is N=10 per treatment. Rats are handled for approximately 2 min each day for 5 days prior to the start of the experimental procedure. On the first day of the experiment (i.e., day 0), after randomization, a training swim session (swim 1) is performed in all animals between 12:00 and 18:00 by placing the rats in individual glass cylinders (46 cm high x 20 cm diameter) containing water at 23-25 ​​°C and 30 cm deep for 15 min. At the end of swim 1, animals are dried with paper towels and placed in a warmed, dry cage for 15 min and then returned to their home cage. Animals are then administered the appropriate drug or vehicle treatment as described above. For clarity, the time of compound administration 23.5 h before swim 2 means 0.5 h after swim 1 has begun and 0.25 h after swim 1 has been completed (i.e., immediately after being returned to the home cage). On day 1 (i.e., 24 hours after beginning swim 1), animals are subjected to a 5 min test swim (swim 2) under otherwise identical conditions to swim 1. Water is replaced for each animal during all swim sessions.

[0173] Behavioral scoring is performed by an observer blinded to the treatment groups. Animals are continuously observed during swim 2 and the total time spent performing the following behaviors is recorded: immobile, swimming, and climbing. A rat is considered immobile if it remains suspended in the water without struggling and makes only those movements necessary to keep its head above the surface. A rat is considered swimming if it makes more active swimming movements (e.g., moving back and forth in the cylinder) than are necessary simply to keep its head above the surface. A rat is considered climbing if it actively moves with its front legs in and out of the water, usually towards the wall.

[0174] Statistical Analysis. Analyses are performed using GraphPad Prism 9. Comparisons between groups are performed using one-way analysis of variance (ANOVA) followed by Dunnett's test compared to vehicle.

[0175] Example 3 Activity of the BIIB-104 / Compound 18R combination in the rat forced swimming test Animals. Male Sprague Dawley rats aged 8-10 weeks are used in the experiments. Animals are housed in groups of two under controlled temperature (22±3°C) and relative humidity (30-70%) conditions, with a 12-h light / dark cycle and food and water available ad libitum. All efforts are made to minimize suffering.

[0176] Drugs and Drug Administration. Test compounds, vehicle, and the positive control desipramine are administered subcutaneously (sc) and doses are calculated based on the free base. A pharmacologically inactive vehicle is used. All compounds are administered in a volume of 5 mL / kg. Test compounds or vehicle are administered 0.5 hours after the start of the training swim (Swim 1) and 23.5 hours before the test swim (Swim 2), as described in more detail below. Desipramine is administered three times at a dose of 20 mg / kg each time, 23.5 hours, 5 hours, and 1 hour before the test swim (Swim 2).

[0177] Forced Swim Test (FST). Animals are randomized based on body weight to ensure that variation between groups is minimal and does not exceed ±20% of the mean body weight across groups. Group size is N=10 per treatment. Rats are handled for approximately 2 min each day for 5 days prior to the start of the experimental procedure. On the first day of the experiment (i.e., day 0), after randomization, a training swim session (Swim 1) is performed in all animals between 12:00 and 18:00 by placing the rats in individual glass cylinders (46 cm high x 20 cm diameter) containing water at 23-25 ​​°C and 30 cm deep for 15 min. At the end of Swim 1, animals are dried with paper towels and placed in a warmed dry cage for 15 min, then returned to their home cage. Animals are then administered vehicle, desipramine (1st dose), or compound 18R (1, 3.2 or 10 mg / kg), followed by a second injection of vehicle or BIIB-104 (0.03 mg / kg) within 10 minutes (desipramine animals receive a vehicle injection). For clarity, the time of compound administration 23.5 hours before swim 2 means 0.5 hours after swim 1 begins and 0.25 hours after swim 1 is completed (i.e., immediately after returning to the home cage). On day 1 (i.e., 24 hours after swim 1 begins), animals are given a test swim (swim 2) for 5 minutes, but otherwise under the same conditions as swim 1. Water is replaced for each animal during all swim sessions.

[0178] Behavioral scoring is performed by an observer blinded to the treatment groups. Animals are continuously observed during swim 2 and the total time spent performing the following behaviors is recorded: immobile, swimming, and climbing. A rat is considered immobile if it remains suspended in the water without struggling and makes only those movements necessary to keep its head above the surface. A rat is considered swimming if it makes more active swimming movements (e.g., moving back and forth in the cylinder) than are necessary simply to keep its head above the surface. A rat is considered climbing if it actively moves with its front legs in and out of the water, usually towards the wall.

[0179] Statistical Analysis. Analyses are performed using GraphPad Prism 9. Comparisons between groups are performed using one-way analysis of variance (ANOVA) followed by Dunnett's test compared to vehicle.

[0180] Results. Compound 18R dose-dependently reduced immobility time, demonstrating an antidepressant-like effect, and this effect was potentiated by co-administration of BIIB-104 (i.e., there was a reduction in the minimal dose required to reduce immobility).

[0181] Example 4 Chronic mild stress Animals. Male Wistar Han or Wistar Kyoto rats (Charles River, Sulzfeld, Germany) are brought to the laboratory at 5 weeks of age (approximately 100 g) approximately 1 month before the start of the experiment. Except for the first 10 days after arrival, when animals are housed in groups of 10, they are housed singly and maintained under constant temperature (22 ± 2 °C) and humidity (45 ± 5%) conditions with food and water available ad libitum and a 12-h light / dark cycle.

[0182] Drugs and Drug Administration. Test compounds or vehicle are administered subcutaneously (sc) and doses are calculated based on the free base. A pharmacologically inactive vehicle (e.g., saline) is used. All compounds are administered in a volume of 2 mL / kg. Test compounds (in either case, the combination of BIIB-104 + Compound 18R, or either compound alone) and vehicle are administered as described below.

[0183] Chronic mild stress (CMS) procedure and sucrose preference. Male rats (250-350 g) are habituated to drinking 1% sucrose to establish stable levels of sucrose intake. Rats are assigned to either the CMS or control (no stress) paradigm so that sucrose intake is balanced across the two cohorts. The CMS procedure is applied for up to 10 consecutive weeks. Each week of the stress regimen consists of two periods of food or water deprivation, two periods of 45 degree cage tilt, two periods of intermittent lighting (2 h light / dark), two periods of soiled cages (250 mL water in sawdust bedding), one period of pair housing, two periods of low intensity strobe lighting (150 flashes / min), and three periods of no stress. All stressors last 10-14 h and are applied individually and continuously day and night. Control, unstressed animals are kept in a separate room and have no contact with stressed animals. Control rats are food and water deprived for 14 hours prior to each sucrose test, but otherwise have food and water available ad libitum. After 2 weeks of the stress or control paradigm, rats are assigned to one of four treatment groups (n=8 / group) with comparable baseline sucrose intake across all groups. Rats continue to be exposed to the stress paradigm for at least 4 weeks.

[0184] Rats are dosed with compound 18R (1.5 mg / kg, ip), BIIB-104 (0.03 mg / kg, sc), or vehicle as shown in Table 1, and sucrose intake is measured 24 hours later. After measuring sucrose intake, rats are dosed with BIIB-104 or vehicle once daily for up to 4 weeks (Table 1).

[0185] [Table 1]

[0186] Sucrose intake is measured once a week in each case, prior to that day's drug administration (approximately 24 hours after the previous drug administration). Administration of compound 18R increases sucrose intake in stressed rats (significantly increased relative to vehicle-treated stressed rats), which is evident after 24 hours and persists for 1-2 weeks. Administration of BIIB-104 from day 2 extends the duration of the effect of compound 18R (S4) on sucrose intake, with sucrose intake still remaining significantly higher than vehicle-treated stressed rats and longer than the group dosed with compound 18R followed by daily vehicle injections (S2), for example over 3 and 4 weeks of dosing. Drug treatment does not alter behavior in unstressed rats.

[0187] Elevated Plus Maze (EPM). Animals are tested in two opaque boxes consisting of two open (50 x 11 x 40 cm) and two closed (50 x 11 x 40 cm) arms. The apparatus is elevated 50 cm from the floor and illuminated by two 25 W bulbs positioned directly below the open arms. Animals are placed in the center of the apparatus and the time spent in each arm and the number of entries into the open and closed arms are recorded during a 5 minute test.

[0188] All rats (all groups in Table 1) are evaluated in the EPM in the third week (typically day 16) of drug testing. Stressed vehicle-treated rats (S1) have higher levels of anxiety as measured by a lower % time spent in the open arms compared to control vehicle-treated rats (C1). Stressed compound 18R-treated rats (S2) spend more time in the open arms than stressed vehicle-treated rats (S1), but less time than non-stressed vehicle-treated rats (C1) because they were tested 2 hours after a single dose of compound 18R. Treatment with the combination of compound 18R followed by BIIB-104 completely reverses the effects of stress, such that the S4 group shows a time spent in the open arms that is not different from the C1 group and is significantly longer than the S1 group. This indicates that BIIB-104 extends the efficacy of compound 18R in reversing the anxiogenic effects of stress. Drug treatment does not alter behavior in unstressed rats.

[0189] Novel Object Recognition (NOR) Test. Animals are tested in an impermeable circular open field (100 cm diameter, 35 cm height, floor divided into painted 16 cm squares). After 2 days of adaptation to the open field (10 min each day), animals are allowed to explore two identical cylindrically shaped white objects (7 cm diameter, 11 cm height) for the time required to complete a 15 s exploration of both objects (T1 session). In a retention trial (T2 session) performed 1 h later, one of the previously presented objects is replaced by a novel prism-shaped black object (5 cm width, 14 cm height). The rat is returned to the open field and the duration of exploration of each object is recorded in a 5 min test. The recognition index is calculated according to the formula: time of novel object exploration - time of familiar object exploration / total exploration time (novel object + familiar object). During the NOR session, the number of crossings of the line is recorded as a measure of locomotor activity.

[0190] All rats (all groups in Table 1) are evaluated in NOR in the drug test on week 3 (typically day 17). Stressed vehicle-treated rats (S1) have recognition memory deficits as indicated by a lower recognition index than vehicle-dosed control rats (C1), meaning that S1 rats spend the same time exploring novel and familiar objects, and C1 rats spend more time exploring novel objects. Stressed compound 18R-treated rats (S2) show limited preference for exploring novel objects, as they are tested 2 hours after a single dose of compound 18R. Treatment with the combination of compound 18R followed by BIIB-104 completely reverses the effects of stress, such that the S4 group shows a preference for novel objects that is not different from the C1 group and is significantly higher than the S1 group. This indicates that BIIB-104 extends the efficacy of compound 18R in reversing the recognition memory deficit effects of stress. Drug treatment does not alter behavior in unstressed rats.

[0191] Example 5 Rotarod Animals. Male C57BL / 6 mice (8-10 weeks old) were housed in groups of 2 or more under standard controlled environmental conditions (22-24°C; 30-70% relative humidity) with a standard 12-h light cycle. Food and water were available ad libitum.

[0192] Drugs and Drug Administration. Test compounds and vehicle are administered subcutaneously (sc) and doses are calculated based on the free base. A pharmacologically inactive vehicle is used. All compounds are administered in a volume of 10 mL / kg. Test compounds (in each case the combination of BIIB-104 + Compound 18R, or either compound alone) and vehicle are administered as described below.

[0193] Rotarod Procedure. Mice will be trained to stay on a rotating bar ("rotarod") on days -4 and -2 by placing them on the bar rotating at 4 rpm for 3 min over 3 sessions approximately 10 min apart. This will be repeated on days -1 and 0 using a faster speed of 15 rpm. Mice with a latency of less than 80 s to fall during training will be excluded from the study. On day 1, mice will be dosed (sc) with vehicle or BIIB-104 (0.03 mg / kg) 0-30 min before vehicle or compound 18R (3.2, 10, or 32 mg / kg) for a total of 8 groups with n=10-12 / group. Five min after the second injection, mice will be placed on the rotarod, which will be accelerated from 4 to 40 rpm over 300 s. The latency of the mice to fall will be recorded. Mice will be returned to their standard cages by 30 minutes after the second dose, at which point testing on the accelerating rotarod will be repeated.

[0194] Results. Compound 18R dose-dependently reduces the latency of mice to fall from the rotarod with an ED50 of approximately 20 mg / kg at both time points. BIIB-104 alone does not alter the latency to fall at either time point. Pretreatment / coadministration of BIIB-104 attenuates the reduction in latency to fall caused by compound 18R alone, resulting in an increased ED50 at both time points. This indicates that BIIB-104 can reduce the motor dysfunction caused by compound 18R.

[0195] Example 6 Visual Identification Animals. Male C57BL / 6 mice (8-10 weeks old) are housed in groups of two or more under standard controlled conditions (22-24°C; 30-70% relative humidity) with a standard 12-h light cycle. Five days prior to the start of operant conditioning experiments, all subjects are placed on an food-restricted diet designed to maintain a stable 80-85% of their free-feeding body weight.

[0196] Drugs and Drug Administration. Test compounds and vehicle are administered subcutaneously (sc) and doses are calculated based on the free base. A pharmacologically inactive vehicle is used. All compounds are administered in a volume of 10 mL / kg. Test compounds (in each case the combination of BIIB-104 + compound 18R, or either compound alone) and vehicle are administered as described below. Mice are tested in a randomized crossover design, so that different compound combinations are tested in the same mice, achieving a sample size of n=8-12 / group. Compound testing sessions are separated by at least 3 days.

[0197] Visual Discrimination Procedure. Cohorts of mice are trained to perform a visual discrimination task according to published methods (Dillon et al., 2009, Behavioural Brain Research 204, 67-76). The test apparatus is a standard operant chamber (Med Associates, St Albans, VT). Food-restricted mice are trained to press a lever following a light stimulus and are required to discriminate between a reinforced and a non-reinforced lever. Mice are required to press a lever signaled by a light stimulus to obtain a food reward. Mice are trained daily for approximately 10 days to reach a high level (approximately 80%) of performance accuracy. Once training is complete, mice are used to evaluate the effects of test compounds. Part 1: Mice are administered (sc) vehicle or Compound 18R (10, 32, or 100 mg / kg) 0–30 min prior to performing the visual discrimination task to identify the dose of Compound 18R that reduces task accuracy. Doses of Compound 18R that reduce accuracy are then tested in combination with BIIB-104 in Part 2. Part 2: Mice are dosed (sc) with BIIB-104 (0.03 mg / kg) or vehicle 0-30 min prior to vehicle or Compound 18R (at the dose identified in Part 1). 0-30 min after the second injection, mice are placed in the operant chambers and subjected to a visual discrimination test.

[0198] Results. Compound 18R dose-dependently reduces the accuracy of the visual discrimination test. Pretreatment / co-administration of BIIB-104 attenuates the decline in test accuracy caused by Compound 18R alone. This indicates that BIIB-104 can reduce the cognitive impairment caused by Compound 18R.

[0199] While there has been shown and described what are presently considered to be the preferred embodiments of the invention, various changes and modifications may be made by those skilled in the art which remain within the scope of the invention as defined by the appended claims.

Claims

1. Components: (i) AMPA receptor positive allosteric modulators (PAMs); and (ii) NMDA receptor antagonists 10. A pharmaceutical composition comprising:

2. 2. The composition of claim 1, wherein component (i) is an ampakine.

3. 3. The composition of claim 2, wherein the ampakine is selected from the group consisting of CX-516 (Amparex), CX-546, CX-554, CX-614, CX-691 (Falangpator), CX-717, CX-1632 (Tulangpator), CX-1739, ORG-26576, ORG-2448, CX-701, CX-929, CX-1501, CX-1796, CX-1837, CX-1846, CX-1942, CX-2007, CX-2076, and S-70340.

4. 3. The composition of claim 2, wherein the ampakine is selected from the group consisting of CX-1632, ORG-26576, CX-516, and CX-691.

5. 10. The composition of claim 1, wherein component (i) is a biarylpropyl sulfonamide.

6. 6. The composition of claim 5, wherein the biarylpropylsulfonamide is selected from the group consisting of LY-451395 (mibanpatol), LY-404187, LY-503430, PF-04958242 (BIIB-104; pesampatol), LY-392098, LY-450108, LY-451646, PF-04778574, CMPDA, CMPDB, and (R,R)-PIMSD.

7. 6. The composition of claim 5, wherein the biarylpropylsulfonamide is selected from the group consisting of LY-451395 (mibanpatol), LY-404187, LY-503430, and PF-04958242 (BIIB-104; pesampatol).

8. 6. The composition of claim 5, wherein the biarylpropylsulfonamide is PF-04958242 (BIIB-104; pesampatol).

9. 9. The composition of claim 8, wherein each dosage unit of the composition contains between about 0.05 mg and about 1 mg of PF-04958242 (BIIB-104; pesampatol).

10. 10. The composition of claim 9, wherein each dosage unit of the composition contains between about 0.1 mg and about 0.5 mg of PF-04958242 (BIIB-104; pesampatol).

11. 10. The composition of claim 1, wherein component (i) is a benzothiadiazide.

12. 12. The composition of claim 11, wherein the benzothiadiazide is selected from the group consisting of BIIR-777, cyclothiazide, diazoxide, hydrochlorothiazide (HCTZ), IDRA-21, and S-18986.

13. 2. The composition of claim 1, wherein component (i) is a racetam.

14. 14. The composition of claim 13, wherein the racetam is selected from the group consisting of piracetam, aniracetam, phenylpiracetam, oxiracetam, pramiracetam, seletracetam, levetiracetam, coluracetam, fasoracetam, brivaracetam, methylphenylpiracetam, dimiracetam, nebracetam, rolziracetam, and nefiracetam.

15. 14. The composition of claim 13, wherein the racetam is selected from the group consisting of piracetam and aniracetam.

16. 2. The composition of claim 1, wherein component (i) is selected from the group consisting of PEPA, PF-04701475, GVS-111, and TAK-653.

17. 17. The composition of any one of claims 1 to 16, wherein component (ii) is an arylcyclohexylamine.

18. The arylcyclohexylamine has the following structure: 【Chemistry 1】 (In the formula: The dashed double bond in formula (3) indicates the optional presence of a keto group; R 1 and R 2 is H and R a are independently selected from R a is H, C 1～10 Alkyl, C 2～10 Alkenyl, C 2～10 Alkynyl, and C 3～7 cycloalkyl; R a optionally contains one or more heteroatoms selected from O, N, S, and halogen; R 1 and R 2 are optionally linked together to form an N-containing ring; R 3 , R 4 , R 5 , R 6 , and R 7 is H, halogen, R b , -CF 3 , -OR b , -C(O)R b , -C(O)O(R b ), -C(O)NR b 2 , -OC(O)R b , -NR b 2 , -NR b C(O)R b , -NR b C(O)NR b -, -NO 2 , -CN, -OP(=O)O 2 R b 2 , -SR b , -S(O)R b , -SO 2 R b , and -SO 2 NR b 2 are independently selected from R b is H, C 1～10 Alkyl, C 2～10 Alkenyl, C 2～10 Alkynyl, C 3～7 independently selected from cycloalkyl, aryl, and heteroaryl, any of which are optionally substituted with a halogen atom; and pharmaceutically acceptable salts thereof.

19. 19. The composition of claim 18, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, S-ketamine, S-norketamine, N-ethylnorketamine, N-propylnorketamine, memantine, amantadine, phencyclidine (PCP), rolicyclidine (PCPy), PCM, PCPr, tenocyclidine (TCP), tiletamine, 2-oxo-PCP, 2-oxo-PCE, gacyclidine, 3-MeO-PCP, 3-OH-PCP, 4-MeO-PCP, deschloroketamine, 2-fluoro-deschloroketamine, eticyclidine (PCE), 3-MeO-PCE, 4-MeO-PCE, 3-OH-PCE, methoxetamine, methoxymethamine, methoxypropamine, methoxyisopropamine, and hydroxetamine.

20. Component (ii) is 【Chemistry 2】 19. The composition of claim 18, selected from the group consisting of:

21. 19. The composition of claim 18, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, S-ketamine, and S-norketamine.

22. Component (ii) is 【Transformation 3】 19. The composition of claim 18, wherein

23. 19. The composition of claim 18, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, and S-ketamine.

24. 18. The composition of claim 17, wherein component (ii) is ketamine or an analog thereof.

25. Component (ii) is 8A-PDHQ, dextromethorphan, dextromethorphan-OD 3 , dextrorphan, dextralorphan, dextromethadone (REL-1017), PD-137889, neramexane, memantine, NEFA, dizocilpine, lanicemine, diphenidine, ephenidine, isopropylphenidine, methoxyphenidine, fluorolintane, xenon, krypton, nitrous oxide, etoxadrol, dexoxadrol, ibogaine, and noribogaine.

26. Component (ii) is dextromethorphan or dextromethorphan-OD 3 26. The composition of claim 25, selected from the group consisting of:

27. 27. The composition of claim 26, further comprising (iii) a third compound selected from the group consisting of quinidine and bupropion.

28. 17. The composition of any one of claims 1 to 16, wherein component (ii) is a compound that selectively blocks or negatively modulates NMDA receptors containing the GluN2B (GRIN2B) subunit.

29. 29. The composition of claim 28, wherein component (ii) is selected from the group consisting of MIJ821, lislenemdaz, eliprodil, ifenprodil, besonprodil, traxoprodil, radiprodil, BMS-986169, BMS-986163, Ro 25-6981, Ro 04-5595, TCN 237, TCS 46b, and Co 101244.

30. The composition of claim 1, further comprising a pharmaceutically acceptable carrier.

31. A method for treating a psychiatric disorder, comprising administering a pharmaceutically effective amount of the following therapeutic compound: (i) AMPA receptor positive allosteric modulators (PAMs); and (ii) NMDA receptor antagonists to a subject having said psychiatric disorder.

32. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject as a single pharmaceutical composition, wherein the therapeutic compounds (i) and (ii) are present in pharmaceutically effective amounts.

33. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within seven days of each other.

34. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 48 hours of each other.

35. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in separate administrations within 24 hours of each other.

36. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 12 hours of each other.

37. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in separate doses within 6 hours of each other.

38. 32. The method of claim 31 , wherein therapeutic compound (i) is administered before therapeutic compound (ii).

39. 32. The method of claim 31 , wherein therapeutic compound (ii) is administered before therapeutic compound (i).

40. 40. The method of claim 39, wherein therapeutic compound (ii) is administered one or more times until a sufficient therapeutic response is achieved, and then therapeutic compound (i) is administered one or more times to prolong or maintain that therapeutic response.

41. 41. The method of claim 40, wherein the therapeutic response is a greater than 50% reduction in score on the Hamilton Depression Rating Scale or the Montgomery Asberg Depression Rating Scale.

42. 41. The method of claim 40, wherein the therapeutic compound (i) is administered daily or twice daily.

43. 32. The method of claim 31, wherein therapeutic compounds (i) and (ii) are administered to the subject as a single pharmaceutical composition, wherein therapeutic compounds (i) and (ii) are present in pharmaceutically effective amounts, one or more times until a sufficient therapeutic response is achieved, and then therapeutic compound (i) is administered one or more times to prolong or maintain the therapeutic response.

44. 32. The method of claim 31 , wherein the therapeutic compounds (i) and (ii) are administered to the subject in amounts that are sub-therapeutic when administered alone, but that, when administered in combination as a single pharmaceutical composition or in separate administrations within seven days of each other, result in a synergistic effect to treat the psychiatric disorder.

45. 32. The method of claim 31 , wherein the psychiatric disorder is selected from the group consisting of major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, severe mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

46. 32. The method of claim 31 , wherein the psychiatric disorder is selected from the group consisting of bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders caused by another medical condition.

47. 32. The method of claim 31, wherein the psychiatric disorder is a substance-related disorder or a substance use disorder.

48. 32. The method of claim 31 , wherein the psychiatric disorder is selected from the group consisting of separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, panic attacks, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder caused by another medical condition.

49. 32. The method of claim 31, wherein the psychiatric disorder is selected from the group consisting of obsessive-compulsive disorder and related disorders, trauma and stressor-related disorders, eating disorders and eating disorders, borderline personality disorder, attention-deficit / hyperactivity disorder, and autism spectrum disorder.

50. 32. The method of claim 31, wherein the psychiatric disorder is a neurocognitive disorder.

51. 32. The method of claim 31, wherein the psychiatric disorder is a treatment-resistant disease or disorder.

52. Feelings of sadness or lethargy or fatigue, depressed mood, inability to feel emotions, feelings of anxiety and worry, fear, tension, restlessness, decreased interest in all or almost all activities, difficulty initiating activities, marked increase or decrease in appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness or low self-esteem, strongly held negative beliefs or pessimistic thoughts about oneself, others, or the world, feelings of helplessness, difficulty concentrating or being distractible, recurring thoughts of death or suicide, feelings of guilt, memory complaints, difficulty experiencing positive emotions 32. The method of claim 31 , wherein the method provides improvement in at least one symptom selected from the group consisting of: feeling isolated or distant from people, hypervigilance, risk-taking behavior, avoidance of thoughts about the stressful or traumatic event, various pains, rumination and obsessions, compulsive behaviors, talking to strangers or people, being the center of attention, disturbing intrusive thoughts, inability to cope with daily life without drug use, guilt about drug use, problems with friends or family due to drug use, and withdrawal symptoms due to drug use.

53. 53. The method of any one of claims 31 to 52, wherein component (i) is an ampakine.

54. 54. The method of claim 53, wherein the ampakine is selected from the group consisting of CX-516 (Amparex), CX-546, CX-554, CX-614, CX-691 (Falangpator), CX-717, CX-1632 (Tulangpator), CX-1739, ORG-26576, ORG-24448, CX-701, CX-929, CX-1501, CX-1796, CX-1837, CX-1846, CX-1942, CX-2007, CX-2076, and S-70340.

55. 55. The method of claim 54, wherein the ampakine is selected from the group consisting of CX-1632, ORG-26576, CX-516, and CX-691.

56. 53. The method of any one of claims 31 to 52, wherein component (i) is a biarylpropylsulfonamide.

57. 57. The method of claim 56, wherein the biarylpropylsulfonamide is selected from the group consisting of LY-451395 (mibanpatol), LY-404187, LY-503430, PF-04958242 (BIIB-104; pesampatol), LY-392098, LY-450108, LY-451646, PF-04778574, CMPDA, CMPDB, and (R,R)-PIMSD.

58. 58. The method of claim 57, wherein the biarylpropylsulfonamide is selected from the group consisting of LY-451395 (mibanpatol), LY-404187, LY-503430, and PF-04958242 (BIIB-104; pesampatol).

59. 59. The method of claim 58, wherein the biarylpropylsulfonamide is PF-04958242 (BIIB-104; pesampatol).

60. 60. The method of claim 59, wherein each dose of PF-04958242 (BIIB-104; pesampatol) is from about 0.05 mg to about 1 mg.

61. 61. The method of claim 60, wherein each dose of PF-04958242 (BIIB-104; pesampatol) is from about 0.1 mg to about 0.5 mg.

62. 53. The method of any one of claims 31 to 52, wherein component (i) is a benzothiadiazide.

63. 63. The method of claim 62, wherein the benzothiadiazide is selected from the group consisting of BIIR-777, cyclothiazide, diazoxide, hydrochlorothiazide (HCTZ), IDRA-21, and S-18986.

64. 53. The method of any one of claims 31 to 52, wherein component (i) is a racetam.

65. 65. The method of claim 64, wherein the racetam is selected from the group consisting of piracetam, aniracetam, phenylpiracetam, oxiracetam, pramiracetam, seletracetam, levetiracetam, coluracetam, fasoracetam, brivaracetam, methylphenylpiracetam, dimiracetam, nebracetam, rolziracetam, and nefiracetam.

66. 66. The method of claim 65, wherein the racetam is selected from the group consisting of piracetam and aniracetam.

67. 53. The method of any one of claims 31 to 52, wherein component (i) is selected from the group consisting of PEPA, PF-04701475, GVS-111, and TAK-653.

68. 53. The method of any one of claims 31 to 52, wherein component (ii) is an arylcyclohexylamine.

69. The arylcyclohexylamine has the following structure: 【Chemistry 4】 (In the formula: The dashed double bond in formula (3) indicates the optional presence of a keto group; R 1 and R 2 is H and R a are independently selected from R a is H, C 1～10 Alkyl, C 2～10 Alkenyl, C 2～10 Alkynyl, and C 3～7 cycloalkyl; R a optionally contains one or more heteroatoms selected from O, N, S, and halogen; R 1 and R 2 are optionally linked together to form an N-containing ring; R 3 , R 4 , R 5 , R 6 , and R 7 is H, halogen, R b , -CF 3 , -OR b , -C(O)R b , -C(O)O(R b ), -C(O)NR b 2 , -OC(O)R b , -NR b 2 , -NR b C(O)R b , -NR b C(O)NR b -, -NO 2 , -CN, -OP(=O)O 2 R b 2 , -SR b , -S(O)R b , -SO 2 R b , and -SO 2 NR b 2 are independently selected from R b is H, C 1～10 Alkyl, C 2～10 Alkenyl, C 2～10 Alkynyl, C 3～7 independently selected from cycloalkyl, aryl, and heteroaryl, any of which are optionally substituted with a halogen atom; and pharmaceutically acceptable salts thereof.

70. 70. The method of claim 69, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, S-ketamine, S-norketamine, N-ethylnorketamine, N-propylnorketamine, memantine, amantadine, phencyclidine (PCP), rolicyclidine (PCPy), PCM, PCPr, tenocyclidine (TCP), tiletamine, 2-oxo-PCP, 2-oxo-PCE, gacyclidine, 3-MeO-PCP, 3-OH-PCP, 4-MeO-PCP, deschloroketamine, 2-fluoro-deschloroketamine, eticyclidine (PCE), 3-MeO-PCE, 4-MeO-PCE, 3-OH-PCE, methoxetamine, methoxymethamine, methoxypropamine, methoxyisopropamine, and hydroxetamine.

71. Component (ii) is 【Transformation 5】 70. The method of claim 69, selected from the group consisting of:

72. 70. The method of claim 69, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, S-ketamine, and S-norketamine.

73. Component (ii) is 【Transformation 6】 70. The method of claim 69, wherein

74. 70. The method of claim 69, wherein component (ii) is selected from the group consisting of ketamine, R-ketamine, and S-ketamine.

75. 69. The method of claim 68, wherein component (ii) is ketamine or an analog thereof.

76. Component (ii) is 8A-PDHQ, dextromethorphan, dextromethorphan-OD 3 , dextrorphan, dextralorphan, dextromethadone (REL-1017), PD-137889, neramexane, memantine, NEFA, dizocilpine, lanicemine, diphenidine, ephenidine, isopropylphenidine, methoxyphenidine, fluorolintane, xenon, krypton, nitrous oxide, etoxadrol, dexoxadrol, ibogaine, and noribogaine.

77. Component (ii) is dextromethorphan and dextromethorphan-OD 3 77. The method of claim 76, selected from the group consisting of:

78. 78. The method of claim 77, further comprising administering to the subject (iii) a pharmaceutically effective amount of a third compound selected from the group consisting of quinidine and bupropion.

79. 53. The method of any one of claims 31 to 52, wherein component (ii) is a compound that selectively blocks or negatively modulates NMDA receptors containing the GluN2B (GRIN2B) subunit.

80. 80. The method of claim 79, wherein component (ii) is selected from the group consisting of MIJ821, lislenemdaz, eliprodil, ifenprodil, besonprodil, traxoprodil, radiprodil, BMS-986169, BMS-986163, Ro 25-6981, Ro 04-5595, TCN 237, TCS 46b, and Co 101244.

81. 53. The method of any one of claims 31 to 52, wherein component (i) and / or component (ii) are in a pharmaceutically acceptable carrier.

82. Components: (i) an AMPA receptor positive allosteric modulator (PAM) or a pharmaceutically acceptable salt thereof; and (ii) (2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one or a pharmaceutically acceptable salt thereof 10. A pharmaceutical composition comprising:

83. 83. The composition of claim 82, wherein component (i) is PF-04958242 (BIIB-104; pesampathol).

84. 84. The composition of claim 83, wherein each dosage unit of the composition contains between about 0.05 mg and about 1 mg of PF-04958242 (BIIB-104; pesampatol).

85. 85. The composition of claim 84, wherein each dosage unit of the composition contains between about 0.1 mg and about 0.5 mg of PF-04958242 (BIIB-104; pesampatol).

86. 83. The composition of claim 82, wherein each dosage unit of the composition contains between about 10 mg and about 100 mg of component (ii).

87. 87. The composition of claim 86, wherein each dosage unit of the composition contains between about 20 mg and about 40 mg of component (ii).

88. 83. The composition of claim 82, further comprising a pharmaceutically acceptable carrier.

89. 1. A method of treating a subject suffering from cognitive impairment associated with schizophrenia, comprising administering to a subject a pharmaceutically effective amount of one of the following therapeutic compounds: (i) an AMPA receptor positive allosteric modulator (PAM) or a pharmaceutically acceptable salt thereof; and (ii) (2R,3S)-2-amino-3-hydroxy-3-pyridin-4-yl-1-pyrrolidin-1-yl-propan-1-one or a pharmaceutically acceptable salt thereof to said subject.

90. 90. The method of claim 89, wherein the therapeutic compounds (i) and (ii) are administered to the subject as a single pharmaceutical composition, wherein the therapeutic compounds (i) and (ii) are present in pharmaceutically effective amounts.

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