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(12) United States Patent (10) Patent No.: US 9.486.453 B2 Javitt (45) Date of Patent: Nov

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(12) United States Patent (10) Patent No.: US 9.486.453 B2 Javitt (45) Date of Patent: Nov USOO9486453B2 (12) United States Patent (10) Patent No.: US 9.486.453 B2 Javitt (45) Date of Patent: Nov. 8, 2016 (54) COMPOSITION AND METHOD FOR 2008. O194631 A1 8, 2008 Trovero et al. TREATMENT OF DEPRESSION AND 2008. O194698 A1 8/2008 Hermanussen et al. PSYCHOSIS IN HUMANS 2010/0216805 A1 8, 2010 Barlow .................. A61K 31, 12 514,249 2011/02O7776 A1 8, 2011 Buntinx (71) Applicant: Glytech, LLC, Ft. Lee, NJ (US) 2011/0237602 A1* 9, 2011 Meltzer ................ A61K 31,496 514,254.04 (72) Inventor: Daniel C. Javitt, Bardonia, NY (US) 2011/0306586 A1 12, 2011 Khan 2012/0041026 A1 2/2012 Waizumi (73) Assignee: Glytech LLC, Ft. Lee, NJ (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 KR 2007 OO17136 A 2, 2007 WO WO 2005.000216 A2 1, 2005 U.S.C. 154(b) by 0 days. WO WO 2005/0653O8 A2 7/2005 WO WO 2005/079756 9, 2005 (21) Appl. No.: 14/844,021 WO WO 2011044089 4, 2011 WO WO 2012.104852 A1 8, 2012 (22) Filed: Sep. 3, 2015 WO WO2O13138322 9, 2013 (65) Prior Publication Data OTHER PUBLICATIONS US 2015/0374,684 A1 Dec. 31, 2015 Fenton, “Depression, Suicide and Suicide Prevention in Schizo Related U.S. Application Data phrenia.” American Foundation for Suicide Prevention Education (62) Division of application No. 13/936,198, filed on Jul. Section, http://www.afsp.org/education/fenton.htm (date accessed— 7, 2013. Dec. 3, 2015).* Jamison, "Suicide and bipolar disorder,” J. Clin Psychiatry, 2000:61 (60) Provisional application No. 61/741,114, filed on Jul. Suppl 9:47-51.* 12, 2012, provisional application No. 61/741,115, Rogoz, Z. et al. “Synergistic effect of uncompetitive NMDA recep filed on Jul. 12, 2012. tor antagonists and antidepressant drugs in the forced Swimming test in rats' Neuropharmacology, Pergamon Press, Oxford, GB, 42(8): (51) Int. Cl. 1024-1030, XP002288820 (Jun. 2002). AOIN 43/00 (2006.01) Heresco-Levy, U. et al. "Controlled trial of d-cycloserine adjuvant A 6LX 3/553 (2006.01) therapy for treatment-resistant major depressive disorder” Journal A6 IK3I/554 (2006.01) of Affective Disorders, Elsevier Biochemical Press, Amsterdam, A6 IK 3/496 (2006.01) NL, 93(1-3): 239-243, XPO24997304 (Jul 2006). A6 IK 3/42 (2006.01) Crane, G.E. "Cycloserine as an antidepressant agent' American A6 IK3I/06 (2006.01) journal of Psychiatry, American Psychiatric Publishing, Inc., US, A6 IK3I/38 (2006.01) 115(11): 1025-1026, XP009 158563 (May 1, 1959). A6 IK3I/55 (2006.01) Ceglia et al., “The 5-HT2A receptor antagonist M100.907 prevents A6 IK3I/38 (2006.01) extracellular glutamate rising in response to NMDA receptor block A6 IK 45/06 (2006.01) ade in the mPFC.” Journal of Neurochemistry, 2004, 91, 189-199. Mony et al., “Identification of a novel NR2B-selective NMDA A6 IK 3/43 (2006.01) receptor antagonist using a virtual screening approach,” Bioorganic A6 IK 3L/4525 (2006.01) & Medicinal Chemistry Letters 2002010) 5552-5558. A 6LX 3/59 (2006.01) Ardayfio et al., J. Pharm and Exp. Ther, 327:891-897, 2008. A6 IK3I/55 (2006.01) Gaisler-Salomon et al., Psychopharm 196:255-267, 2008. A6 IK3I/35 (2006.01) Carlsson et al., J. Neuraltrans. 106:123-129, 1999. (52) U.S. Cl. De Paulis, Curr Opin in Invest Drugs 2:123-132, 2001. CPC ............. A61 K3I/496 (2013.01); A61 K3I/06 (2013.01); A61K 31/135 (2013.01); A61 K * cited by examiner 3 1/138 (2013.01); A61K 3 1/381 (2013.01); A61K 31/42 (2013.01); A61K 31/431 Primary Examiner — Jared D Barsky (2013.01); A61K 31/4525 (2013.01); A61 K (74) Attorney, Agent, or Firm —JMB Davis Ben-David 31/519 (2013.01); A61 K3I/55 (2013.01); A6 IK3I/551 (2013.01); A61 K3I/553 (57) ABSTRACT (2013.01); A61 K3I/554 (2013.01); A61 K Compositions and methods for the treatment of depression 45/06 (2013.01) and psychoses in humans are disclosed. More particularly, (58) Field of Classification Search the invention is directed to formulations containing antip None sychotic and/or antidepressant medications and also con See application file for complete search history. taining an NMDAR antagonist. The present Invention Is also directed to methods tor the treatment of humans suffering (56) References Cited from depression and other psychoses, including, Schizophre nia, by administration of the inventive compositions in U.S. PATENT DOCUMENTS antidepressant and/or antipsychotic effective amounts. 6,228,875 B1 5, 2001 Tsai et al. 2006/0204486 A1 9/2006 Pyke et al. 6 Claims, 1 Drawing Sheet US 9,486,453 B2 1. 2 COMPOSITION AND METHOD FOR disorder, dissociative disorders, personality disorders or TREATMENT OF DEPRESSION AND adjustment disorders with depressed mood (DSM-IV). PSYCHOSIS IN HUMANS Current treatments for major depression consist primarily of older antidepressants, such as monoamine oxidase inhibi CROSS REFERENCE TO RELATED tors (MAOI) and tricyclic antidepressants (TCAS) (e.g. APPLICATIONS imipramine, amitryptiline, desipramine, clomipramine) that were first developed in the 1960s, and newer agents such as This is a divisional of co-pending U.S. patent application tetracyclic antidepressants (TeCAS), e.g. amoxapine, Setip Ser. No. 13/936,198, filed Jul. 7, 2013, which claims the tiline, maprotiline, mianserin, mirtazapine), serotonin benefit of provisional application No. 61/741,114, filed Jul. 10 (SSRI) and serotonin/norephinephrine (SNRI) reuptake 12, 2012, and provisional application No. 61/741,115, filed inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, citalo Jul. 12, 2012, the contents of each of which are hereby pram, escitalopram, dulloxetine, Venlafaxine, dapoxetine, incorporated by reference. indalpine, ValZodone). These agents work by modulating BACKGROUND OF THE INVENTION 15 brain levels of monoamines, in particular norepinephrine and serotonin, and/or by blocking 5-HT2A receptors. Schizophrenia is a clinical syndrome associated with MAOIs and TCAS are considered “broader spectrum' agents psychotic symptoms such as delusions and hallucinations, as than SSRIs/SNRIs that were developed subsequently well as a decline in function in Such areas as work, social MAOI, TCAS, TeCAs, SSRIs, and SNRIs may collectively relation or self care. be considered traditional antidepressants. Diagnosis of Schizophrenia may be determined using Antipsychotics may also be effective in treatment of standard textbooks of the art, such as the Diagnostic and depression. Potentially beneficial antipsychotic medications Statistical Manual of Mental Disorders-fourth edition include but are not limited to risperidone, olanzapine, que (DSM-IV) published by the American Psychiatric Associa tiapine, aripiprazole, clozapine, illoperidone, sertindole, tion. Symptoms of Schizophrenia are typically measured 25 asenapine, lurasidone, cariprazine. using rating scales such as the Positive and Negative Syn Other antipsychotics and antidepressants in development drome Scale (PANSS). include Valdoxan (agomelatine, AGO178) (Servier, Novar Symptoms of schizophrenia are treated with antipsychotic tis), Lu AA2 1004 (Lundbeck, Takeda), F2695, levomil medications, which function primarily by blocking dop nacipran (Forest, Pierre Fabre), SEP-227162 (Sepracor), amine D2 receptors. 30 LuAA24530 (Lundbeck, Takeda). SEP-225289 (Sepracor), Antipsychotics may be divided into typical (e.g. chlorpro Epivanserine (Sanofi-Aventis), SR463 9 (Sanofi-Aventis). mazine, haloperidol. perphenazine) vs. atypical (e.g. amisul LY12624803, HY10275 (Lilly, Hypnion), TI-301/ pride, aripiprazole, asenapine, bioanserin, bifeprunoX, car LY 156735 (Tikvah Therapeutics), Lonasen (bioanserin, iprazine, clotiapine, clozapine, illoperidone, lurasidone, Dainippon), LU-31-130 (Lundbeck), SLV313 (Solvay). Edi mosaproamine, olanzapine, paliperidone, peroSpirone, que 35 voxetine (LY2216684, Lilly), OPC-34712 (Otsuka/Lund tiapine, remoxipride, risperidone, sertindole, Sulpiride, Zip beck), Vyvanse (lisdexamfetamine, Shire), BCI-224 (sa rasidone, Zotepine) based upon receptor binding, preclinical comeline, BrainCells), BCI-540 (clouracetam, BrainCells), effects and side effect profile. Clinically effective doses of BMS-82036 (BMS/AMRI). antipsychotic medication typically produce >60% occu However, current treatment approaches have severe limi pancy of dopamine D2 receptors. Atypical antipsychotics 40 tations. Only 60-65% of patients respond to the initial may be partial or full D2 antagonists and may also have regimen and among those responding, less than half either activity at additional catecholamine and serotonin receptor reach remission or become symptom-free. Individuals not types, including 5-HT2A and 5-HT2C receptors and adren responding to a first course of antidepressant treatment are ergic alpha1 and alpha2 receptors. Atypical antipsychotics often switched to a different drug, with results that are may also affect other receptor types, such as such as mus 45 generally modest and incremental. carinic cholinergic receptors. 5-HT2A receptors are a type of receptor for the neu Major depression is a clinical syndrome that includes a rotransmitter serotonin. 5-HT2A antagonists are compounds persistent sad mood or loss of interest in activities, which that inhibit effects of agonists such as serotonin on 5-HT2A persists for at least two weeks in the absence of treatment. receptors. Inverse agonists are compounds that, in addition, Symptoms of major depression are typically measured using 50 reduce activity below basal levels. 5-HT2A receptor antago rating scales such as the Hamilton Depression Rating Scale nists can be non-selective for 5-HT2A vs. other serotonin (HAM-D) or the Beck Depression inventory (BDI). In receptors (e.g. 5-HT2C), or selective for 5-HT2A receptors. addition to including symptoms relevant to depressed mood, Selective 5-HT2A antagonists can be developed and char the HAM-D also contains symptoms sensitive to psychosis, acterized using standard assay procedures, such as those including items for guilt, depersonalization/derealization 55 described in U.S. Pat. No. 7,713.995 issued on May 11, and paranoia. Major depression may also be associated with 2010, which is herein incorporated by reference in its symptoms of anxiety, which may be measured with rating entirety. scales such as the Hamilton Rating Scale for Anxiety Agents that act as non-selective serotonin receptor (HAM-A).
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