US 20140018348A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0018348 A1 Javitt (43) Pub. Date: Jan. 16, 2014

(54) COMPOSITION AND METHOD FOR A63L/38 (2006.01) TREATMENT OF DEPRESSION AND A613 L/55 (2006.01) PSYCHOSIS IN HUMANS A63L/06 (2006.01) A613 L/554 (2006.01) (71) Applicant: Daniel C. Javitt, Bardonia, NY (US) (52) U.S. Cl. CPC ...... A61K 31/42 (2013.01); A61 K3I/06 (72) Inventor: Daniel C. Javitt, Bardonia, NY (US) (2013.01); A6 IK3I/496 (2013.01); A61 K 3I/554 (2013.01); A61 K3I/381 (2013.01); (21) Appl. No.: 13/936,198 A6 IK3I/55 (2013.01); A61 K3I/138 (2013.01) 1-1. USPC 514/211.13: 514/728; 514/380: 514/254.04; (22) Filed: Jul. 7, 2013 514/214.02 Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/741,114, filed on Jul. 12, 2012, provisional application No. 61/741,115, Compositions and methods tor the treatment of depression filed on Jul. 12, 2012. and psychoses inhumans are disclosed. More particularly, the invention is directed to formulations containing Publication Classification and/or medications and also containing an NMPAR antagonist. The present invention is also directed to (51) Int. Cl. methods for the treatment of humans suffering from depres A6 IK3I/42 (2006.01) sion and other psychoses, including, , by A6 IK3I/496 (2006.01) administration of the inventive compositions in antidepres A6 IK3I/38 (2006.01) sant and/or antipsychotic effective amounts. Patent Application Publication Jan. 16, 2014 US 2014/0018348 A1

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SNW NON INS NI. US 2014/0018348 A1 Jan. 16, 2014

COMPOSITION AND METHOD FOR disorders such as generated anxiety disorder, dissociative TREATMENT OF DEPRESSION AND disorders, personality disorders or adjustment disorders with PSYCHOSIS IN HUMANS depressed mood (DSM-IV). 0007 Current treatments for major depression consist pri CROSS REFERENCE TO RELATED marily of older , such as monoamine oxidase APPLICATIONS inhibitors (MAOI) and antidepressants (TCAS) (e.g. 0001. This application claims the benefit of provisional , amitryptiline, , ) that were first developed in the 1960s. and newer agents such as application No. 61/741,114, filed Jul. 12, 2012, and provi tetracyclic antidepressants (TeCAS), e.g., , Setip sional application No. 61/741, 115, filed Jul. 12, 2012, the tiline, , , ), (SSRI) contents of each of which are hereby incorporated by refer and serotonin/norephinephrine (SNRI) reuptake inhibitors CCC. (e.g., , fluvoxamine, paroxetine, citalopram, escit BACKGROUND OF THE INVENTION allopram, dulloxetine, Venlafaxine, dapoxetine, indalpine, Val Zodone). These agents work by modulating brain levels of 0002 Schizophrenia is a clinical syndrome associated monoamines, in particular norepinephrine and serotonin, with psychotic symptoms such as delusions and hallucina and/or by blocking 5-HT2A receptors. MAOIs and TCAS are tions, as well as a decline in function in Such areas as work, considered “broader spectrum' agents than SSRIs/SNRIs Social relation or self care. that were developed subsequently. MAOI, TCAS. TeCAs, 0003 Diagnosis of schizophrenia may be determined SSRIs, and SNRIs may collectively be considered traditional using standard textbooks of the art Such as the Diagnostic and antidepressants. Statistical Manual of Mental Disorders-fourth edition (DSM 0008 may also be effective in treatment of IV) published by the American Psychiatric Association depression. Potentially beneficial antipsychotic medications Symptoms of Schizophrenia are typically measured using include but are not limited to , , que rating scales Such as the Positive and Negative Syndrome tiapine, , , lioperidone, , Scale (PANSS). , , 0004 Symptoms of schizophrenia are treated with antip 0009. Other antipsychotics and antidepressants in devel sychotic medications, which function primarily by blocking opment include Valdoxan (, AGO178) (Servier, D2 receptors. Novartis), Lu AA2 1004 (Lundbeck. Takeda). F2685, levom 0005 Antipsychotics may be divided into typical (e.g. illnacipran (Forest, Pierre Fabre; SEP-227162 (Sepracor). , , ) vs. atypical (e.g. LuAA24530 (Lundbeck, Takeda), SEP-225289 (Sepracor), , aripiprazole, asenapine, bioanserin, bifeprunoX, Epivanserine (Sanofi-Aventis), SR4834S (Sanofi-Aventis). cariprazine, , clozapine, , lurasidone, LY12824803, HY1D275 (Lilly, Hypnion). TIK-301/ mosaproamine, olanzapine, , , que LY 156735 (Tikvah Therapeutics), Lonasen (bioanserin, tiapine, , risperidone, sertindole, Sulpride, Dainippon), LU-31-130 (Lundbeck), SLV313 (Solvay), Edi , ) based upon receptor binding, preclini voxetine (LY2218884, Lilly), OPC-34712 (Otsuka/Lund cal effects and side effect profile. Clinically effective doses of beck Vyvanse (lisdexamfetamine, Shire). BCI-224 (sacome antipsychotic medication typically produce >60% occupancy line, BrainCells), BCI-540 (clouracetam. BrainCells), BMS of dopamine D2 receptors. Atypical antipsychotics may be 82036 (BMS/AMRI). partial or full D2 antagonists and may also have activity at additional catecholamine and serotonin receptor types, 0010. However, current treatment approaches have severe including 5-HT2A and 5-HT2C receptors and adrenergic limitations. Only 60-65% of patients respond to the initial alpha1 and alpha2 receptors. Atypical antipsychotics may regimen and among those responding, less then half either also effect other receptor types, such as Such as muscarinic reach remission or become symptom-free, individuals not cholinergic receptors. responding to a first course of antidepressant treatment are 0006 Major depression is a clinical syndrome that often switched to a different drug, with results that are gen includes a persistent sad mood or loss of interest in activities, erally modest and incremental. which persists for at least two weeks in the absence of treat 0011 5-HT2A receptors are a type of receptor for the ment. Symptoms of major depression are typically measured neurotransmitter serotonin. 5-HT2A antagonists are com using rating scales Such as the Hamilton Depression Rating pounds that inhibit effects of such as serotonin on Scale (HAM-D) or the Beck Depression Inventory (BDI). in 5-BT2A receptors, inverse agonists are compounds that in addition to including symptoms relevant to depressed mood, addition, reduce activity below basal levels, 5-HT2A receptor the HAM-D also contains symptoms sensitive to psychosis, antagonists can be non-selective for 5-HT2A vs. other sero including items for guilt, depersonalization/derealization and tonin receptors (e.g. 5-HT2C), or selective for 6-HT2A paranoia. Major depression may also be associated with receptors. Selective 5-HT2A antagonists can be developed symptoms of anxiety, which may be measured with rating and characterized using standard assay procedures, such as scales such as the Hamilton Rating Scale for Anxiety (HAM those described In U.S. Pat. No. 7,713.988 issued on May 11, A). Depressive disorders are divided in major depression 2010, which is hereinincorporated by reference in its entirety. (MDD) and bipolar depression (BPD), which may be diag 0012 Agents that act as non-selective serotonin receptor nosed using criteria set forth in the Diagnostic and Statistical antagonists include , , Seganserin and Manual. 4th edition, published by the American Psychiatric ICI-169369. Agents that act as selective 5-HT2A antagonists Association (DSM-IV), which provides as well additional or inverse agonists include (MDL100.907, also description of mental disorders. Major depression may also known as M100907) (EMD281014). epiivan occur with and without melancholic features. In addition, serin, CYR-101 and (ACP-103). Selective depressive symptoms may occur in the context of anxiety 5-HT2A receptor antagonists and inverse agonists are pres US 2014/0018348 A1 Jan. 16, 2014

ently under development for treatment of both depression and described, for example, in Schdev & Brune, Animal models psychosis and are viewed as potential antidepressant/antip of acute drug-induced akathisia—a review, Neurosci Biobe sychotic agents. hav Rev 24:269-277, 2000). 0013 Additional 5-HT2A receptor antagonists or inverse 0022 Antipsychotics and antidepressants, inducing agonists are described in U.S. Pat. No. 7,875,832 which was 5-HT2A receptor antagonists, may also be used therapeuti Issued on Jan. 25, 2011; U.S. Pat. No. 7,368,176 issued on cally in the treatment of bipolar disorder (manic depressive Jan. 11, 2011; U.S. Pat. No. 7,863,298 issued on Jan. 4, 2011; psychosis), Alzheimers disease, Parkinsons disease, demen U.S. Pat. No. 7,820,095 issued Oct. 26, 2010; and/or U.S. Pat. tia, anxiety disorders, pain and developmental disorders No. 7,713,995 issued May 11, 2010 which are herein incor including autism. porated by reference in its entirety. 0023 N-methyl-D-aspartate receptors (NMDAR) are a 0014 Treatment-refractory depression refers to a form of type of receptor for the brain neurotransmitter glutamate, depression that responds poorly to currently available treat NMDAR participate in a range of brain functions including ments (e.g. http://www.nimh.nih.gov/trials/practical/stard/ sensory processing, cognition, and emotion regulation. index.shtml June 2011) and which may have different under 0024 NMDAR are comprised of multiple subunits termed lying etiopathologleal mechanisms compared with other GluN1, GluN2 and GluN3 (formerly NR1, NR2, NR3). Mul forms of depression. Combinations of antidepressants have tiple forms of GluN1. GluN2 and GluN3 exist. In particular, not been shown to be superior to monotherapy for refractory GluR2 subunits are divided into GluN2A-D subforms, which depression and typically increase risk of side effects and are are also termed NR2A-D subunits. NMDAR may consist of various combinations of GluN1, GluN2 and GluN3 subunits not recommended. in various amounts. Agonists and antagonists may affect all 0015 Risk for suicide is significantly increased in depres NMDAR equivalently, or may be selective for NMDAR con sive disorders, but may respond differentially to medication taining specific Subunit types. Versus depressive symptoms as a whole. When Suicide (0025 NMDAR contain binding sites for both the neu occurs, it is often accompanied by feelings of worthlessness rotransmitter glutamate and for the endogenous modulatory or inappropriate guilt, as well as recurrent thoughts of death amino acids glycine and D-serine. or Suicidal ideation and guilt is an accepted proxy for Suicide. 0026. The glutamate binding site also selectively binds the While the risk of suicide increases in subjects with a depres synthetic glutamate derivative N-methyl-D-aspartate with sive disorder, medications used to date to typically treat high affinity. This site is alternately referred to as the depressive disorders paradoxically increase Suicidal tenden glutamate recognition site of the NMDA recognition site of C1GS. the NMDAR. 0016. A major limitation in use of antipsychotic and anti 0027. The glycine/D-serine binding site has been referred depressant medications is the liability to produce behavioral to as the glycine modulatory site, the aliosteric modulatory side effects, especially anxiety, agitation, and akathisia. site or the glycine-B receptor. These can be differentiated from symptoms of the illness by (0028 NMDAR form an ion channel that is blocked by consideration of both time course and specific patterns of several drugs of abuse, such as (PCP), ket symptoms. amine or (MK-801). These compounds bind to a 0017. In addition to akathisia, antipsychotics also produce site that has been termed the PCP receptor. Agents that block extrapyramidal symptoms such as stiffness, tremor or dyski the NMDAR-associated ion channel are collectively termed nesia. Akathisia, however, is differentiated from extrapyra non-competitive NMDAR antagonists, or NMDAR channel midal symptoms and shows differential treatment response. blockers. Blockade of NMDAR by channel blockers leads to At present, there are no approved treatments for antipsy a clinical psychotic state that closely resembles Schizophre chotic-induced akathisia. 18. 0018 Use of antidepressants is also limited by liability to (0029. Other compounds that block NMDA receptors via produce anxiety, agitation, and akathisia. the channel site include AZD6765 (AstraZeneca) and Glyx 13 (Naurex). NRX-1059 (Naurex) 00.19 Limitations of antidepressants are summarized in a 0030. Other NMDAR antagonists are described in U.S. “black box” warning required by the FDA, as follows: “The Patent appl. #201 10306586 published Dec. 15, 2011 which is following symptoms, anxiety, agitation, panic attacks, insom herein incorporated by reference in its entirety. nia, irritability, hostility, aggressiveness, impulsivity, akathi 0031 Low affinity NMDAR antagonists, such as meman sia (psychomotor restlessness), hypomania, and mania have tine, may be distinguished from high affinity antagonists Such been reported in adult and pediatric patients being treated as PCP, or dizocilpine. In general, low affinity with antidepressants for major depressive disorder as well as NMDAR antagonists do not induce schizophrenia-like psy for other indications, both psychiatric and non-psychiatric. chosis or PCP-like behavioral effects in rodents. Although a causal link between the emergence of such symp 0032) NMDAR may also be inhibited by antagonists that toms and either the worsening of depression and/or the emer bind to the glutamate recognition sites, the glycine recogni gence of Suicidal impulses has not been established, there is tion site, or the channel binding site. concern that such symptoms may represent precursors to 0033 Selfotel (CGS19755) is an example of an antagonist emerging suicidality” (Trivedi et al., J. Clin Psychiatry, that binds to the glutamate recognition site. Several Such 72:765-774, 2011). compounds were developed for CNS indications such as 0020. As with antipsychotic-induced akathisia, there are stroke or epilepsy. When used at doses sufficient to signifi at present no known treatments for antidepressant induced cantly inhibit NMDAR, these compounds, like channel anxiety, agitation, or akathisia. blockers, lead to clinical psychotomimetic symptoms. 0021 Anxiety and akathisia may be studied in animal 0034 Additional compounds that functions as antagonists models, such as the rat defection or restlessness models, as of the glutamate recognition site include aptiganel (Cerestat US 2014/0018348 A1 Jan. 16, 2014

CNS-1102) and related compounds as described in Reddy et 324, which published on Nov. 9, 1993. The foregoing patents at, J Med Chem37:280-7. 1984. and patent applications are incorporated herein by reference 0035. Additional compounds that function as antagonists in their entireties. of the glutamate recognition site include alpha.-amino-car 0041. Other examples of glycine site antagonists that can boxylic acid and phosphonic acid functionalities separated by be used in the pharmaceutical composition and methods of a variety of spacer units. An unembellished example is this invention are N-(6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahy 2-amino-5-phosphonovaleric acid (AP5) (Watkins. J. C. dro-quinoxalin-5-yl)-N(2-hydroxy-ethyl)-methanesulfona Evans, R. H., Anna. Rev. Pharmacol. Toxicol. 1881, 21, 185), mide and 6,7-dichloro-5-3-methoxymethyl-5-(1-oxypyri which contains a saturated carbon chain, yore complex din-3-yl)-1,2,4-triazol-4-yl-1,4-dihydro-quinoxa-line-2,3- examples, which contain elements enhancing structural rigid dione. ity and therefore potency, include CPP, cis-4-(phosphonom 0042 Additional NMDAR antagonists are described in ethyl)-2-piperidinecarboxylic acid (CGS-19755) (Lehman, J. Schiene et al., U.S. Pat. Appl. No. US2001/0306674 A1, et al. J. Pharmacol Exp. Ther. 1988. 246, 65), and (E)-2- which is incorporated herein by reference in its entirety, and amino-4-methyl-5-phosphono-3-pentenoic acid (CGP include without being limited thereto, N-containing phospho 37849) (Schmutz, M. et al., Abs. Soc. Neurosci. 1888, 14, nic acids, such as norvaline (AP5), D-norvaline (D-AP5), 804). See U.S. Pat. No. 7,345,032, issued Mar. 18, 2008 and 4-(3-phosphono-propyl)--2-carboxylic acid U.S. Pat. No. 5,188,103, incorporated herein by reference in (CPP), D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-car its entirety. boxylic acid (D-CPPene), cis-4-(phosphonomethyl)-2- 0036 NMDAR may also be inhibited by antagonists that pipendine carboxylic acid (Selfotel, CGS 19755), SDZ bind to the glycine recognition site. 220681, PD-134705, LY-274614 and WAY-126090; 0037 D-cycloserine is a compound that acts as a partial quinolinic acids, such as kynurenic acid, 7-chloro-kynurenic glycine-site antagonist, D-cycloserine doses may be divided acid, 7-chloro-thiokynurenic acid and 5,7-dichloro into low doses (0-250 mg), moderate (>250-500 mg) or high kynurenic acid, prodrugs thereof. Such as 4-chlorokynurenine (>500mg). At low dose, D-cycloserine may function as a net and 3-hydroxy-kynurenine, 4-aminotetrahydrochinolin-car NMDAR . At high doses, D-cycloserine may function boxylates, such as L-689,560: 4-hydroxyquinolin-2(1H)- as a net NMDAR antagonist. Plasma concentrations associ ones, such as L-701,324; quinoxalinediones, such as licosti ated with moderate or high dose administration are >25 nel (ACEA-1021) and CGP-68,730A: 4,6-dichloro-indole-2- microgram/ml. carboxylate derivatives such as MDL-105,519, gavestinel 0038. Felbamate is another example of a compound that (GV-150,526) and GV-196.771A; tricyclic compounds, such may act via the glycine binding site. When administered to as ZD-9,379 and MRZ-2/576, (+)-HA-966, morphinan humans, felbamate produces psychotic effects that limit its derivatives such as dextromethorphan and dextrophan; ben clinical utility (e.g. Besag FM. Expert Opin Drug Saf 3:1-8, Zomorphans, such as BIII-277CL other opioids, such as dex 2004). tropropoxyphene, ketobemidone, dextromethadone and 0039 Gavestinel (GV-150,526) is another example of a D-morphine; amino-adamantanes, such as and glycine binding site antagonist. Other compounds are ; amino-alkyl-cyclohexanes, such as MRZ-2/579; described in DiFabrio et al. J Med Chem 40:841-50, 1997, ifenprodil and ifenprodile-like compounds such as eliprodil which is hereby incorporated by reference. and PD-196,880; immopyrimidines; or other NMDA-antago 0040. Other examples of glycine site antagonists that are nists such as nitroprusside, D-cycloserine, 1-aminocyclopro Suitable for use in the pharmaceutical compositions and pane-carboxylic acid, dizocilpine (MK 801) and its analogs, methods of this invention are those referred to in the follow phencyclidine (PCP), ketamine ((R.S)-2-(2-Chlorphenyl)-2- ing; U.S. Pat. No. 6,667,317 which was issued on Dec. 23, (methylamino)cyclohexan-1-on). (R)-ketamine, (S)-ket 2003: U.S. Pat. No. 6,030,743 which was issued Jun. 27, amine, remacemide and its des-glycinyl-metabolite FPL-12, 2000; U.S. Pat. No. 5,990,108. which was issued on Nov. 23, 495, AR-R-15,896, methadone, sulfazocine, AN19/AVex 1999; U.S. Pat. No. 6,842,540, which issued on Aug. 24, 144. AN2/AVex-73, Besonprodil, CGX-1007, EAB-318, 1999: World Patent Application WO99/34790 which issued Felbamate and NPS-1407. NMDA-Antagonists are, for on Jul. 15. 1999: WO 08/47878, which was published on Oct. example, disclosed in "Analgesics, edited by H. Buschmann, 29, 1998: World Patent Application WO98/42673, which was T. Christoph, E., Friderichs, C. Maul, B. Sundermann, 2002. published on Oct. 1, 1988: European Patent Application EP Wiley-VCB Verlag GmbH & Co. KGaA, Weinheim, Ger 966475A1, which was published on Dec. 29. 1991; World many, in particular pages 389-428. The respective parts of the Patent Application 98/39327, which was published on Sep. description are hereby incorporated by reference and form 11 1990; World Patent Application WO98/04556, which was part of the present disclosure. published on Feb. 5, 1993: World Patent Application WO 0043 Antagonists may be selective for the GluN2B 97/37652, which was published on Oct. 16. 1997: U.S. Pat. (NR2B) containing subtype. Examples of compounds that are No. 5,837,705, which was issued on Oct. 9, 1996; World selective for NR2B containing receptors include ifenprodil, Patent Application WO 97/20553, which was published on traxoprodil (CP-101,806), besonprodll. Ro25-6981, Jun. 12, 1997: U.S. Pat. No. 5,888,018, which was issued on MKO657 and EVT-101. Mar. 23, 1999: U.S. Pat. No. 5,801,183, which was issued on 0044 Along with identified NMDAR antagonists, addi Sep. 1, 1998: World Patent Application WO95/07887, which tional can be identified using well-validated electrophysi was issued on Mar. 23, 1996: U.S. Pat. No. 5,686,481, which ological assays such as modulation of NMDA-receptor medi was issued on Nov. 11, 1907: U.S. Pat. No. 5,622,902, issued ated responses to NMDA glutamate-site agonists, or Apr. 22, 1997: U.S. Pat. No. 5,614.509, which was issued on radioreceptor assays, such as modulation of binding to the Mar. 25, 1997: U.S. Pat. No. 5,510,367, which was issued on NMDA PCP-receptor channel binding site. Glycine site ago Apr. 23, 1996: European Patent Application 617,347A1, nists and antagonists can also be distinguished based upon which was published on Dec. 9, 1992; U.S. Pat. No. 5,260, both electrophysiology and receptor binding from com US 2014/0018348 A1 Jan. 16, 2014 pounds such as phencyclidine (PCP) or ketamine that bind to serotonin reuptake inhibitor (SSRI), a serotonin/norephi the channel site. Partial agonists are defined as compounds nephrine reuptake inhibitor (SNRI) a 5-HT2A antagonist/ that have reduced efficacy for inducing conformational inverse agonist or a combination thereof. change in receptors (typically 40-80%) relative to full ago 0056 5-HT2A receptor antagonists/inverse agonists may nists, and which may induce agonist effects at low dose but be drawn from a list that includes volinanserin (MDL 100, antagonist effects at high dose. 007, also known as M100907) pruvanserin (EMD281014), 0045. The NMDAR antagonist ketamine is currently , CYR-101 and pimavanserin (ACP-103). approved as an anesthetic agent. It has also been reported to 0057 NMDAR antagonists may be drawn from antago show beneficial effects in treatment resistant depression in nists at the glycine, glutamate or channel recognition sites. small scale clinical trials. However, its utility is limited by 0.058 NMDAR antagonists may be non-selective antago psychotomimetic effects. The low affinity NMDAR antago nists or selective antagonists at NMDAR containing specific nist memantine is approved for use in dementia. Otherwise, subunits such as the NR2A or NR2B subunits. NMDAR antagonists have no established clinical utility. 0059. In some embodiments of the invention, the antide 0046. In general, NMDAR antagonists are considered pressant may be selected from the group consisting of contraindicated for use in Schizophrenia or depression. For includes imipramine, amitryptiline, desipramine, clomi example, the NMDAR antagonist D-cycloserine is contrain pramine, amoxapine, , maprotiline, mianserin, mir dicated by FDA for use in depression, severe anxiety or psy tazapine, fluoxetine, fluvoxamine, paroxetine, citalopram, chosis. escitalopram, dulloxetine, Venlafaxine, dapoxetine, indalpine, 0047. Here we show unexpectedly that NMDAR antago valzodone nists unexpectedly reduce akathisia and anxiety associated 0060. In some embodiments of the invention, the first with antidepressant and/or antipsychotic treatment. therapeutic agent is drawn from a list that includes ago 0048. Here we show unexpectedly that antidepressants melatine, Lu AA2 1004, F2695, levomlinacipran, SEF prevent psychotic symptoms associated with NMDAR ago 227182, LuAA24530, SEP-225289, Epivanserine, SR46349, nist usage. LY 12624803, HY 10275, TIK-301/LY.156735, Lonasen, 0049. These findings provide a method for improved treat LU-31-130, SLV313, Edivoxetine, OPC-34712, lisdexamfe ment of humans requiring treatment with an antipsychotic, tamine, Sacomeline, clouracetam, and BMS-82036. antidepressant, or NMDAR antagonist medication. 0061. In some embodiments, the second therapeutic agent is drawn from a list that includes ketamine, dextromethor BRIEF DESCRIPTION OF THE DRAWING phan, CNS-1102, AZD6765, or CGS-19755. 0050 FIG. 1 is a graphical representation of the results 0062. In a preferred embodiment of the invention, the described in the Example described hereinafter showing the second therapeutic agent consists of D-cycloserine, adminis percent of time spent in the open arms of the testing device for tered at a dosage of at least 500 mg per day. very drugs or combination of drugs. 0063. In some embodiments, the NMDA receptor antago nists consists of D-cyoloserine, administered at a dose that SUMMARY OF THE INVENTION produces serum levels in excess of 25 microgram/mL. 0051. The present invention is directed towards composi 0064. In soma embodiments, this invention provides a tions for the treatment of depression and psychoses in method for treatment of a psychosis in a subject in need humans. More particularly, the invention is directed to for thereof, said method comprising providing said Subject with mulations containing antipsychotic and/or antidepressant an oral or parenteral dosage regimen as herein described. medications including selective 5-HT2A receptor antago 0065. In some embodiments this invention provides a nists/inverse agonists and also containing an NMDAR method for treatment of depression in a subject in need antagonist. The present invention is also directed to methods thereof, said method comprising providing said Subject with for the treatment of humans suffering from depression and an oral or parenteral dosage regimen as herein described other psychoses, including, Schizophrenia, by administration 0066. In some embodiments, the subject suffers from of the inventive compositions in antidepression and/or antip mania, or in Some embodiments, the Subject Suffers from sychotic effective amounts. bipolar disorder. 0052. In one embodiment, this invention provides an oral 0067. In some embodiments, this invention provides a or parenteral dosage regimen consisting essentially of two method for treating symptoms of autism in a subject in need therapeutic agents, wherein a first of said two active ingredi thereof, said method comprising providing said Subject with ents is an antidepressant or antipsychotic agent, and the sec an oral or parenteral dosage regimen as herein described. ond agent consists of an NMDAR . 0068. In some embodiments, the invention provides a 0053. In some embodiments of the invention, the first method for reducing side effects associated with antipsy compound consists of a typical or chotic medications to a subject in need of such treatment, said agent. method comprising providing said subject with an oral or 0054. In some embodiments of the invention, the first parenteral dosage regimen as herein described. therapeutic agent is drawn from a list that includes amisul 0069. In some embodiments, this invention provides a pride, aripiprazole, asenapine, bifeprunoX, bioanserin, car method for reducing side effects associated with antidepres iprazine, clotiapine, clozapine, lioperidone, lurasidone, sant medications to a Subject in need of Such treatment, said mosaproamine, olanzapine, paliperidone, peroSpirone, que method comprising providing said subject with an oral or tiapine, remoxipride, risperidone, sertindole, , parenteral dosage regimen as herein described. Ziprasidone, Zotepine 0070. In some embodiments, this invention provides a 0055. In some embodiments, the first therapeutic agent method for reducing side effects associated with NMDAR comprises a tetracyclic antidepressant (TeCA), selective antagonist medications to a Subject in need of such treatment, US 2014/0018348 A1 Jan. 16, 2014

said method comprising providing said Subject with an oral or I0085. In some embodiments, the second therapeutic agent parenteral dosage regimen as herein described. acts at NMDAR containing NR2A subunits. 0071. In some embodiments, a gelling agent Such as I0086. In some embodiments, the second therapeutic agent hydroxypropyl methylcellulose, together with one or more acts at NMDAR containing NR2B subunits. pharmaceutically acceptable excipients is used for manufac I0087. In some embodiments, the second therapeutic agent ture of the Sustained release agent. is drawn from a list that includes ketamine. Selfotel, apti 0072. In some embodiments, the sustained release formu ganel, CPP, CGP-37849, felbamate, Gavestinel N-(6,7- lation comprises a hydrophilc matrix composing a gelling dichloro-2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-N- agent, preferably hydroxypropyl methylcellulose, an NMDA 2-hydroxy-ethyl)-methanesulfonamide and 6,7-dichloro-5- receptor antagonist, an antidepressant and pharmaceutically 3-methoxymethyl-5-(1-oxypyridin-3-yl)-1,2,4-triazol-4- acceptable salts thereof, together with one or more pharma yl-1,4-dihydro-quinoxa-line-2,3-dione, 4-(3-phosphono ceutically acceptable excipients. propyl)-piperazine-2-carboxylic acid (D-CPPene), SDZ 0073. In some embodiments both the NMDA receptor 220581, PD-134705, LY-274614 and WAY-126090; antagonist and the antidepressant or antipsychotic medica quinoilinic acids, such as kynurenic acid, 7-chloro-kynurenic tion would be manufactured for Sustained release in common. acid. 7-chloro-thiokynurenic acid and 5,7-dichloro 0074. In some embodiments, the NMDA receptor antago kynurenic acid, prodrugs thereof. Such as 4-chiorokynurenline nist would be manufactured for Sustained release, and com and 3-hydroxy-kynurenine, 4-aminotetrahydrochinolin-car bined with an antidepressant or antipsychotic agent hoxylates, such as L-689,560: 4-hydroxyquirroilin-2(1H)- 0075. In some embodiments, the antidepressant or antip ones, such as L-701,324; quinoxalinediones, such as licosti sychotic agent would be manufactured for Sustained release, nel (ACEA-1021) and CGP-68.730A; 4,6-dichloro-indole-2- and combined with an NMDA receptor antagonist. carboxylate derivatives such as MDL-105,519, gavestinel 0076. In one embodiment, an NMDA receptor antagonist (GV150,526) and GV-196.771A; tricyclic compounds, such and an antidepressant or antipsychotic agent would be as ZD-9,379 and MRZ-2/576, (+)-HA-966. morphinan selected for release characteristics permitting once daily dos derivatives such as dextromethorphan and dextrophan; ben ing of the combined medicament, and would not require Zomorphans, such as BIII-277CL other opioids, such as dex separate Sustained release manufacture. tropropoxyphene, ketobemibone, dextromethadone and D-morphine; amino-adamantanes, such as amantadine and DETAILED DESCRIPTION OF THE INVENTION memantine; amino-alkyl-cyclohexanes, such as MRZ-2/579; 0077. This invention provides, in some embodiments, ifenprodil and ifenprodile-like compounds such as eliprodil parenteral or intravenous dosage regimens, which are useful and PD-196,860; iminopyrimidines; or other NMDA-antago in the treatment of schizophrenia or depression in a subject in nists such as nitroprusside. D-cycloserine, 1-aminocyclopro need thereof, or in the reduction of the incidence orakathisia pane carboxylic acid, dizocilpine (UK 801) and its analogs, or anxiety in a Subject or population in need thereof. (R)-ketamine, (S)-ketamine, remacemide and its des-glyci 0078. In some embodiments, the invention provides an nyl-metabolite FPL-12,495, AR-R-15,896, methadone, sul oral or parenteral dosage regimen consisting essentially of fazocine, AN19/AVex-144, AN2/AVex-73, Besonprodil, two active ingredients, whereina first of said ingredients is an CGX-1007, EAB-318, and NFS-1407. antipsychotic or antidepressant agent I0088. In some embodiments, the second compound is 0079. In some embodiments, according to this aspect, the D-cycloserine, administered at a dose of 500 mg or greater. first therapeutic agent comprises any Such agent as herein I0089. In some embodiments, the two active ingredients described, for example, a tetracyclic antidepressant (TeCA). are provided in a single pharmaceutical composition, and in selective serotonin reuptake inhibitor (SSRI), a serotonin/ Some embodiments, the invention contemplates a kit or com norephinephrine reuptake inhibitor (SNRI), a selective bined dispenser packet containing each of the two active 5-HT2A receptor antagonist, a selective 5-HT2A receptor ingredients. inverse agonist, an antipsychotic approved for use in treat 0090. It is to be understood that the invention contem ment of depression or a combination thereof. plates the co-administration of either of the two active ingre 0080. In some embodiments, ins selective 5-HT2A dients to a subject, whether Such administration is combined antagonist/inverse agonist is selected from the group consist in a single formulation or in separate formulations and ing of volinanserin (MDL100,907, M100907) pruvanserin (EMD281014), eplivanserin CYR-101 and pimavanserin whether Such administration is coincident or staggered. (ACP-103). 0091. The inventive composition may be administered by 0081. In some embodiments, the first therapeutic agent is a variety of well-established medicinal routes including intra an antipsychotic agent, consisting of a typical or atypical venously, intraperitoneally, parentally, intramuscularly, or antipsychotic orally. 0082 In some embodiments, the antipsychotic agent is 0092. In some embodiments, this invention provides a selected from the group consisting of amisulpride, aripipra method for treating depression in a subject in need thereof, Zole, asenapine, bioanserin, bifeprunoX, cariprazine, clotiap said method comprising administering an effective amount of ine, clozapine, illoperidone, lurasidone, mosaproamine, olan the inventive composition in the form of an oral or parenteral Zapine, paliperidone, peroSpirone, , remoxipride, dosage or a parenteral injection as herein described. risperidone, sertindole, Sulpiride, Ziprasidone, Zotepine 0093. In some embodiments, the subject suffers from 0083. In some embodiments, the second therapeutic agent Schizophrenia, or in Some embodiments, the Subject Suffers is an NMDAR antagonist. from bipolar disorder in some embodiments, the invention 0084. In some embodiments, the second therapeutic agent provides a method for reducing the incidence or treating acts at the glycine, glutamate or channel recognition sites. Suicide or Suicide ideation in a subject or population in need US 2014/0018348 A1 Jan. 16, 2014 thereof, the method comprising providing the Subject with an ments for anxiety, Subjects treated according to the methods oral or parenteral or parenteral dosage regimen as herein of the invention will experience, in some embodiments, described, greater improvement, or more long-lasting improvement, as 0094. In some embodiments, reference to an “effective' measured by any clinically recognized assessment method amount or a “therapeutically effective amount of therapeutic for anxiety (e.g., the Hamilton Anxiety Rating Scale). It agents referenced herein, it is meant a nontoxic but sufficient should be noted that not every subject will benefit from the amount of the same to provide the desired effect, in a combi methods of the invention, just as other pharmaceutical agents nation therapy of the present invention, an “effective amount do not typically benefit every patient. of one component of the combination is the amount of that 0101. A subject undergoing treatment with the methods of compound that is effective to provide the desired effect when the invention can experience significant improvements in used in combination with the other components of the com akathisia. Relative to subjects treated with alternative treat bination. The amount that is “effective’ will vary from subject ments for akathisia, Subjects treated according to the methods to Subject, depending on the age and general condition of the of the invention will experience. In some embodiments, individual, the particular active agent or agents, and the like. greater improvement, or more long-lasting improvement, as Thus, it is not always possible to specify an exact “effective measured by any clinically recognized assessment method amount” However, an appropriate “effective' amount in any for akathisia (e.g., the Barnes Akathisia Rating Scale). It individual case may be determined by one of ordinary skill in should be noted that not every subject will benefit from the the art using routine experimentation methods of the invention, just as other pharmaceutical agents 0095. The terms “treating” and “treatment” as used herein do not typically benefit every patient. refer to reduction in severity and/or frequency of symptoms: 0102) A subject undergoing treatment with the methods of elimination of symptoms and/or underlying cause, prevention the invention can experience significant improvements in of the occurrence of symptoms and/or their underlying cause, psychosis. Relative to subjects treated with alternative treat and improvement or remediation of damage. Thus, for ments for psychosis, Subjects treated according to the meth example, “treating a patient involves prevention of a particu ods of the invention will experience, in Some embodiments, lar disorder or adverse physiological event in a susceptible greater improvement, or more long-lasting improvement, as individual as well as treatment of a clinically symptomatic measured by any clinically recognized assessment method individual. for psychosis (e.g., the Positive and Negative Symptom 0096 D-cycloserine, or DCS, refers to the chemical D-cy Scale). It should be noted that not every subject will benefit closerine (CA index Name: 3-Isoxazolidinone, 4-amino from the methods of the invention, just as other pharmaceu (4R)-(SCI); CAS Registry No. 68-41-7). or pharmaceutical tical agents do not typically benefit every patient. acceptable salts thereof. DCS is an FDA (United States Food and Drug Administration)—approved drug for treatment of EXAMPLE tuberculosis, and is sold by Ell Lilly and Company under the trade name Seromycin R. DCS is a structural analog of D-ala Example nine, and is a broad-spectrum antibiotic produced by some strains of Streptomyces Orchidaceus and S. garphalus. In Effect of NMDAR Antagonists on Akathisia Induced Some embodiments, the inventive combination may be used by Antagonists in the treatment of tuberculosis. 0103 Background: Drug induced akathisia is a common 0097 Indicia is provided and disposed adjacent the col side effects of both antipsychotic and antidepressant medica umns and rows for displaying common days and Successive tion and may be seen even with newer atypical antipsychotics weeks. Thus, the package provides for a titration schedule (Iqbal et al., CNS Spectrums, 12:1-13, 2007). This syndrome which prevents adverse events as a result of mis-dosing. As a has also been described as anxiety fitterness syndrome (Sin result the package in accordance with the present invention clair et al., Br J Psychiatry, 194:463-90, 2009), which is also provides for a safer and accordingly more beneficial method seen following both SSRIs and tricyclic antidepressants. for enabling compliance with the regimen. 0104. Although no exact animal models exist at present, 0098. In some embodiments, according to this aspect, the rodent activity measures which asses partial restlessness have first therapeutic agent is administered at a dosage, which is been proposed to have face validity (Sachdev and Brune, considered to be suboptimal for treating depression or psy Neurosci Biobehav Rd 24:269-277, 2000), justifying their chosis in said Subject when treating said Subject with said first use. Agonists at the 5-HT2A receptor, such as (+/-)-1-(2,5- therapeutic agent alone. dimethoxy-4-iodophenyl)-2-aminopropane (DOI) have well 0099. A subject undergoing treatment with the methods of described anxiolytic properties that may be defected in rodent the invention can experience significant improvements in assays such as the four-plate test or the elevated plus maZe depression. Relative to subjects treated with alternative treat (Nic Dhonnchadha et al. Behavioural brain research. 147: ments for depression, Subjects treated according to the meth 175-84. 2003). Effects of 5-HT2A ligands may be mediated ods of the invention will experience, in some embodiments, in part via the GABA system (Masse et al., Behav Brain Res greater improvement, or more long-lasting improvement, as 177:214-26, 2007), increasing the relevance of this mecha measured by any clinically recognised assessment method for nisms for akathisia, depression (e.g., the item Hamilton Depression Rating 0105. The present investigation tests the hypothesis that Scale). It should be noted that not every subject will benefit NMDA receptor antagonists may reverse the akathasia-in from the methods of the invention, just as other pharmaceu duced effects of agents that work in whole or in part through tical agents do net typically benefit every patient. 5-HT2A blockade, including selective 5-HT2A antagonists/ 0100. A subject undergoing treatment with the methods of inverse agonists, anti-depressants, and atypical antipsychot the invention can experience significant improvements in ics. For this study, the primary NMDA receptor antagonist anxiety. Relative to subjects treated with alternative treat used was D-cycloserine (DCS) US 2014/0018348 A1 Jan. 16, 2014 7

0106 Methods: All studies were performed at Psy- and entries in each arm were automatically recorded fey the choGenic, Inc., headquartered at 765 Old Saw Mill River computer. The EPM was thoroughly cleaned after each test. Road, E.town, using s E. t (EPM) 0110 Medications: dedications were administered by ip apparalus to assess penaV1oral eIIects of med1cauon. injection. All medications were dissolved in appropriate 0107 Preparation: Mala C57BL/6J mice from Jackson vehicle. Doses are expressed in milligrams per kilogram laboratories (Bar Harbor, Maine) were used for this study. (mpk). Mice were received at 6-weeks of age. Upon receipt, mice 0111 Statistical analysis: The primary dependent measure were assigned unique identification numbers (fall marked) O - 0 and were group doused with 4 mice/cage in OPTI mouse for this study- 0 consisted of% of time spent within the open ventilated cages. All animals remained housed in groups of arms, which is considered a measure of anti-anxiety effects. four during the remainder of the study. All mice were accli Between-condition comparisons were performed using post mated to the colony room for at least 1 week nor to testing and hoc LSD with one-tailed significance of p-0.05. were Subsequently tested at an average of 7 weeks of age. 0112 Results: Specific effects of NMDA receptor antago 0108. During the period of acclimation, mice were exam- nists on anxietyakathisia related symptoms were assessed ined on a regular basis, handled, and weighed to assure using- - - - the measure 96 time in open arms, which measures adequate health and Suitability.- - - - Animals were maintained on willingness to enter an exposed VS. enclosed section of the a 12/12 light/dark cycle; testing was performed during the EPM. Because it represents a ratio between activity in open liight phase. The room temperature was maintained between and closed arms, it is relatively insensitive to changes in 20 and 23°C.O with a relative humidity- maintained between overall activity levels. Potential non-specific - effects were 30%O and 70%.O Chow and water were provided act libitum- 0 for assessed using the total distance travelled, which is a measure the durabon of the study, in each test, animals were randomly of overall activation. Locomotor hyperactivity induced by assigned across treatment groups. All animals were eutha NMDAR antagonists is considered a rodent model of psycho nized after the completion of the study sis, 5HT2A antagonists are known to reverse effects of high affinity NMDAR channel blockers on rodent activity, reflect (01.09 Apparatus: The elevated plus maZe test assessed ing their potential use as antipsychotics. However, no studies anxiety. The maze (Kinder Scientific: Poway, Calif.) consists have previously investigated the ability of competitive of two closed arms (14.5 cm hx5 cm wX35 cm I) end two open NMDAR antagonists acting at either the glycine or glutamate arms (6 cm wx35 cm 1) forming a cross, with a square center sites to reverse potential akathisia-related anxiogenic effects platform (6x6 cm). All visible surfaces are made of black of high affinity 5-HT2A antagonists: or other compounds acrylic. Each arm of the maze was placed on a support column Such as antidepressants or atypical antipsychotics potentially 56 cm above the floor. Antistatic black vinyl curtains (7" high) associated with antagonism at 5-HT2A receptors surround the EPM to make a 5' wx5' 1 enclosure. Animals 0113. Descripti fth t were allowed to acclimate to the experimental room at least 1 escripuon of une results. hr before: the test. Mice were placed in the center of the 0114. The results of the foregoing described experiments elevated plus maze facing the closed arm for a 5-min run All are set forth in Table 1. Results of an individual representative animals were tested once. The time spent, distance traveled, experiment are set forth in Table 2 and depicted in FIG. 1. TABLE 1.

% time spent in ODCI IIIl Distance

Dose 5-HT2A NMDA Std. travelled

DOI Control DO antagonist Dose antagonist Dose N Mean Dew. Mean Std. Dev.

Control O O 22.438 14.8418 786.3O 68.631 DOI 1 mpk — O 46.8S9 22.3661. 687.10 108.721 DOI 2 mpk — 30 37.241 17.7616 678.2O 96.958 DOID-cycloserine 2 mpk — D-cycloserine 30 mpk 10 44.598 10.6373 781.50 96.345 DOID-cycloserine 2 mpk — D-cycloserine 300 mpk 10 48.086 14.9833 733.70 76.2O2 DOI (2 mpk) + 1 MDL1 OO907 0.3 milk - O 26.76O 17.8137 693.2O 69.089 MDL100907 MDL100907 2 milk MDL1OO907 0.3 milk - 40 21.938 21.4108 741.70 85.718 MDL100907, D- 2 mpk MDL100907 0.3 mpk D-cycloserine 30 mpk 10 20.807 24.1793 735.10 131.341 cycloserine MDL100907, D- 2 mpk MDL100907 0.3 mpk D-cycloserine 300 mpk 10 35.826 29.2316 887.10 105.288 cycloserine MDL100907, CGS1975S 2nk MDL1 OO907 0.3 milk CGS-1975S O 21.749 19.22S2 S27.OO 139.276 MDL100907, CPPene 2 milk MDL1OO907 0.3 mik D-CPPene O 31.813 22.6649 727.9O 66.527 MDL100907, CP101806 2nk MDL1 OO907 0.3 milk CP101806 9 25.122 18.958O 77S.OO 157.463 MDL100907, GV1SO526A 2nk MDL1 OO907 0.3 milk GV1SOS26A 1 20.818 16.8459 863.SS 93.861 MDL100907, L701,324 2 milk MDL1OO907 0.3 milk L7O1324 O 25.980 31.5739 622.90 189.097 MDL100907, PCP 2 milk MDL1OO907 0.3 mk PCP 1 mpk 10 14.916 13.8546 792.60 155.336 Ketanserin 2 mpk Ketanserin 2 mpk — O 10.400 11.066O 648.90 161515 Ketanserin/D-cycloserine 2 mpk Ketanserin 2 mpk D-cycloserine 300 mpk 10 21.390 18.2661 640.60 96.388 EMD281014 2 milk EMD281014 30 mk = O 23.OSO 20.7267 628.20 110.375 US 2014/0018348 A1 Jan. 16, 2014

TABLE 1-continued

% time spent in ODCIl IIIl Distance

Dose 5-HT2A NMDA Std. travelled

DOI Control DOI antagonist Dose antagonist Dose N Mean Dew. Mean Std. Dev. EMD281014, D- 2 mpk EMD281014 30 mpk D-cycloserine 300 mpk 10 27.380 26.7496 541.10 148.076 cycloserine Antipsychotics Lurasidone 2 mpk Lurasidone 1 mpk — 10 36.02O 16.2589 71S.SO 116.712 Lurasidone, D-cycloserine 2 mpk Lurasidone 1 mpk D-cycloserine 300 mpk 10 53.230 17.6298 739.10 91594 Quetiapine 2 mpk Quetiapine 30 mpk — 10 8.9SO 10.6937 676.SO 116.319 Quetiapine? D-cycloserine 2 mpk Quetiapine 30 mpk D-cycloserine 300 mpk 10 26.004 28.9504 630.20 140.271 Antidepressents Duloxetine 2 mpk Duloxetine 10 mpk D-cycloserine 300 mpk 10 22.290 30.4841 979.50 181.190 Mirtazapine 2 mpk Mirtazapine 5 mpk D-cycloserine 300 mpk 10 25.282 22.3245 764.20 97.790 Vanilafaxine 2 mpk Vaniafaxine 16 mpk D-cycloserine 300 mpk 10 21.144 12.0805 928.50 78.921

TABLE 2 open arms in the presence of combined D-cycloserine/DOI/ MDL100907 was significantly greater than in the presence of Bar No. Condition Mean SEM N combined PCP/DOI/MDL100907 (p<0.05). 1 PTS - DOI (2 35.56903 6.428943 10 0118. In addition to selective 5-HT2A antagonists/inverse mg/kg) agonists, the atypical antipsychotics quetiapine (p<0.001) 2 DCS (30 mg/kg) - 44.59.616 3.3638.23 10 and lurasidone (p<0.05) also significantly reduced '% time in DOI (2 mg/kg) 3 DCS (300 mg/kg) - 48.1 4.7 10 open arms, suggesting a liability to induce akathisia. For both DOI (2 mg/kg) quetiapine (p<0.05) and iurasildone (p<0.05) effects were 4 MDL100907 (0.3 9.553678 2.931,169 10 significantly reversed by DCS 300 mpk. mg/kg) - DOI (2 mg/kg) 0119 Finally, three antidepressants—duloxetine, mir 5 MDL100907 (0.3 20.8 7.6 10 tazapine, and Venlafaine were tested m the presence of D-cy mg/kg) + DCS closerine (300 mpk) and DOI (2 mpk). All 3 showed signifi (30 mg/kg) - cantly reduced 96 open arm entries vs. DOI alone, consistent DOI (2 mg/kg) 6 MDL100907 (0.3 35.8 9.2 10 with ability to induce akathisia clinically. mg/kg) + DCS I0120 Distance Travelled (DT) (300 mg/kg) - DOI I0121. As opposed to % time in open arms, DOI (2 mpk) (2 mg/kg) significantly reduced total distance travelled, MDL100907 significantly increased DT vs. DOI (2 mpk) alone (p< 05). 0115 DOI (2 mpk) significantly increased 96 time spent in and this effect was enhanced (rather than reversed) by D-cy open arms vs. Saline at doses of both 1 mpk(p<0.05) and 2 mg closerine (300 mpk) (p<0.001). Other 5-HT2A and NMDAR (p<0.05). DCS had no significant effect when added to DOI antagonists had inconsistent effects alone and in combination alone at doses of either 30 mpk or 300 mpk, Suggesting with pattern different for that observed for the '% time spent in absence of nonspecific behavioral effects in this assay sys open arm measure, reflecting specificity of the anti-akathisia tem. DCS (300 mpk) significantly reversed effects of effects. As a group, dulloxetine, Venlafaxine and mirtazapine MDL100709 (p<0.05), whereas effects of DCS (30 mpk) added to DOI (2 mpk) and D-cycloserine (300 mpk) signifi were non-significant. Furthermore: % time spent in open cantly enhanced DT compared to DOI (2 mpk) and D-cyclos arms was numerically greater for combined DCS (300 mpk) erine (300 mpK) alone (p<0.05). and both ketanserin and EMD281014 than with either agent alone. When analyses were performed within experiment, a SUMMARY highly significant effect of D-cycioserine (300 mpk) vs. DOI 0.122 These findings demonstrate an unexpected ability of (2 mpk) and MDL100.907 (0.3 mpk) alone was observed D-cycloserine, at high doses, to reverse reductions in % time (p<0.01) (FIG. 1). spent in the open arm of the elevated plus maze induced by 0116. In the presence of DOI (2 mpk), both the 5-HT2A 5-HT2A antagonists such as MDL100709, ketanserin or antagonists/inverse antagonists MDL100907 (p-0.001) and atypical antipsychotics Pro-therapeutic effects were seen not Ketanserin (p<001) and EMD281014 (p<0.05) significantly only for D-cycloserine, but also for other NMDA receptor reduced '% time spent in open arms, suggesting a significant antagonists such as D-C-PPene. CGS19755 or CP101606. In liability for akathisia. contrast the traditional channel blocker PCP worsened per 0117 The competitive glutamate site antagonist D-CP formance relative to DCS, Suggesting that agents working at Pene produced trend level reversal of effects of MDL100,907 the glutamate or glycine binding sites, or lower affinity chan (p<0.1) on% time spent in open arms. Other NMDA receptor nel blockers, such as GlyX-13, may be superior to higher antagonists, including CGS19755 and CP 101606 produced affinity non-competitive antagonists such as PCP or MK-801. numerics; improvement No significant effect was observed Furthermore, although 5-HT2A antagonists are known to for the channel site antagonist PCP, although the tendency reverse hyperactivity induced by NMDA channel blockers was for exacerbation of effect. Furthermore, 96 time spent in such as ketamine, MK-80, or PCP, the '% open arm measure US 2014/0018348 A1 Jan. 16, 2014

(which compares distance travelled in open vs. closed arms) tions, combinations, and permutations in which one or more corrects for overall changes in activity levels. limitations, elements, clauses, descriptive terms, etc., from 0123. Although the present animal models leave open the one or more of the listed claims is introduced into another degree to which the phenomenon observed in rodents is iso claim dependent on the same base claim unless otherwise morphic with drug-induced akathisia and/or jitteriness/anxi indicated or unless it would be evident to one of ordinary skill ety syndrome in humans, this issue is immaterial to the in the art that a contradiction or inconsistency would arise. claimed invention, which nevertheless shows highly potent Where elements are presented as lists, e.g. in Markush group and unexpected reversal of anxiogenic properties of 5-HT2A format or the like, it is to be understood that each subgroup of antagonistic and atypical antipsychotic compounds by D-cy the elements is also disclosed, and any element(s) can be closerine and other NMDA receptor anatagonists. These find removed from the group. It should it be understood that, in ings thus Suggest a unique and unexpected benefit from the general, where the invention, or aspects of the invention, addition of NMDA receptor antagonists to 5-HT2A antago is/are referred to as comprising particular elements, features, nists including typical/atypical antagonists and antidepres etc, certain embodiments of the invention or aspects of the sants, and Suggests that undesirable anxiogenlc side effects of invention consist, or consist essentially of Such elements, these compounds can be minimized by the use of NMDAR features, etc. For purposes of simplicity those embodiments antagonists. have not in every case been specifically set forth inhaec verba 0124 While contain features of the invention have been herein. Certain claims are presented independent form for the illustrated and described herein, many modifications, Substi sake of convenience, but Applicant reserves the right to tutions, changes, and equivalents will now occur to those of rewrite any dependent claim in independent format to include ordinary skill in the art. It is, therefore, to be understood that the elements or limitations of the independent claim and any the appended claims are intended to cover all Such modifica other claim(s) on which Such claim depends, and Such rewrit tions and changes as fall within the true spirit of the invention. ten claim is to be considered equivalent in all respects to the 0.125. It will be understood by those skilled in the art that dependent claim in whatever form if is in (either amended or various changes in form and details may be made therein unamended) poor to being rewritten in independent format. without departing from the spirit and scope of the invention as 1. A composition for treating depression or psychosis in a set forth in the appended claims. Those skilled in the art will human in need of Such treatment comprising an antidepres recognize, or be able to ascertain using no more than routine sion orantipsychosis effective amount of an oral or parenteral experimentation, many equivalents to the specific embodi dosage composed of a first compound selected from the group ments of the invention described herein. Such equivalents are consisting of an antidepressants agent and an antipsychotic intended to be encompassed in the scope of the claims. agent, which first compound includes a selective 5-HT2A 0126 All publications, patents, and patent applications receptor antagonist/inverse agonist and a second compound mentioned herein are hereby incorporated by reference in selected from the group consisting of a NMDAR receptor their entirety as if each individual publication or patent was antagonists. specifically and individually indicated to be incorporated by 2. The composition of claim 1 wherein the NMDAR recep reference. In case of a conflict between the specification and tor antagonist is selected from the group consisting of non an incorporated reference, the specification shall control. selective antagonists, selective antagonists and combinations Where number ranges are given in this document, endpoints thereof. are included within the range unless otherwise specified. Fur 3. The composition of claim 1 wherein the antipsychotic is thermore, it is to be understood that unless otherwise indi selected from the group consisting of risperidone, olanzapine, cated or otherwise evident from the context and understand quetiapine, aripiprazole, clozapine, illoperidone, sertindole, ing of one of ordinary skill in the art. Values that are expressed asenapine, lurasidone, and cariprazine. as ranges can assume any specific value or Subrange within the stated ranges, optionally including or excluding either or 4. The composition of claim 1 wherein the antidepressant is both endpoints, in different embodiments of the invention, to selected from the group consisting a tetracyclic antidepres the tenth of the unit of the lower limit of the range, unless the sant (TeCA), a selective serotonin reuptake inhibitor (SSRI), context clearly dictates otherwise. Where a percentage is a serotonin/norephinephrine reuptake inhibitor (SNRI), a recited in reference to a value that, intrinsically has units that 5-HT2A antagonist or inverse agonist and combinations are whole numbers, any resulting fraction may be rounded to thereof. the nearest whole number. 5. The composition of claim 1 wherein the antidepressant is selected from the group consisting of imipramine, amitryp 0127. In the claims articles sued as “a” “an and “the tiline, desipramine, clomipramine, amoxapine, setiptiline, mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions maprotiline, mianserin, mirtazapine, fluoxetine, fluvoxam that, include 'or' or “and/or between members of a group ine, paroxetine, citalopram, escitalopram, dulloxetine, Ven are considered satisfied if one, more than one, or all of the lafaxine, dapoxetine, indalpine, and valZodone. group members am present in, employed in, or otherwise 6. The composition of claim 1 wherein the selective relevant to a given product or process unless indicated to the 5-HT2A receptor antagonist/inverse agonist is selected from contrary or otherwise evident from the context. The invention a group including MDL100.907, ritanserin, ketanserin, epli includes embodiments in which exactly one member of the vanserin, CYR-101 and pimavanserin (ACP-103) group is present in, employed in, or otherwise relevant to a 7. The composition of claim 1 wherein the NMDAR given product or process. The invention also includes antagonist selected from the group consisting of antagonists embodiments in which more than one or all of the group of the glycine, glutamate and channel recognition sites. members are present in, employed in, or otherwise relevant to 8. The composition of claim 1 wherein the NMDAR a given product or process. Furthermore, it is to be understood antagonist is selective for NMDAR containing an NR2B sub that the invention provides, in various embodiments, all varia unit. US 2014/0018348 A1 Jan. 16, 2014

9. The composition of claim 1 wherein the NMDAR chosis effective amount of the composition of claim 1 in the antagonist consists of D-cycloserine, administered at a dose form of an oral or parenteral dosage. of 500 mg/d or greater 15. A method for the treatment of symptoms of autism 10. The composition of claim 1 wherein the NMDAR psychosis in a human Subject comprising administering to the antagonist is selected from the group consisting of CGS human an anti-autism effective amount of the composition of claim 1 in the form of an oral or parenteral dosage. 19755, D-CPPene, MK-0657, AZD6765, Glyx-13, NRX 16. A method for reducing the side effects associated with 1059, or EVT-101 medications administered to a human Subject for treatment of 11. The composition of claim 1 is in the form of an oral or mental illness comprising administering a side-effect reduc parenteral dosage. ing effective amount of the composition of claim 1 in the form 12. A method for the treatment of depression or psychosis of an oral or parental dosage to the Subject. in a human Subject comprising administering to the human an 17. A pharmaceutical composition for the treatment of anti-depression or anti-psychosis effective amount of the psychosis or depression comprising an anti-depression or composition of claim 1 orally, intramuscularly, intravenously, anti-psychosis effective amount of an oral or parenteral dos intraperitoneally, parentally or orally. age composed of a first compound selected from the group 13. A method for the treatment of depression in a human consisting of an antidepressants agent and an antipsychotic Subject comprising administering to the human an anti-de agent which compound includes a selective 5-HT2A receptor pression effective amount of the composition of claim 1 in the agonist/inverse antagonist and a second compound selected form of an oral or parenteral dosage. from the group consisting of a NMDAR receptor antagonist 14. A method for the treatment of psychosis in a human in the form of a Sustained release dosage. Subject comprising administering to the human an anti-psy k k k k k