US 20170181989A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0181989 A1 Tsai (43) Pub. Date: Jun. 29, 2017

(54) SORBC AND BENZOIC ACID AND Publication Classification DERVATIVES THEREOF ENHANCE THE (51) Int. Cl. ACTIVITY OF A NEUROPHARMACEUTICAL A63L/92 (2006.01) (71) Applicant: Los Angeles Biomedical Research A 6LX 3/553 (2006.01) Institute at Harbor-UCLA Medical (52) U.S. Cl. Center, Torrance, CA (US) CPC ...... A61K 31/192 (2013.01); A61 K3I/5513 (2013.01) (72) Inventor: Guochuan Emil Tsai, Pasadena, CA (US) (57) ABSTRACT Methods and compositions are provided for treating neu (73) Assignee: Los Angeles Biomedical Research ropsychiatric disorders such as Schizophrenia, depression, Institute at Harbor-UCLA Medical attention deficit disorder, mild cognitive impairment, Center, Torrance, CA (US) dementia, and bipolar disorder. The methods entail admin istering to a patient diagnosed as having a neuropsychiatric disorder (e.g., Schizophrenia, depression, attention deficit (21) Appl. No.: 15/409,655 disorder, mild cognitive impairment, dementia bipolar dis order, etc.) or as at risk for a neuropsychiatric disorder a (22) Filed: Jan. 19, 2017 benzoic acid, benzoic acid salt, and/or benzoic acid deriva tive, and/or a Sorbic acid, Sorbic acid salt, and/or Sorbic acid Related U.S. Application Data derivative, in combination with a neuropharmacological agent (e.g., an antipsychotic, an antidepressant, medications (62) Division of application No. 14/552,298, filed on Nov. for attention deficit and hyperactivity disorder, cognitive 24, 2014, which is a division of application No. impairment, or dementia, etc.) where the benzoic acid, 12/689,957, filed on Jan. 19, 2010, now Pat. No. benzoic acid salt, or benzoic acid derivative, and/or a Sorbic 9,649,304. acid, Sorbic acid salt, and/or Sorbic acid derivative, is in an (60) Provisional application No. 61/145,931, filed on Jan. amount Sufficient to increase the efficacy of the neurophar 20, 2009. macological agent. Patent Application Publication Jun. 29, 2017 Sheet 1 of 3 US 2017/O181989 A1

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SORBIC AND BENZOIC ACID AND SUMMARY OF THE INVENTION DERVATIVES THEREOF ENHANCE THE ACTIVITY OF A NEUROPHARMACEUTICAL 0007. In certain embodiments this invention pertains to “combination’ pharmaceutical compositions comprising a CROSS-REFERENCE TO RELATED benzoic acid, benzoic acid salt, benzoic acid ester or other APPLICATIONS benzoic acid derivative, and/or a Sorbic acid, Sorbic acid salt, sorbic acid ester, or other sorbic acid derivative and a 0001. This application claims benefit of and priority to neuropharmaceutical (e.g., an antipsychotic (e.g., ris U.S. Ser. No. 61/145,931, filed on Jan. 20, 2009, which is peridone, olanzapine, etc.), and antidepressant (e.g., Sertra incorporated herein by reference in its entirety for all pur line, fluoxetine hydrochloride, etc.), a psychotropic medica poses. tion for attention deficit and hyperactivity disorder (e.g., STATEMENT AS TO RIGHTS TO INVENTIONS Ritalin, Dexedrine, Atomoxetine, etc.), a psychotropic medi MADE UNDER FEDERALLY SPONSORED cation for dementia (e.g., Aricept, memantine), and the like). RESEARCH AND DEVELOPMENT Typically, the benzoic acid, benzoic acid salt, benzoic acid ester or other benzoic acid derivative, and/or a sorbic acid, 0002. Not Applicable sorbic acid salt, sorbic acid ester, or other sorbic acid derivative is present in an amount Sufficient to increase the FIELD OF THE INVENTION efficacy of the neuropharmaceutical. In certain embodiments 0003. This is invention pertains the field of neuropsy the benzoic acid is provided as a benzoic acid salt (e.g. chiatry. In particular treatment methods are provided for Sodium benzoate, potassium benzoate, calcium benzoate, neuropsychiatric disorders. etc.). In certain embodiments the benzoic acid, benzoic acid salt, or derivative thereof is selected from the group con BACKGROUND OF THE INVENTION sisting of benzoic acid, Sodium benzoate, potassium benzo ate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, 0004 Schizophrenia, Alzheimer's Disease, autism, and 4-aminobenzoate. In certain embodiments the Sorbic depression, benign forgetfulness, childhood learning disor acid is provided as a Sorbic acid salt (e.g., sodium Sorbate, ders, close head injury, and attention deficit disorder (ADD), potassium Sorbate, calcium Sorbate, etc.). In certain embodi dementia, mild cognitive impairment, ataxia, Spinocerebel ments the Sorbic acid, Sorbic acid salt, Sorbic acid ester, lar degeneration, Parkinson's disease, obsessive compulsive and/or sorbic acid derivative is selected from the group disorder (OCD), substance abuse, and substance dependence consisting of Sorbic acid, Sodium Sorbate, potassium Sorbate, are examples of neuropsychiatric disorders. Autism, for calcium Sorbate, Sorbohydroxamic acid, a Sorbic aldehyde, a example, is a developmental mental disorder characterized Sorbic acid-thiol adduct, 8-quinolinylsorbate, and m-ni by autistic behavior, social failure, and language delay. trosorbanilide. Alzheimer's Disease is a form of dementia that typically involves progressive mental deterioration, manifested by 0008. In certain embodiments the ratio of benzoic acid, memory loss, confusion, and disorientation. Alzheimer's benzoic acid salt, or benzoic acid derivative and/or sorbic Disease typically is treated by acetylcholine esterase inhibi acid, Sorbic acid salt, or Sorbic acid derivative to neurop tors such as hydrochloride or donepezil. Attention harmaceutical is stoichiometrically greater than 2:1, greater Deficit Disorder is a disorder that is most prevalent in than 3:1, greater than 4:1 greater than 5:1, greater than 6:1, children and is associated with increased motor activity and greater than 7:1, greater than 8:1, greater than 9:1, or greater a decreased attention span. Attention Deficit Disorder com than 10:1 or 20:1. monly is treated by administration of psychoStimulants or 0009. In certain embodiments the neuropharmaceutical is other medications such as Ritalin, Dexedrin, or atomoxetin. selected from the group consisting of an antidepressant, an Depression is a clinical syndrome that includes a persistent antipsychotic, a psychoStimulant, a mood stablizer, an anxi sad mood or loss of interest in activities, which persists for olytic, an ADHD therapeutic, and an Alzheimer's disease at least two weeks in the absence of treatment. Conventional therapeutic. In certain embodiments the neuropharmaceuti therapeutics include uptake inhibitors (e.g., PRO cal is an antipsychotic drug (e.g., butyrophenone, phenothi ZAC(R), inhibitors, and tricyclic anti azine, fluphenazine, perphenazine, prochlorperazine, thior depressants. idazine, trifluoperazine, mesoridazine, promazine, 0005. The term schizophrenia represents a group of neu triflupromazine, levomepromazine, promethazine, thioxan ropsychiatric disorders characterized by dysfunctions of the thene, chlorprothixene, flupenthixol, thiothixene, Zuclopen thinking process. Such as delusions, hallucinations, and thixol, clozapine, olanzapine, risperidone, quetiapine, Zip extensive withdrawal of the patients interests from other rasidone, amisulpride, asenapine, paliperidone, aripiprazole, people. Approximately one percent of the worldwide popu a partial agonist, lamotrigine, memantine, tetra lation is afflicted with schizophrenia, and this disorder is benazine, cannabidiol, and/or LY2140023). In certain accompanied by high morbidity and mortality rates. embodiments the neuropharmaceutical is an antidepressant 0006 Conventional antipsychotic , which act on the drug (e.g., a monoamine oxidase inhibitor (MAOI), a tricy dopamine D, receptor, can be used to treat the positive clic antidepressant (TCA), a tetracyclic antidepressant symptoms of Schizophrenia, Such as delusion and halluci (TeCA), a selective serotonin reuptake inhibitor (SSRI), and nation. In general, conventional antipsychotic drugs and the a serotonin- reuptake inhibitor (SNRT). In new atypical antipsychotic drugs, which act on the dop certain embodiments the the neuropharmaceutical is an amine D, and 5HT2 serotonin receptor, are limited in their ADHD medication (e.g., Ritalin, Dexedrine, Atomoxetine, ability to treat cognitive deficits and negative symptoms and the like). In certain embodiments the neuropharmaceu Such as affect blunting (i.e., lack of facial expressions), tical is a medication for improving cognition and/or inhib anergia, and Social withdrawal. iting neurodegeneration (e.g., Aricept. memantine, etc.). US 2017/O181989 A1 Jun. 29, 2017

0010 Also provided are methods for mitigating one or LY2140023). In certain embodiments the, the neuropsychi more symptoms of a neuropsychiatric disorder (e.g., Schizo atric disorder is depression, and the neuropharmaceutical is phrenia, depression, attention deficit disorder, mild cogni an antidepressant drug (e.g., a monoamine oxidase inhibitor tive impairment, dementia, attention deficit hyperactivity (MAOI), a tricyclic antidepressant (TCA), a tetracyclic disorder (ADHD), bipolar disorder, and the like). The meth antidepressant (TeCA), a selective serotonin reuptake inhibi ods typically involve administering to a subject in need tor (SSRI), and a serotonin-norepinephrine reuptake inhibi thereof a benzoic acid, benzoic acid salt, or benzoic acid tor (SNRI). In certain embodiments, the neuropsychiatric derivative and/or a sorbic acid, sorbic acid salt, or sorbic disorder is ADHD and the neuropharmaceutical is an ADHD acid derivative in an amount Sufficient to mitigate one or medication (e.g., ritalin, dexedrine, atomoxetine, and the more symptoms of a neuropsychiatric disorder. In certain like). In certain embodiments, the neuropsychiatric disorder embodiments the method comprises administering to the is characterized by loss in cognition and/or neurodegenera Subject the benzoic acid, benzoic acid salt, or benzoic acid tion (e.g. Alzheimer's disease), and the neuropharmaceutical derivative and/or a sorbic acid, sorbic acid salt, or sorbic is a medication for improving cognition and/or inhibiting acid derivative in conjunction with a neuropharmaceutical, neurodegeneration (e.g., Aricept, memantine, etc.). In vari where the benzoic acid, benzoic acid salt, or benzoic acid ous embodiments of the methods, the Subject is a human derivative and/or a sorbic acid, sorbic acid salt, or sorbic diagnosed having or as at risk for a neuropsychiatric disor acid derivative is administered in an amount Sufficient to der. In various embodiments the Subject is a non-human increase the efficacy of the neuropharmaceutical. In certain mammal (e.g., a canine, a feline, an equine, etc.). In various embodiments the benzoic acid, benzoic acid salt, benzoic embodiments the methods are performed prophylactically, acid ester, or derivative thereof and/or a sorbic acid, sorbic or therapeutically. acid salt, sorbic acid ester, or derivative thereof and the 0014. Uses for benzoic acid, benzoic acid salt, or benzoic neuropharmaceutical are administered simultaneously (i.e., acid derivative and/or a sorbic acid, Sorbic acid salt, or separately or in a combined formulation). In certain embodi Sorbic acid derivative as active agents in the manufacture of ments the benzoic acid, benzoic acid salt, benzoic acid ester, medicaments for the treatment of a neuropsychiatric disor or derivative thereof and/or a sorbic acid, sorbic acid salt, der are provided where the benzoic acid, benzoic acid salt, sorbic acid ester, or derivative thereof is administered before benzoic acid ester, or benzoic acid derivative and/or a sorbic or after the neuropharmaceutical. acid, Sorbic acid salt, Sorbic acid ester or Sorbic acid deriva 0011. In certain embodiments of the methods, the benzoic tive is present in an amount effective to mitigate one or more acid is provided as a benzoic acid salt (e.g. sodium benzoate, symptoms of the neuropsychiatric disorder are also pro potassium benzoate, calcium benzoate, etc.). In certain vided. Similarly, uses for benzoic acid, benzoic acid salt, or embodiments the benzoic acid, benzoic acid salt, or deriva benzoic acid derivative and/or a Sorbic acid, Sorbic acid salt, tive thereof is selected from the group consisting of benzoic or sorbic acid derivative in combination with a neurophar acid, Sodium benzoate, potassium benzoate, calcium benzo maceutical in the manufacture of a medicament for the ate, 2-aminobenzoate, 3-aminobenzoate, and 4-aminoben treatment of a neuropsychiatric disorder, where the benzoic Zoate. In certain embodiments the Sorbic acid is provided as acid, benzoic acid salt, or benzoic acid derivative and/or a a Sorbic acid salt (e.g., Sodium Sorbate, potassium Sorbate, sorbic acid, sorbic acid salt, or sorbic acid derivative is calcium Sorbate, etc.). In certain embodiments the Sorbic present in an amount Sufficient to increase the efficacy of the acid, Sorbic acid salt, Sorbic acid ester, and/or sorbic acid neuropharmaceutical are provided. In various embodiments derivative is selected from the group consisting of Sorbic the benzoic acid, benzoic acid salt, benzoic acid ester, and/or acid, sodium Sorbate, potassium Sorbate, calcium Sorbate, benzoic acid derivative is a benzoic acid salt. In various Sorbohydroxamic acid, a Sorbic aldehyde, a Sorbic acid-thiol embodiments the benzoic acid, benzoic acid salt, benzoic adduct, 8-quinolinylsorbate, and m-nitrosorbanilide. acid ester, and/or benzoic acid derivative is selected from the 0012. In certain embodiments of the methods, the ratio of group consisting of benzoic acid, Sodium benzoate, potas benzoic acid, benzoic acid salt, or benzoic acid derivative sium benzoate, calcium benzoate, 2-aminobenzoate, and/or sorbic acid, sorbic acid salt, or sorbic acid derivative 3-aminobenzoate, and 4-aminobenzoate. In various embodi to neuropharmaceutical is stoichiometrically greater than ments the Sorbic acid, Sorbic acid salt, Sorbic acid ester, 2:1, greater than 3:1, greater than 4:1 greater than 5:1, and/or sorbic acid derivative is a sorbic acid salt. In certain greater than 6:1, greater than 7:1, greater than 8:1, greater embodiments the sorbic acid, sorbic acid salt, sorbic acid than 9:1, or greater than 10:1 or 20:1. ester, and/or sorbic acid derivative is selected from the group 0013. In certain embodiments of the methods, the neu consisting of Sorbic acid, Sodium Sorbate, potassium Sorbate, ropharmaceutical is selected from the group consisting of an calcium Sorbate, Sorbohydroxamic acid, a Sorbic aldehyde, a antidepressant, an antipsychotic, a psychoStimulant, a mood Sorbic acid-thiol adduct, 8-quinolinylsorbate, and m-ni stablizer, an anxiolytic, an ADHD therapeutic, and an trosorbanilide. In various embodiments the neuropharma Alzheimer's disease therapeutic. In certain embodiments the ceutical, when present, includes any one or more of the , the neuropsychiatric disorder is schizophrenia and/or bipo neuropharmaceuticals described herein. lar disorder, and the neuropharmaceutical is an antipsychotic 0015. In certain embodiments this invention pertains to drug (e.g., butyrophenone, phenothiazine, fluiphenazine, per the discovery that administration of any two or all three of phenazine, prochlorperazine, thioridazine, trifluoperazine, (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) mesoridazine, promazine, triflupromazine, levomepromaz a glycine transporter inhibitor, and/or (iii) a D-amino Acid ine, promethazine, thioxanthene, chlorprothixene, flupen Oxidase Inhibitor (DAAOI) to a subject having or at high thixol, thiothixene, Zuclopenthixol, clozapine, olanzapine, risk for a neuropsychiatric disorder, provides Substantially risperidone, quetiapine, Ziprasidone, amisulpride, asenapine, greater efficacy at reducing or eliminating symptoms of the paliperidone, aripiprazole, a dopamine partial agonist, lam disorder than previously known single-agent therapeutic otrigine, memantine, tetrabenazine, cannabidiol, and/or regimes. In various embodiments, this invention also pro US 2017/O181989 A1 Jun. 29, 2017 vides pharmacological compositions comprising any two or , physostigmine, , huperzine alpha, all three agents in combination and methods utilizing Such Vitamine c, vitamine, carotenoids, ginkgo biloba, statinsam combined formulations. phetamine, modafinil, desoxyn, methamphetamine, cocaine, 0016. Accordingly in certain embodiments, a pharmaceu arecoline, dexmethylphenidate, dextroamphetamine, meth tical composition (and method of use thereof) is provided ylphenidate, lisdexamfetamine dimesylate (Vyvanse), mixed where the composition comprises a D-amino Acid Oxidase salts amphetamine, atomoxetine, clonidine hydrochloride, Inhibitor (DAAOI) (e.g., benzoic acid, benzoic acid salt, or guanfacine hydrochloride, arecoline, pemoline, donepezil, benzoic acid derivative and/or a Sorbic acid, Sorbic acid salt, tacrine, rivastigmine, memantine, lamotrigine, acamprosate, or sorbic acid derivative) and/or an NMDA enhancer and/or tetrabenazine, riluzole). a glycine transporter inhibitor. In certain embodiments, a 0018. In certain embodiments any of the compositions pharmaceutical composition is provided where the compo described herein is formulated as a unit dosage formulation. sition comprises a benzoic acid, benzoic acid salt, or benzoic In certain embodiments the active agent(s) comprising the acid derivative and/or a sorbic acid, Sorbic acid salt, or composition are independently formulated as salts, esters, or sorbic acid derivative; and an NMDA enhancer. In certain prodrugs. In certain embodiments the composition is for embodiments, a pharmaceutical composition is provided mulated for administration by a route selected from the where the composition comprises a benzoic acid, benzoic group consisting of oral administration, transdermal admin acid salt, or benzoic acid derivative and/or a Sorbic acid, istration, transnasal administration, intramuscular adminis Sorbic acid salt, or Sorbic acid derivative; and a glycine tration, rectal administration, intravenous administration, transporter inhibitor. In certain embodiments, a pharmaceu intrathecal administration, intraperitoneal administration, tical composition is provided where the composition com administration in a Subcutaneous depot formulation, and prises a benzoic acid, benzoic acid salt, or benzoic acid administration as an inhalant. derivative and/or a sorbic acid, sorbic acid salt, or sorbic 0019. Also provided are methods of mitigating one or acid derivative; an NMDA enhancer; and a glycine trans more symptoms of a neuropsychiatric disorder. The methods porter inhibitor. In various embodiments of these composi typically involve administering to a subject in need thereof tions, the D-amino Acid Oxidase Inhibitor comprises ben a benzoic acid, benzoic acid salt, or benzoic acid derivative Zoic acid, benzoic acid salt, or benzoic acid derivative and/or and/or a Sorbic acid, Sorbic acid salt, or Sorbic acid deriva a Sorbic acid, Sorbic acid salt, or Sorbic acid derivative alone tive in conjunction with an NMDA enhancer and/or a together with each other, or alone or together with each other glycine transporter inhibitor. In certain embodiments the and an additional DAAO inhibitor described herein. In composition comprises any of the drug combinations various embodiments the NMDA enhancer, when present, described herein. In certain embodiments the neuropsychi comprises one or more NMDA enhancers described herein. atric disorder is schizophrenia. In certain embodiments the In various embodiments the glycine transporter inhibitor, neuropsychiatric disorder is bipolar disorder or mania, or when present comprises one or more glycine transporter hypomania. In certain embodiments the neuropsychiatric inhibitors described herein. disorder is mild cognitive impairment, Alzheimer's disease 0017. In various embodiments these compositions com and/or Parkinson's disease and/or dementia. In certain prise an additional neuropharmaceutical, e.g., an antipsy embodiments the neuropsychiatric disorder is ataxia and/or chotic, an antidepressant, a psychoStimulant, a mood stabi spinocerebellar degeneration. In certain embodiments the lizer, an anxiolytic, an Alzheimer's disease therapeutic, neuropsychiatric disorder is autism or Asperger's disorder. and/or other psychotropic. In certain embodiments the addi In certain embodiments the neuropsychiatric disorder is tional therapeutic agent is one or more agents selected from depression or dysthymia. In certain embodiments the neu the neuropharmaceuticals described herein (e.g., diazepam, ropsychiatric disorder is benign forgetfulness or mild cog bromazepam, prazepam, chlordiazepoxide, clobazam, esta nitive impairment. In certain embodiments the neuropsychi Zolam, flurazepam, clonazepam, temazepam, triazolam, atric disorder is a childhood learning disorder (e.g., attention alprazolam, midazolam, brotizolam, nitrazepam, flunitraze deficit disorder). In certain embodiments the neuropsychi pam, oxazepam, quaZepam, lorazepam, temazepam, triaZo atric disorder is close head injury. In certain embodiments lam, Zolpidem, Zopiclone, Zaleplon, chlorpromazine, thior the neuropsychiatric disorder is anxiety disorders including idazine, mesoridazine, fluphenazine, perphenazine, obsessive compulsive disorder, generalized anxiety disorder, trifluoperazine, thiothixene, haloperidol, loxapine, molin panic disorder, phobia, Social phobia. In certain embodi done, clozapine, risperidone, olanzapine, quetiapine, halo ments the neuropsychiatric disorder is close post-traumatic peridol decanoate, fluiphenazine decanoate, fluiphenazine stress disorder. In certain embodiments the neuropsychiatric enanthate, risperdal consta, Sulpiride, Ziprasidone, aripipra disorder is substance abuse and/or substance dependence. Zole, paliperidone, acetophenazine, chlorprothixene, dro 0020. In certain embodiments any of the uses and/or peridol, pimozide, butaperazine, carphenazine, remoxipride, methods described herein expressly exclude one or more piperacetazine, amitriptyline, imipramine, nortriptiline, pro neuropsychiatric disorders selected from the group consist triptyline, desipramine, trimipramine, amoxapine, bupro ing of Schizophrenia, bipolar disorder, Alzheimer's disease, pion, bupropion Sr, citalopram, S-citalopram, clomipramine, Parkinson's disease, dementia, ataxia, Spinocerebellar desipramine, doxepin, dulloxetine, milnacipran, fluoxetine, degeneration, ADD, ADHD, depression, and mild cognitive fluvoxamine, imipramine, , , iproni impairment. In certain embodiments the use benzoic acid, azid, fluoxetine, paroxetine, Sertraline fluvoxamine, Venla salt, ester, or other benzoic acid derivative and/or sorbic faxine, Velafaxine Xr, milnacipram and dulloxetine, mirtazap acid, salt, ester, or other sorbic acid derivative in the ine, mianserin, reboxetine, , , treatment of neurodegenerative conditions (e.g., Alzheim traZodone, nefazodone, , lamatrogine, lithium, er's disease, senile dementia of the Alzheimer type, etc.) is topiramate, gabapentin, carbamazepine, oxacarbazepine, excluded. In certain embodiments the use benzoic acid, salt, Valporate, maprotiline, mirtazapine, , gepirone, ester, or other benzoic acid derivative in the treatment of US 2017/O181989 A1 Jun. 29, 2017 neurodegenerative conditions (e.g., Alzheimer's disease, diagnosed as suffering from dementia by using the DSM-IV senile dementia of the Alzheimer type, etc.) is excluded. criteria. Dementia also includes mild cognitive impairment (MCI, also known as incipient dementia, or isolated memory Definitions impairment) which is a diagnosis given to individuals who 0021. As used herein, the term “neuropsychiatric disor have cognitive impairments beyond that expected for their der” refers to a disease having a pathophysiological com age and education, but that do not interfere significantly with ponent of attenuated NMDA receptor-mediated neurotrans their daily activities. It is considered to be the boundary or mission. Examples of Such disorders include Schizophrenia, transitional stage between normal aging and dementia. bipolar disorder, These individuals tend to progress to probable Alzheimer's 0022 Alzheimer's disease, dementia, autism, Asperger's disease at a rate of approximately 10% to 15% per year. disorder, depression, benign forgetfulness, mild cognitive Additionally, when individuals have impairments in impairment, childhood learning disorders, close head injury, domains other than memory it is classified as non-amnestic ataxia, Spinocerebellar degeneration, Parkinson's disease, single- or multiple-domain MCI and these individuals are general anxiety disorder, panic disorder, obsessive compul believed to be more likely to convert to other dementias (i.e. sive disorder, phobia including social phobia, Substance dementia with Lewy bodies). abuse, Substance dependence, and attention deficit disorder. 0027. As used herein, the term “autism” refers to a state 0023. As used herein, the term "schizophrenia' refers to of mental introversion characterized by morbid self-absorp a psychiatric disorder that includes at least two of the tion, Social failure, language delay, and stereotyped behav following: delusions, hallucinations, disorganized speech, ior. Patients can be diagnosed as Suffering from autism by grossly disorganized or catatonic behavior, or negative using the DSM-IV criteria. symptoms. Patients can be diagnosed as Schizophrenic using 0028 Asperger's disorder (syndrome) is an autism spec the DSMIV criteria (APA, 1994, Diagnostic and Statistical trum disorder, and people with it therefore show significant Manual of 30 Mental Disorders (Fourth Edition), Washing difficulties in Social interaction, along with restricted and ton, D.C.). repetitive patterns of behavior and interests. It differs from 0024 Bipolar disorder or manic-depressive disorder (also other autism spectrum disorders by its relative preservation referred to a bipolarism or manic depression) is a psychiatric of linguistic and cognitive development. Although not diagnosis that describes a category of mood disorders required for diagnosis, physical clumsiness and atypical use defined by the presence of one or more episodes of abnor of language are frequently reported. Patients can be diag mally elevated mood clinically referred to as mania or, if nosed as suffering from Asperger's disorder by using the milder, hypomania. Individuals who experience manic epi DSM-IV criteria. sodes also commonly experience depressive episodes or 0029. As used herein, the term “depression” refers to a symptoms, or mixed episodes in which features of both clinical syndrome that includes a persistent sad mood or loss mania and depression are present at the same time. These of interest in activities, which lasts for at least two weeks in episodes are usually separated by periods of “normal mood, the absence of treatment. The DSM-IV criteria can be used but in Some individuals, depression and mania may rapidly to diagnose patients as Suffering from depression. alternate, known as rapid cycling. Extreme manic episodes 0030 The term “benign forgetfulness,” as used herein, can sometimes lead to psychotic symptoms such as delu refers to a mild tendency to be unable to retrieve or recall sions and hallucinations. The disorder has been subdivided information that was once registered, learned, and stored in into bipolar I, bipolar II, cyclothymia, and other types, based memory (e.g., an inability to remember where one placed on the nature and severity of mood episodes experienced; one’s keys or parked one’s car). Benign forgetfulness typi the range is often described as the bipolar spectrum. Patients cally affects individuals after 40 years of age and can be can be diagnosed as having bipolar disorder using the recognized by standard assessment instruments such as the DSMIV criteria. Wechsler Memory Scale (Russell (1975) J. Consult Clin. 0025. The term “Alzheimer's Disease” refers to a pro Psychol. 43: 800-809). gressive mental deterioration manifested by memory loss, confusion and disorientation beginning in late middle life 0031. As used herein, the term “childhood learning dis and typically resulting in death in five to ten years. Patho orders' refers to an impaired ability to learn, as experienced logically, Alzheimer's Disease can be characterized by by certain children. Such learning disorders can be diag thickening, conglutination, and distortion of the intracellular nosed by using the DSM-IV criteria. neurofibrils, neurofibrillary tangles and senile plaques com 0032. The term “close head injury, as used herein, refers posed of granular or filamentous argentophilic masses with to a clinical condition after head injury or trauma which an amyloid core. Methods for diagnosing Alzheimer's Dis condition can be characterized by cognitive and memory ease are known in the art. For example, the National Institute impairment. Such a condition can be diagnosed as "amnestic of Neurological and Communicative Disorders and Stroke disorder due to a general medical condition' according to Alzheimer's Disease—and the Alzheimer's Disease and DSM-IV. Related Disorders Association (NINCDS-ADRDA) criteria 0033. The term “attention deficit disorder, as used can be used to diagnose Alzheimer's Disease (McKhann et herein, refers to at disorder that is most commonly exhibited al. (1984) Neurology 34: 939-944). The patient’s cognitive by children and which can be characterized by increased function can be assessed by the Alzheimer's Disease Assess motor activity and a decreased attention span. The DSM-TV ment Scale-cognitive subscale (ADAS-cog; Rosen et al. criteria can be used to diagnose attention deficit disorder. (1984) Am. J. Psychiatry 141: 1356-1364). 0034. The terms “D-serine' and “D-alanine' refer to the 0026 Dementia is the progressive decline in cognitive D isomers of the amino acids serine and alanine, respec function due to damage or disease in the brain beyond what tively. As D isomers, rather than L isomers, these amino might be expected from normal aging. Patients can be acids are not naturally found in proteins. US 2017/O181989 A1 Jun. 29, 2017

0035 “Negative' symptoms of schizophrenia include due to a failure of the fine coordination of muscle move affect blunting, anergia, alogia and Social withdrawal, which ments, along with other symptoms. can be measured using SANS (the Scales for the Assessment 0046 “Parkinson's disease'99 belongs to a group of of Negative Symptoms; see Andreasen (1983) Scales for the chronic and progressive conditions called movement disor Assessment of Negative Symptoms (SANS), Iowa City, ders. It is characterized by muscle rigidity, tremor, a slowing Iowa). of physical movement (bradykinesia) and, in extreme cases, 0036 “Positive' symptoms of schizophrenia include a loss of physical movement (akinesia). The primary symp delusion and hallucination, which can be measured using toms are the results of decreased stimulation of the motor PANSS (Positive and Negative Syndrome Scale; see Kay et cortex by the basal ganglia, normally caused by the insuf al. (1987) Schizophrenia Bulletin 13:261-276). ficient formation and action of dopamine, which is produced 0037 "Cognitive' symptoms of schizophrenia include in the dopaminergic neurons of the brain. Secondary symp impairment in obtaining, organizing, and using intellectual toms may include high level cognitive dysfunction and knowledge which can be measured by the Positive and Subtle language problems. Negative Syndrome Scale-cognitive subscale (PANSS-cog 0047. “Obsessive compulsive disorder is a mental dis nitive subscale) (Lindenmayer et al. (1994) J. Nerv. Ment. order most commonly characterized by a intrusive, repeti Dis. 182: 631-638) or with cognitive tasks such as the tive thoughts resulting in compulsive behaviors and mental Wisconsin Card Sorting Test and battery of Measurement acts that the person feels driven to perform, according to and Treatment Research to Improve Cognition in Schizo rules that must be applied rigidly, aimed at preventing some phrenia (MATRICS, “www.matrics.ucla.edu/matrics-psy imagined dreaded event; however, these behaviors or mental chometrics-frame.htm). acts are not connected to the imagined dreaded event. 0038 A “full agonist of the NMDA receptor is a com Patients can be diagnosed as having obsessive compulsive pound that produces a maximal response at full receptor disorder using the DSMIV criteria. Occupancy. 0048 Generalized anxiety disorder (GAD) is an anxiety 0039. A “partial agonist of the NMDA receptor is a disorder that is characterized by excessive, uncontrollable compound that produces a lower maximal response at full and often irrational worry about everyday things that is receptor occupancy than do full agonists. disproportionate to the actual source of worry. This exces sive worry often interferes with daily functioning, as indi 0040. A “glycineuptake inhibitor of the NMDA receptor” viduals suffering GAD typically anticipate disaster, and are is a compound that inhibits the re-uptake of glycine and overly concerned about everyday matters such as health increases the availability of glycine for the NMDA receptor issues, money, death, family problems, friend problems or (e.g., N-methylglycine). work difficulties. They often exhibit a variety of physical 0041. The phrase “in conjunction with when used in Symptoms, including fatigue, fidgeting, headaches, nausea, reference to the use of one or more drugs (active agents) numbness in hands and feet, muscle tension, muscle aches, described herein indicates that the drug(s) and the active difficulty swallowing, bouts of difficulty breathing, trem agent(s) are administered so that there is at least some bling, twitching, irritability, Sweating, insomnia, hot flashes, chronological overlap in their physiological activity on the and rashes. Patients can be diagnosed as Suffering from organism. Thus the active agent(s) can be administered GAD by using the DSM-IV criteria. simultaneously and/or sequentially. In sequential adminis 0049 Panic disorder is an anxiety disorder characterized tration there may even be some Substantial delay (e.g., by recurring severe panic attacks. It may also include minutes or even hours or days) before administration of the significant behavioral change lasting at least a month and of second moiety as long as the first administered drug/agent ongoing worry about the implications or concern about has exerted some physiological alteration on the organism having other attacks. The latter are called anticipatory when the second administered agent is administered or attacks. Patients can be diagnosed as Suffering from panic becomes active in the organism. disorder by using the DSM-IV criteria. 0042. The phrase "enhancing the in vivo activity” or 0050 Phobia is an intense and persistent fear of certain "enhancing the apparent activity when referring to the situations, activities, things, animals, or people. The main agents described herein indicates that the agents, when symptom of this disorder is the excessive and unreasonable administered in conjunction with a pharmaceutical produce desire to avoid the feared subject. When the fear is beyond a greater biological response in the organism than the same one’s control, and if the fear is interfering with daily life, dosage administered without the agent. then a diagnosis under one of the anxiety disorders can be 0043. The term mammal includes essentially any mam made. Patients can be diagnosed as Suffering from phobia by mal including, but not limited to dogs, cats, sheep, cattle, using the DSM-IV criteria. horses, goats, mice, rats, rabbits, hamsters, pigs, monkeys 0051 Social Phobia is anxiety (emotional discomfort, and other non-human primates, and humans. Thus, Veteri fear, apprehension, or worry) about social situations, inter nary as well as medical applications of this invention are actions with others, and being evaluated or scrutinized by contemplated. other people. It occurs early in childhood as a normal part of 0044 “Ataxia” is a neurological sign and symptom con the development of social functioning, but may go unnoticed sisting of gross lack of coordination of muscle movements. until adolescence or may surface in adulthood. People vary 0045 “Spinocerebellar degeneration” refers to a group of in how often they experience Social anxiety and in which genetic disorders characterized by slowly progressive inco kinds of situations. Patients can be diagnosed as Suffering ordination of gait and often associated with poor coordina from social phobia by using the DSM-IV criteria. tion of hands, speech, and eye movements. Frequently, 0.052 “Substance abuse', the disorder is characterized by atrophy of the cerebellum occurs. As with other forms of a pattern of continued pathological use of a medication, ataxia, results in unsteady and clumsy motion of the body non-medically indicated drug or toxin, that results in US 2017/O181989 A1 Jun. 29, 2017

repeated adverse social consequences related to drug use, individual treatment), or with vehicle for one week before Such as failure to meet work, family, or school obligations, the test. The mice continued to receive the drug until one interpersonal conflicts, or legal problems. The Substance can week later when amphetamatine (10 mg/kg) was adminis be, but not limited to: Alcohol, Amphetamine (or amphet tered 30 minutes before the experiments. For PPI, stronger amine-like), Cannabis, Cocaine, Hallucinogen, Inhalant, prepulse inhibited pulse response more (inhibition of 525 Nicotine, Opioid, Phencyclidine (or phencyclidine-like), HZ>487 HZD468 Hz). Amphetamine disrupted the inhibition Sedative, hypnotic, or anxiolytic or Poly Substance depen in all treatments. For example, in 487 Hz paradigm, the dence. Patients can be diagnosed as Substance abuse using disruption by amphetamine is most pronounced in vehicle the DSMIV criteria (APA, 1994, Diagnostic and Statistical treated mice (left column), partially corrected by either Manual of Mental Disorders (Fourth Edition), Washington, sarcosine (NMG) or benzoate (middle 2 columns) and was D.C.). When an individual persists in use of alcohol or other best corrected by the combination treatment (right column). drugs despite problems related to use of the Substance. 0057 FIG. 3. Six weeks of adjunctive benzoate vs. pla Compulsive and repetitive use may result in tolerance to the cebo treatment in patients receiving risperidone treatment, at effect of the drug and withdrawal symptoms when use is weeks 0, 2, 4, and 6, respectively. BE, benzoate, PANSS reduced or stopped. This, along with Substance Abuse are total, Positive and Negative Syndrome Scale total score; considered Substance Use Disorders The substance can be, PANSS-positive, Positive and Negative Syndrome Scale but not limited to: Alcohol, Amphetamine (or amphetamine positive subscale score; SANS, Scales for the Assessment of like), Cannabis, Cocaine, Hallucinogen, Inhalant, Nicotine, Negative symptoms. Opioid, Phencyclidine (or phencyclidine-like), Sedative, hypnotic, or anxiolytic or Polysubstance dependence. Sub DETAILED DESCRIPTION stance dependence can be diagnosed with physiological 0058. In various embodiments methods are provided for dependence, evidence of tolerance or withdrawal. Patients treating a patient diagnosed as Suffering from a neuropsy can be diagnosed as Substance dependence using the chiatric disorder or at high risk for a neuropsychiatric DSMIV criteria (APA, 1994, Diagnostic and Statistical disorder, particularly a disorder characterized by a deficit in Manual of 30 Mental Disorders (Fourth Edition), Washing neurotransmission via the NMDA receptor (e.g., schizophre ton, D.C.). nia, bipolar disorder, Alzheimer's Disease, dementia, mild 0053 A “neuropharmaceutical refers to a drug used to cognitive impairment, autism, Asperger's disorder, depres treat neuropsychiatric, neuropsychological, or nervous-sys Sion, benign forgetfulness, childhood learning disorders, tem disorders including, but not limited to depression, close head injury, and attention deficit disorder, ataxia, Schizophrenial, bipolar disorder, attention deficit hyperac spinocerebellar degeneration, Parkinson's disease, obses tivity disorder (ADHD), schizophrenia, Alzheimer's dis sive compulsive disorder (OCD), phobia, social phobia, ease, and the like. Substance abuse, and Substance dependence). As described 0054 Where Markush groups are indicated herein (e.g., above, a variety of methods for diagnosing these disorders "where X is selected from the group consisting of A, B, and are known to those of skill in the art of clinical psychiatry, C”) subgroups are contemplated comprising any one or and any conventional diagnostic method can be used in more of the elements making up the Markush group (e.g., A conjunction with the invention. and B, A and C, B and C, A alone, B alone, C alone, for 0059. In various embodiments this the compositions and Markush Group A, B, and C). methods described herein pertain to the use of “combina tion therapies, where the Subjects are administered a com BRIEF DESCRIPTION OF THE DRAWINGS bination of one or more neuropharmaceuticals (e.g., an 0055 FIG.1. The difference of startle responses between antipsychotic, an antidepressant, a psychoStimulant, a mood the initial and the last group of trials of single acoustic stablizer, an anxiolytic, an Alzheimer's disease therapeutic, stimulus were considered the amount of habituation. Three other psychotropics), and/or an NMDA (N-methyl-D-aspar groups of mice each were treated with sarcosine (200 tate)-Enhancer, and/or a glycine transporter inhibitor, and/or mg/kg), benzoate (100 mg/kg), a combination of both Sar a D-amino Acid Oxidase Inhibitor (DAAOI). In certain cosine and benzoate. Amphetamatine (10 mg/kg) was embodiments the combination therapy comprises a combi administered 30 minutes before the experiments. There was nation of an NMDA (N-methyl-D-aspartate)-Enhancer, and/ no difference in the habituation at baseline across the groups or a Glycine Transporter Inhibitor, and/or a DAAOI inhibi (left group). Combination treatments (right) induce a stron tor. In certain embodiments the administration of at least two ger habituation effect than benzoate (left) or sarcosine of these agents in conjunction with each other is contem treatment alone (middle). However, the effect of benzoate is plated, and in certain embodiments, the administration of all close to the effect seen in the combination treatment. The three agents in conjunction with each other is contemplated. same trend of habituation (combination treatment In various embodiments the agents can be utilized individu >benzoates sarcosine) was evident when amphetamine was ally as well. administered and disrupted the habituation (right group). 0060. It was also a surprising discovery that DAACI The combination treatment corrected the amphetamine-in inhibitors (especially sorbic acid and/or benzoic acid and duced disruption of habituation back to a normal state while derivatives thereof) when used individually or in combina single treatment of NMG or benzoate only partially cor tion with each other are capable of mitigating one or more rected the deficit (right group). The effect of benzoate, symptoms of a neuropsychiatric disorder. In addition, they however, was better than sarco sine and close to that seen in are capable of enhancing the activity of neuropharmaceuti the combination treatment. cals (e.g., antipsychotics, antidepressants, ADHD medica 0056 FIG. 2. Four groups of 10 mice each were treated tions, etc.). Accordingly, in certain embodiments, composi with sarcosine (200 mg/kg), benzoate (100 mg/kg), a com tions that provide a prophylactically ortherapeutically active bination of both sarco sine and benzoate (same doses as the amount of benzoic acid, a benzoic acid salt, a benzoic acid US 2017/O181989 A1 Jun. 29, 2017

ester, or other benzoic acid derivative, and/or Sorbic acid, a contemplated. Similarly medicaments comprising a benzoic Sorbic acid salt, a Sorbic acid ester, or other Sorbic acid acid, benzoic acid salt, benzoic acid ester or other benzoic derivative are provided. In various methods such composi acid derivative and/or Sorbic acid, a Sorbic acid salt, a Sorbic tions can be used for the treatment of a neuropsychiatric acid ester or other sorbic acid derivative and one or more disorder and/or for the manufacture for a medicament for the neuropharmaceuticals (e.g., agents for the treatment of a treatment of a neuropsychiatric disorder. condition Such as Schizophrenia, bipolar disorder, Alzheim 0061. In certain other embodiments, methods are con er's disease, dementia, autism, Asperger's disorder, depres templated that provided for the use of one or more D-amino Sion, benign forgetfulness, mild cognitive impairment, Acid Oxidase Inhibitors in conjunction with one or more childhood learning disorders, close head injury, ataxia, Spi neuropharmaceuticals. In this regard, in certain preferred nocerebellar degeneration, Parkinson's disease, general embodiments, the DAAOI comprises benzoic acid, a ben anxiety disorder, panic disorder, obsessive compulsive dis Zoic acid salt, a benzoic acid ester, or other benzoic acid order, phobia including Social phobia, Substance abuse, derivative, and/or sorbic acid, a Sorbic acid salt, a Sorbic acid Substance dependence, attention deficit disorder, etc.) are ester, or other sorbic acid derivative. Similarly, compositions contemplated. Typically, the benzoic acid, benzoic acid salt, comprising a combination of benzoic acid, a benzoic acid benzoic acid ester, or other benzoic acid derivative, and/or salt, a benzoic acid ester, or other benzoic acid derivative, sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic and/or sorbic acid, a Sorbic acid salt, a sorbic acid ester, or acid derivative, is provided in the method or medicament in other Sorbic acid derivative, and a neuropharmaceutical an amount Sufficient to enhance the efficacy of the neurop (e.g., an antipsychotic, an antidepressant, an ADHD medi harmaceutical. cation, etc.) are contemplated. In addition kits comprising of 0064. Without being bound to a particular theory, it is benzoic acid, a benzoic acid salt, a benzoic acid ester, or believed that the DAAOI enhances the levels of both D-ser other benzoic acid derivative, and/or sorbic acid, a sorbic ine and D-alanine which are agonists of NMDA receptor and acid salt, a sorbic acid ester, or other sorbic acid derivative have been shown by the inventor to be beneficial for patients are contemplated. In various embodiments the DAAOI and with schizophrenia and other disorders. It can help a wide the neuropharmaceutical can be provided in separate con variety of patients with cognitive impairment and other tainers. In certain embodiments the DAAOI and the neuro mental or behavioral symptoms. The combination therapies pharmaceutical can be provided in the same container (e.g., boost the NMDA and/or neuropharmaceutical activity and as a combined/compound formulation). benefit Subjects more than single agent treatments (e.g., 0062 Previous treatments using an NMDA enhancer or a antipsychotic drug, antidepressant, anxiolytic, mood stabi glycine transporter inhibitor alone have had limited efficacy. lizer, psychotropic medication for attention deficit and It was discovered that the use of a DAAOI alone, especially hyperactivity disorder, drug for dementia, and the like). a benzoic acid, benzoic acid salt, benzoic acid ester or other 0065 Accordingly, in certain preferred embodiments, benzoic acid derivative and/or sorbic acid, a Sorbic acid salt, “combination therapies are contemplated, where the sub a sorbic acid ester or other sorbic acid derivative can result jects are administered a benzoic acid, a benzoic acid salt, a in unexpected and Surprising improvement in Subjects diag benzoic acid ester, or another benzoic acid derivative, and/or nosed with a neuropsychiatric disorders. Accordingly in a Sorbic acid, a Sorbic acid salt, Sorbic acid ester, or another certain embodiments, the use of a benzoic acid salt, or other Sorbic acid derivative, in conjunction with a neuropharma derivative and/or a sorbic acid, salt, or other derivative in the ceutical (e.g., a therapeutic agent selected from the group treatment of a neuropsychiatric disorder (e.g., Schizophre consisting of an antipsychotic, an antidepressant, a psycho nia, bipolar disorder, Alzheimer's disease, dementia, autism, stimulant, a mood stabilizer, an anxiolytic, an Alzheimer's Asperger's disorder, depression, benign forgetfulness, mild disease therapeutic, and/or other psychotropic for the treat cognitive impairment, childhood learning disorders, close ment of a neuropsychiatric disorder). head injury, ataxia, spinocerebellar degeneration, Parkin 0066. In certain embodiments (e.g., for the treatment of son's disease, general anxiety disorder, panic disorder, Schizophrenia, bipolar disorder, and the like) the neurophar obsessive compulsive disorder, phobia including Social pho maceutical used in the “combination' treatment is an antip bia, Substance abuse, Substance dependence, attention deficit sychotic drug. In certain embodiments the antipsychotic disorder, etc.) are contemplated. Similarly medicaments drug is a drug selected from the group consisting of buty comprising a benzoic acid, benzoic acid salt, benzoic acid rophenone (e.g., Haloperidol (HALDOL(R), phenothiazine ester or other benzoic acid derivative and/or sorbic acid, a (e.g., chlorpromazine (THORAZINE(R), fluphenazine sorbic acid salt, a sorbic acid ester or other sorbic acid (PROLIXINR), perphenazine (TRILAFONR), prochlo derivative in an amount Sufficient to mitigate one or more rperazine (COMPAZINE(R), thioridazine (MELLARIL(R), symptoms of a neuropsychiatric disorder are contemplated. trifluoperazine (STELAZINE(R), mesoridazine, promazine, 0063. In addition, it was discovered that combination triflupromazine (VESPRINR), levomepromazine (NOZI treatment(s), e.g., a benzoic acid, benzoic acid salt, benzoic NANR), promethazine (PHENERGANR), thioxanthene acid ester or other benzoic acid derivative and/or sorbic acid, (e.g., chlorprothixene, flupenthixol (DEPIXOLR, FLU a Sorbic acid salt, a Sorbic acid ester or other Sorbic acid ANXOL(R), thiothixene (NAVANE(R), Zuclopenthixol derivative in combination with one or more neuropharma (CLOPIXOLR, ACUPHASE(R), clozapine (CLOZARIL(R), ceuticals, results in unexpected and Surprising improvement olanzapine (ZYPREXAR), risperidone (RISPERDAL(R), in Subjects diagnosed with a neuropsychiatric disorders. RISPERDAL CONSTAR), quetiapine (SEROQUEL(R), Thus methods comprising the administration of benzoic ziprasidone (GEODONR), amisulpride (SOLIANR), acid, a benzoic acid salt, a benzoic acid ester, or other asenapine, paliperidone, Aripiprazole (ABILIFYR), dop benzoic acid derivative, and/or Sorbic acid, a Sorbic acid salt, amine partial agonists (BIFEPRUNOXOR, NORCLOZAP a sorbic acid ester, or other sorbic acid derivative, in INE(R) (ACP-104)), lamotrigine (LAMICTAL(R), meman conjunction with one or more neuropharmaceuticals are tine (AXURAR, AKATINOLR, NAMENDAR, EBIXAR), US 2017/O181989 A1 Jun. 29, 2017

ABIXAR), tetrabenazine (NITOMANR, XENAZINE(R), (0071. In various embodiments the benzoic acid, benzoic cannabidiol, LY2140023, and the like). acid salt, or derivative thereof, and/or sorbic acid, a sorbic 0067. In certain embodiments (e.g., for the treatment of acid salt, or a derivative thereof, can be administered sepa depression, panic disorder, Social phobial, GAD, etc.) the rately before, after, or simultaneously with one or more the neuropharmaceutical used in the “combination treatment neuropharmaceuticals. For example, the the benzoic acid, comprises an antidepressant and/or mood Stabilizer. In cer benzoic acid salt, or derivative thereof, and/or sorbic acid, a tain embodiments the antidepressant comprises a monoam sorbic acid salt, or a derivative thereof can be provided in ine oxidase inhibitor (MAOI), a tricyclic antidepressant one formulation and the neuropharmaceutical(s) in another (TCA), a tetracyclic antidepressant (TeCA), a selective formulation. serotonin reuptake inhibitor (SSRI), a noradrenergic and 0072. In certain embodiments where the benzoic acid, specific serotonergic antidepressant (NASSA), a norepi benzoic acid salt, or derivative thereof, and/or sorbic acid, a nephrine (noradrenaline) reuptake inhibitor, a norepineph sorbic acid salt, or a derivative thereof is administered rine-dopamine reuptake inhibitor, and/or a serotonin-norepi simultaneously with the neuropharmaceuticals they can be nephrine reuptake inhibitor (SNRI). provided as a combined formulation. Accordingly, in certain 0068. In certain embodiments the antidepressant is a drug embodiments, corresponding combination therapeutics are selected from the group consisting of a tricyclic antidepres also provided. Thus, in certain embodiments, a pharmaceu sant (e.g., IMIPRAMINE(R) and variants), a selective sero tical composition is provided comprising a benzoic acid, tonin reuptake inhibitor (SSRI) (e.g., fluoxetine (PRO benzoic acid salt, benzoic acid ester, or other benzoic acid ZACR), paroxetine (PAXIL(R), SEROXATR), escitalopram derivative and/or Sorbic acid, a Sorbic acid salt, a Sorbic acid (LEXAPROR, ESIPRAMR), citalopram (CELEXAR), ser ester, or other Sorbic acid derivative and a neuropharmaceu traline (ZOLOFTR), fluvoxamine (LUVOX(R)), a sero tical (e.g., an antidepressant, an anxiolytic, an antipsychotic tonin-norepinephrine reuptake inhibitor (SNRI) (e.g., ven drug, etc.), where the benzoic acid, benzoic acid salt, lafaxine (EFFEXORR)), milnacipram and duloxetine benzoic acid ester, or other benzoic acid derivative and/or (CYMBALTAR), a noradrenergic and specific serotonergic Sorbic acid, a Sorbic acid salt, a Sorbic acid ester, or other antidepressant (NASSA) (e.g., mirtazapine (AVANZAR), Sorbic acid is present in an amount Sufficient to increase the ZISPINR), REMERONR), mianserin), a norepinephrine efficacy of neuropharmaceutical (e.g., risperidone, olanzap (noradrenaline) reuptake inhibitor (NRI) (e.g., reboxetine ine, etc.). Also provided are formulations comprising a (EDRONAX(R)), a norepinephrine-dopamine reuptake benzoic acid, benzoic acid salt, or derivative thereof (e.g., a inhibitors (e.g., bupropion (WELLBUTRINR, ZYBANR)), benzoate, and/or Sorbic acid, Sorbic acid salt, or a derivative Amitriptyline, Nortriptiline, Protriptyline. Desipramine, thereof (e.g., a Sorbate); and an antidepressant drug, where Trimipramine, Amoxapine, Bupropion, Bupropion SR, the benzoic acid benzoic acid salt, or derivative thereof, S-Citalopram, Clomipramine, Desipramine, Doxepin, Iso and/or thereof, and/or Sorbic acid, Sorbic acid salt, or a carboxazid, Velafaxine XR. Tranylcypromine, Trazodone, derivative thereof, is present in a concentration sufficient to Nefazodone, PhenelZine, Lamatrogine, Lithium, Topira increase the efficacy of the antidepressant drug (e.g., Sertra mate, Gabapentin, Carbamazepine, Oxacarbazepine, Valpo line hydrochloride, fluoxetine hydrochloride, etc.). rate, Maprotiline, Mirtazapine, Brofaromine, Gepirone, 0073. Also provided are formulations comprising the Moclobemide, isoniazid, , and the like. benzoic acid, benzoic acid salt, benzoic acid ester, or other 0069. In certain embodiments (e.g., for the treatment of benzoic acid derivative, and/or Sorbic acid, Sorbic acid salt, ADD or ADHD), the neuropharmaceutical used in the sorbic acid ester, or other sorbic acid derivative, and a “combination treatment comprises an agent for the treat neuropharmaceutical e.g., as described above. Typically, the ment of ADD and/or ADHD. In certain Suitable ADHD benzoic acid, benzoic acid salt, benzoic acid ester, or other medications include, but are not limited to an ADHD medi benzoic acid derivative, and/or Sorbic acid, Sorbic acid salt, cation selected from the group consisting of Amphet sorbic acid ester, or other sorbic acid derivative, is present in amine, Modafinil. Desoxyn, Methamphetamine, cocaine, an amount Sufficient to increase the efficacy of the neurop arecoline, Dexmethylphenidate (Focalin, Focalin XR), dex harmaceutical (e.g., Aricept, memantine, etc.). troamphetamine (Dexedrine, Dexedrine SpanSules, Dextro 0074. In certain embodiments the combination formula amphetamine ER, Dextrostat), methylphenidate (Concerta, tion for the treatment of schizophrenia, bipolar disorder, and Daytrana, Metadate CD, Metadate ER, Methylin, Methylin the like comprises a combination of benzoic acid, benzoic ER, Ritalin, Ritalin-LA, Ritalin-SR), lisdexamfetamine acid salt, benzoic acid ester, or other benzoic acid derivative, dimesylate (Vyvanse), mixed salts amphetamine (Adderall, and/or Sorbic acid, Sorbic acid salt, Sorbic acid ester, or other Adderall XR), Atomoxetine (Strattera), clonidine hydro Sorbic acid derivative and an antipsychotic drug. Suitable chloride (Catapres), guanfacine hydrochloride (Tenex), are antipsychotic drugs include, but are not limited to the coline, and Pemoline. antipsychotic drugs described above. 0070. In certain embodiments (e.g., for the treatment of a 0075. In certain embodiments the combination formula cognitive disorder, and/or a condition characterized by neu tion for the treatment of schizophrenia, bipolar disorder, and rodegeneration (e.g. Alzheimer's disease, Parkinson's dis the like comprises a combination of depression, panic dis ease, etc.)) the neuropharmaceutical used in the “combina order, social phobial, GAD, and the like comprises a com tion treatment can include, but is not limited to an agent bination of benzoic acid, benzoic acid salt, benzoic acid selected from the group consisting of Donepezil, Tacrine, ester, or other benzoic acid derivative, and/or sorbic acid, Rivastigmine, memantine (AXURAR), AKATINOLR), sorbic acid salt, sorbic acid ester, or other sorbic acid NAMENDAR), EBIXAR), ABIXAR), aricept, physostig derivative and an antidepressant and/or mood stabilizer. mine, nicotine, arecoline, huperzine alpha, selegiline, Suitable antidepressants and mood stabilizers include, but rilutek. R (riluzole), Vitamine c, vitamine e, carotenoids, are not limited to the antidepressants and mood stabilizers ginkgo biloba, and the like. described above. US 2017/O181989 A1 Jun. 29, 2017

0076. In certain embodiments the combination formula 0080. In various embodiments the benzoic acid, benzoic tion for the treatment of ADD and/or ADHD, and the like acid salt, benzoic acid ester, or other benzoic acid derivative, comprises a combination of benzoic acid, benzoic acid salt, and/or Sorbic acid, Sorbic acid salt, Sorbic acid ester, or other benzoic acid ester, or other benzoic acid derivative, and/or Sorbic acid derivative, is typically provided in an amount sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic sufficient to improve the therapeutic efficacy of the neuro acid derivative and an agent for the treatment of ADD and/or pharmaceutical (e.g., antipsychotic and/or antidepressant ADHD. Suitable agents for the treatment of ADD and/or and/or therapeutic for attention deficit and hyperactivity ADHD include, but are not limited to the agents for the disorder and/or therapeutic for dementia). Thus, typical treatment of ADD and/or ADHD described above. dosages of the benzoic acid, benzoic acid salt, benzoic acid ester, or other benzoic acid derivative, and/or sorbic acid, 0077. In certain embodiments the combination formula sorbic acid salt, sorbic acid ester, or other sorbic acid tion for the treatment of a cognitive disorder, and/or a derivative, range from range is from about 5 mg. to about condition characterized by neurodegeneration (e.g. 500 grams, more preferably about 25 mg to about 400, 300 Alzheimer's disease, Parkinson's disease, etc.) comprises a grams, 200 grams, or 100 grams, still more preferably about combination of benzoic acid, benzoic acid salt, benzoic acid 50 mg to 50 or to 100 or 150 grams. ester, or other benzoic acid derivative, and/or sorbic acid, I0081. Most of the neuropsychiatric disorders present with sorbic acid salt, sorbic acid ester, or other sorbic acid cognitive deficits, behavioral and mental symptoms. The derivative and an agent for the treatment of a cognitive various treatment strategies described herein can be applied disorder, and/or a condition characterized by neurodegen to most if not all of them including, for example, learning eration. Suitable agents for the treatment of a cognitive disorder, attention deficit and hyperactivity disorder, Schizo disorder, and/or a condition characterized by neurodegen phrenia, bipolar disorder, depression, Alzheimer's Disease, eration include, but are not limited to the agents for the autism, benign forgetfulness, close head injury, dementia, treatment of a cognitive disorder, and/or a condition char mild cognitive impairment, ataxia, spinocerebellar degen acterized by neurodegeneration described above. eration, Parkinson's disease, obsessive compulsive disorder 0078 Typically, in various embodiments, the benzoic (OCD), phobia, social phobia, generalized anxiety disorder acid, benzoic acid salt, or derivative thereof (e.g., a benzo (GAD), panic disorder, Substance abuse, and Substance ate), and/or sorbic acid, a Sorbic acid salt, or a derivative dependence. In addition to their benefits for human subjects, thereof, is present in an amount Sufficient to enhance thera the treatments described herein can be used in veterinary peutic efficacy of the neuropharmaceutical rather than as a applications (e.g., to canines, felines, equines, bovines, preservative, and/or melting point lowering agent, and/or porcines, etc.) with treatment of household pets (e.g., canine, stabilizer, and/or a lubricant, and/or a stabilizer, etc. In feline) being of considerable interest. In addition, the com effect, the benzoic acid, benzoic acid salt, or derivative bination treatments described herein can improve cognition thereof, and/or sorbic acid, sorbic acid salt, or a derivative in animal models of learning and model of Schizophrenia, thereof, is an active agent. Thus, in various embodiments the depression, anxiety, and the like. benzoic acid, benzoic acid salt, benzoic acid ester, or other 0082 In certain embodiments the treatment methods of benzoic acid derivative, and/or Sorbic acid, Sorbic acid salt, the invention entail administering to a Subject in need sorbic acid ester, or other sorbic acid derivative, is not thereof (e.g., a patient diagnosed as having or at risk for a Substantially present as an acid addition salt of the neurop neuropsychiatric disorder) one or more a pharmaceutical harmaceutical (or at least the majority of the benzoic or compositions containing a therapeutically effective amount Sorbic acid or derivative thereof) is not present as an acid salt (s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/ addition salt of the neuropharmaceutical. Similarly, in cer or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino tain embodiments the benzoic acid, benzoic acid salt, ben Acid Oxidase Inhibitor (DAAOI). Where combinations of Zoic acid ester, or other benzoic acid derivative, and/or two or all three of these agents are utilized they can be sorbic acid, sorbic acid salt, sorbic acid ester, or other sorbic administered separately (simultaneously or sequentially), in acid derivative, (or at least the majority of the benzoic or a single “combination formulation, or in simultaneously or Sorbic acid or derivative thereof) is not present as a co sequentially a combination formulation comprising two crystal of the neuropharmaceutical. agents and a second formulation comprising a single agent. 0079. In certain compositions, and treatments, the ratio of I0083. The effective doses of the active agent(s) (of an benzoic acid, benzoic acid salt, benzoic acid ester, or other NMDA (N-methyl-D-aspartate)-Enhancer, and/or Glycine benzoic acid derivative, and/or Sorbic acid, Sorbic acid salt, Transporter Inhibitor, and/or D-amino Acid Oxidase Inhibi sorbic acid ester, or other sorbic acid derivative, to neuro tor (DAAOI)) can vary, depending upon factors such as the pharmaceutical (e.g., antidepressant, antipsychotic drug, condition of the patient, the severity of the symptoms of the therapeutic for attention deficit and hyperactivity disorder, disorder, and the manner in which the pharmaceutical com therapeutic for dementia, and/or mood stabilizer, or other position is administered. In various embodiments, for human pharmaceutical) is stoichiometrically greater than 2:1, pref patients, the effective unit dose of typical compounds erably greater than about 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, include: DAAOI (e.g., benzoate, range of 50 mg-150 10:1, 15:1, or 20:1. In certain embodiments the benzoic acid, grams), NMDA enhancers (D-serine, range of 50 mg-50 benzoic acid salt, benzoic acid ester, or other benzoic acid grams; D-alanine, range 1-150 grams), glycine transporter derivative, and/or Sorbic acid, Sorbic acid salt, Sorbic acid inhibitor (for example: Sarcone, range 50 mg-50 grams); ester, or other Sorbic acid derivative, combinations expressly including DAAOI+NMDA enhancer, DAAOI+glycine exclude a psychoactive pharmaceutical other than an antip transporter inhibitor, NMDA enhancers+glycine transporter sychotic and/or antidepressant and/or therapeutic for atten inhibitor or three classes of compound together. tion deficit and hyperactivity disorder and/or therapeutic for 0084. In various embodiments, then, effective doses of dementia. each of the active agent(s) ranges from 1 mg, 10 mg, 50 mg. US 2017/0181989 A1 Jun. 29, 2017

100 mg, 250 mg. or 500 mg. 300g, 200g. 150 g. 100 g, 50 vehicles can include solutions, emulsions, syrups, and elixirs g, 25 g, 10g, 5 g, or 1 g depending of factors including, but containing, together with the active compound(s), wetting not limited to 150 g. In certain embodiments the compounds agents, Sweeteners, coloring agents, and flavoring agents. and compositions of the present invention can be adminis Various liquid and powder compositions can be prepared by tered to a patient at dosage levels in the range of about 0.1 conventional methods for inhalation into the lungs of the to about 1,000 mg per day. For a normal human adult having patient to be treated. a body weight of about 70 kilograms, it is estimated that a 0090. In certain embodiments injectable compositions dosage in the range of about 0.01 to about 100 mg per can contain various carriers such as vegetable oils, dimethy kilogram of body weight per day is sufficient. The specific lacetamide, dimethylformamide, ethyl lactate, ethyl carbon dosage used, however, can vary. For example, the dosage ate, isopropyl myristate, , polyols (glycerol, propyl can depend on a numbers of factors including the require ene glycol, liquid polyethylene glycol, and the like). For ments of the patient, the severity of the condition being intravenous injections, the compounds may be administered treated, and the pharmacological activity of the compound by the drip method, whereby a pharmaceutical composition being used. The determination of optimum dosages for a containing the active compound(s) and a physiologically particular patient is well-known to those skilled in the art. acceptable excipient is infused. Physiologically acceptable The amount of active ingredient(s) that may be combined excipients may include, for example, 5% dextrose, 0.9% with the carrier materials to produce a single dosage form saline, Ringer's solution or other suitable excipients. For will vary depending upon the host treated and the particular intramuscular preparations, a sterile composition of a Suit mode of administration. It will be understood, however, that able soluble salt form of the compound can be dissolved and the specific dose level for any particular patient will depend administered in a pharmaceutical excipient such as Water upon a variety of factors including the activity of the specific for-Injection, 0.9% saline, or 5% glucose solution, or depot compound(s) employed, the age, body weight, general forms of the compounds (e.g., decanoate, palmitate, unde health, sex, diet, time of administration, route of adminis cylenic, enanthate) can be dissolved in sesame oil. Alterna tration, and rate of excretion, drug combination and the tively, the pharmaceutical composition can be formulated as severity of the particular disease undergoing therapy. a chewing gum, lollipop, or the like. 0085. In all of the methods of the invention, appropriate 0091. In various embodiments combined formulations dosages of the active agent(s) can readily be determined by are contemplated. In certain embodiments such formulations those of ordinary skill in the art of medicine by monitoring contain at least two of the following three active agent(s): (i) the patient for signs of disease amelioration or inhibition, an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a and increasing or decreasing the dosage and/or frequency of glycine transporter inhibitor, and/or (iii) a D-amino Acid treatment as desired. Oxidase Inhibitor (DAAOI). In certain embodiments all I0086. In various embodiments an amount equivalent to a three active agent(s) are present in a single formulation. In dosage of about 10 mg to about 50 g/day, more preferably combined formulations the different components can be about 10 mg to about 10 g/day is administered to a patient segregated, for example, in different layers of a tablet, in in need of such treatment. For example, the dosage can be different microbeads/microcapsules, and the like. In certain in an amount of 10 mg, 50 mg, 100 mg, 200 mg. 300 mg. embodiments two of more of the active agents are inter such as 150 to 300 mg (e.g., 175 mg, 200 mg, 225 mg. or 250 mixed and/or suspended, e.g., in a single excipient. Typi mg). cally the different active agent(s) will be provided each in a I0087 Generally, treatment continues for at least one therapeutically effective dose. week and can continue for several years or life-long as needed to control the subject's symptoms. D-amino Acid Oxidase Inhibitor (DAAOI) Administration and Formulations. 0092. Many D-amino Acid Oxidase Inhibitors (DAAOIs) suitable for use in the methods of the present invention are 0088. In various embodiments the pharmaceutical com well known to those of skill in the art. Suitable DAAC) positions can be administered to the subject (e.g., patient) by inhibitors include, for example, but are not limited to any, or a combination, of several routes, such as oral, benzoic acid and derivatives, sorbic acid and derivatives, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pull 2-oxo-3-pentynoate; Aminoguanidine (Guanylhydrazine: monary, transdermal, transnasal, ocular, buccal, Sublingual, Carbamimidic : ; GER 11; Hydrazin intraperitoneal, intrathecal, intramuscular, or long term ecarboximidamide) or hydrochloride salt (Guanylhydrazine depot preparation. In certain embodiments solid composi hydrochloride), bicarbonate salt, salt, sulfate (2:1) tions for oral administration can contain suitable carriers or salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic excipients, such as corn starch, gelatin, lactose, acacia, acid; sodium benzoate: 2-aminobenzoate: 3-aminobenzoate: sucrose, microcrystalline cellulose, kaolin, mannitol, dical 4-aminobenzoate (p-aminobenzoate, PABA, Vitamin BX. cium phosphate, calcium carbonate, sodium chloride, lipids, Vitamin H1); bis(guanylhydrazone) (also alginic acid, or ingredients for controlled slow release. known as: Methyl GAG; Mitoguazone; 1,114(methyl Disintegrators that can be used include, without limitation, ethanediylidene)dinitrilo)diguanidine; Hydrazinecarboximi micro-crystalline cellulose, corn starch, sodium starch gly damide, 2,2'-(1-methyl-1,2-ethanediylidene)bis-, Pyruval colate and alginic acid. Tablet binders that can be used dehyde bis(amidinohydrazone); Megag, MitoguaZona include, without limitation, acacia, methylcellulose, sodium (INN-Spanish: , 1,1'-((methylethanediylidene) carboxymethylcellulose, polyvinylpyrrolidone (Povidone), dinitrilo)di-: 1,1'-((Methylethanediylidene)dinitrilo) hydroxypropyl methylcellulose, sucrose, starch, and ethyl diguanidine); Methylglyoxal bis(guanylhydraZone), dihy cellulose. drochloride; phenylglyoxalbis(guanylhydrazone) (PhGBG); 0089. In various embodiments liquid compositions for bis(guanylhydrazone) (GBG: Guanidine, 1.11-(eth oral administration prepared in water or other aqueous anediylidenedinitrilo)di(8C1); Hydrazinecarboximidamide, US 2017/O181989 A1 Jun. 29, 2017

2,2'-(1,2-ethanediylidene)bis-(9C1)); indole-propionic (IPA, argylglycine; 2-Amino-4-pentynoic acid; D.L-Propargylgly 3-(3-Indolyl)propanoic acid): 3-indole- (Hetero cine; L-2-Amino4-pentynoic acid; Progesterone auxin, IAA); Indole-3-acetic acid Sodium salt; Indole-3- (4-Pregnene-320-dione): FAD (Flavin adenine dinucleotide acetone; Indole-3-acetamide; Indole-3-acetyl-L-aspartic 1H-Purin-6-amine, flavin dinucleotide, Adenosine 5'-(tri acid; Indole-3-acetyl-L-alanine; Indole-3-acetylglycine; hydrogen pyrophosphate), 5'-5'-ester with riboflavin); Indole-3-acetaldehyde Sodium Bisulfite Addition com 6-OH-FAD; Phenylglyoxal (2.2-Dihydroxyacetophenone); pound; Indole-3-carboxylic acid; Indole-3-pyruvic acid (3- Phenylglyoxal Monohydrate (2,2-Dihydroxyacetophenone (3-Indolyl)-2-oxopropanoic acid); salicylic acid (2-Hy monohydrate); Cyclothionine (Perhydro-1,4-thiazepine-3,5- dicarboxylic acid, 1,4-Hexahydrothiazepine-3,5-dicarbox droxybenzoic acid); salicylic acid Sodium Salt; Salicylic ylic acid, 1,4-Thiazepine-3,5-dicarboxylic acid, hexa acid Potassium Salt; Dansyl chloride (5-(Dimethylamino) hydro-); alpha-alpha-iminodipropionic (Alanopine; 2.21 naphthalene-1-sulfonyl chloride); Dansyl fluoride (5-(Dim Iminodipropionic acid; L-Alanine, N-(1-carboxyethyl)-); ethylamino)naphthalene-1-sulfonyl fluoride); dansyl gly Meso-Diaminosuccinic acid (3-Aminoaspartic acid; cine; Alanine ; benzoic tetrazole; tetrazole; Diaminosuccinic acid; CAS RN: 921-52-8); meso-2,3-Di Riboflavin 5'-pyrophosphate (RPP 5-Phospho-alpha-D-ri aminosuccinic acid (CAS RN: 23220-52-2); Thiosemicar bosyl diphosphate, PRib-PP, P-RPP); DL-propargylglycine bazide (thiocarbamoyl hydrazide); Thiourea (Sulfourea; (DL-PG, 2-Amino-4-pentynoic acid); L-C-Propargylgly Thiocarbamide); Methylthiouracil (4(6)-Methyl-2-thioura cine; N-Acetyl-DL-propargylglycine; (+)-Sodium 3-hy cil, 4-Hydroxy-2-mercapto 6-methylpyrimidine); Sulphathi droxybutyrate; Trigonelline Hydrochloride (1-Methylpyri azole (N1-(2-Thiazolypsulfanilamide, 4-Amino-N-2-thiaz dinium-3-carboxylate); N-methylnicotinate; Methyl olylbenzenesulfonamide); Sulfathiazole Sodium Salt 6-methylnicotinate; Ethyl 2-methylnicotinate; Kojic acid (4-Amino-N-2-thiazolylbenzenesulfonamide sodium salt); (2-Hydroxymethyl-5-hydroxy-gamma-pyrone, 5-Hydroxy thiocyanate; 3-methylbenzyl thiocyanate; methimazole 2- hydroxymethyl-4-pyranone); derivatives of kojic acid, (2-mercapto-1-methylimidazole, 1-methylimidazole-2- Such as: 6-(pyrrolidinomethyl)-kojic acid hydrochloride, thiol); dicarboxylic hydroxyacids; 1,3-Acetonedicarboxylic 6-(morpholinomethyl)-kojic acid, 6-(diethylaminomethyl)- acid (3-Oxoglutaric acid); D-tartaric acid ((25.35)-(-)-tar kojic acid hydrochloride; O-(2,4-dinitrophenyl)hydrox taric acid, unnatural tartaric acid); L-tartaric acid ((2R, ylamine; 2,4-dinitrophenylglycine; Hydroxylamine Hydro 3R)-(+)-tartaric acid, natural tartaric acid); DL-tartaric acid; chloride; Methyl-p-nitrobenzenesulfonate (Methyl potassium tartrate; D-malic acid; (R)-(+)-malic acid, (R)- 4-nitrobenzenesulfonate); Aminoethylcysteine-ketimine (+)-hydroxySuccinic acid; L-malic acid: (S)-(-)-malic (AECK, Thialysine ketimine, 2H-1,4-Thiazine-5,6- acid, (S) (-)hydroxysuccinic acid; DL-Malic acid (DL dihydro-3-carboxylic acid, S-Aminoethyl-L-cysteine hydroxySuccinic acid); Alpha-keto acids that are analogues ketimine, 2H-1,4-Thiazine-3-carboxylic acid, 5,6-dihydro-); of the amino acids alanine, leucine, phenylanaline, phenyl 1,4-thiazine derivatives: 4-Phenyl-1,4-sulfonazan (Tetra glycine, , serine, aspartate, and salts and derivatives hydro-4-phenyl-4H-1,4-thiazine 1-oxide, 4H-1,4-Thiazine, thereof; pyruvic acid (2-Oxopropionic acid, alpha-Ketopro tetrahydro-4-phenyl-, 1-oxide); 1. Phenothiazine (Thiodi pionic acid); sodium pyruvate; Pyruvic acid methyl ester phenylamine, 1 OH-Phenothiazine, AFI-Tiazin, Agrazine, (methyl pyruvate); Phenylpyruvic acid; Calcium phe Antiverm, Dibenzo-1,4-thiazine); 3,4-Dihydro-2H-1,4-thi nylpyruvate (calcium pyruvate); Phenylpyruvic acid Sodium azine-3,5-dicarboxylic acid (3,4-Dhtca, CASi36360-62-5); salt (Sodium phenylpyruvate); 4-hydroxyphenyl pyruvic Nifurtimox (Nifurtimox IBAN:INN), 1-((5-Nitrofurfu acid; sodium alpha-ketoisovaleric acid (3-Methyl-2-oxobu rylidene)amino)-2-methyltetrahydro-1,4-thiazine-4,4-diox tyric acid sodium salt, 3-methyl-2-oxobutanoic acid sodium ide, 3-Methyl-4-(5-nitrofurylidene-amino)-tetrahydro-4H salt, C.-Ketoisovaleric acid Sodium salt; Ketovaline Sodium 1,4-thiazine-1,1-dioxide, BAY 2502, 4-((5- salt); benzoylformic acid (C-Oxophenylacetic acid, Phenyl Nitrofurfurylidene)amino)-3- methylthiomorpholine 1,1- glyoxylic acid): 4-methylthio-2-oxopentanoic acid; dioxide); 3-(1-Pyrrolidinylmethyl)-4-(5,6-dichloro-1- 4-Methyl-2-oxopentanoic acid (4-Methyl-2-oxovaleric acid; indancarbonyl)-tetrahydro-1,4-thiazine hydrochloride (R alpha-Ketoisocaproic acid; ; 4-methylthio-2-oxybutanoic 84760; R 84761; Thiomorpholine, 4-((5,6-dichloro-2,3-di acid; 2-oxybutanoic acid (hydroxybutyrate: 2-Hydroxybu hydro-1 Hinden-1-yl)carbonyl)-3-(1-pyrrolidinylmethyl)- tyric acid; alpha-Hydroxy-n-butyric acid; DL-alpha-Hy monohydrochloride, (R-(R*.S*))-); ketimine reduced forms: droxybutyric acid Sodium Salt (sodium (+)-2-Hydroxybu cyStathionine; cystathionine ketimine; lanthionine ketimine; tyrate); Indole-3-pyruvic acid (alpha-Keto analogue of thiomorpholine-2-carboxylic acid; thiomorpholine-2,6-di ); The reaction product between cysteamine and carboxylic acid; TMDA (1,4-Thiomorpholine-3,5-dicarbox bromopyruvate; cysteamine (2-Aminoethanethiol: 2-Mer ylic acid): 1-chloro-1-nitroethane; anthranilate: Ethyl captoethylamine); pantetheline; 5-adenosylmethionine; 2-aminobenzoate (ethyl anthranilate); Methyl 2-aminoben Ethyl bromopyruvate; Methyl bromopyruvate; Bromopyru Zoate (Methyl anthranilate); picolinate; Ethyl picolinate (2- vate; and 5-S-Cysteinyldopamine (see, e.g., PCT Publica (Ethoxycarbonyl)pyridine, Ethyl 2-pyridinecarboxylate, tion WO 03/047558 and U.S. Patent Publication No: 2003/ L-Leucine methyl ester, hydrochloride: L-leucine ((S)-(+)- leucine); Fluorodinitrobenzene (1-Fluoro-2,4-dinitroben 0185754 A1). Zene, 2,4-DNFB, Benzene, 1-fluoro2,4-dinitro-, VAN); Benzoic and Sorbic Acid Salts and Derivatives. Dinitrochlorobenzene (1-Chloro-2,4-dinitrobenzene, 1,3- Dinitro-4-chlorobenzene); 1.2-cyclohexanedione; Allylgly (0093. In certain embodiments preferred DAAOIs cine (D-Allylglycine, 4-Pentenoic acid, 2-amino-); 2-amino include, but are not limited to a benzoic acid, benzoic acid 2.4-pentadienoate, 2-hydroxy-2,4-pentadienoate: 2-amino salt, benzoic acid ester and/ or a derivative thereof, and/or 4-keto-2-pentenoate; 2-hydroxybutyrate; Sodium sorbic acid, a sorbic acid salt, or a derivative thereof. 2-hydroxybutyrate; N-chloro-D-leucine; N-Acetyl-D-leu Illustrative benzoic acid salts include, but are not limited to cine; D-Leu (D-2-Amino-4-methylpentanoic acid); D-prop Sodium benzoate, potassium benzoate, calcium benzoate, US 2017/O181989 A1 Jun. 29, 2017

lithium benzoate, magnesium benzoate, benzoate, and N-3-5 -Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzo the like. In certain embodiments the benzoate is selected furan-1-yl)-1-propyl-N-methylglycine, N-3-1-(3-chloro from the group consisting of benzoic acid; sodium benzoate; phenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl -N-meth 2-aminobenzoate: 3-aminobenzoate, 4-aminobenzoate ylglycine, N-3-1-(3-trifluoromethylphenyl)-1,3- (p-aminobenzoate, PABA, Vitamin Bx, Vitamin H1, and dihydroisobenzofuran-1-yl)-1-propyl-N-methylglycine, benzodisoxazol-3-ol derivatives (see, e.g., U.S. Pat. No. N-3-1-(3-trifluoromethylphenyl)-1,3-dihydroisobenzo 7,166,725, PCT Publication WO 03/047558, and U.S. Patent furan-1-yl)-1-propyl-N-methyl(1-ethyl)glycine, N-3-1-(4- Publication No: 2003/0185754 A1 which are incorporated methylphenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl herein by reference), and the like. In certain embodiments N-methylglycine, N-3-1-(4-fluorophenyl)-1,3- the compounds discloses in U.S. Pat. No. 7,166,725, PCT dihydroisobenzofuran-1-yl)-1-propyl-N-methylglycine, Publication WO 03/047558, and U.S. Patent Publication No: N-3-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)- 2003/0185754 A1 are expressly excluded. 1-propyl-N-methylalanine, N-3-1-(4-fluorophenyl)-1,3- 0094 Illustrative sorbic acid (2,4-hexadienoic acid) salts dihydroisobenzofuran-1-yl)-1-propyl-N-methyl(1-ethyl) include, but are not limited to Sodium Sorbate, potassium glycine, N-3-4-chloro-1-(3-methyl-4-fluorophenyl)-1,3- sorbate, calcium sorbate. Other sorbic acid derivatives dihydroisobenzofuran-1-yl)-1-propyl-N-methylglycine, include, but are not limited to sorbohydroxamic acid, sorbic N-3-4-chloro-1-(4-chlorophenyl)-1,3-dihydroisobenzo aldehyde, Sorbic acid-thiol adducts, 8-quinolinylsorbate, furan-1-yl)-1-propyl-N-methylglycine, N-3-5-chloro-1- m-nitrosorbanilide, and the like. (4-chlorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-pro pyl-N-methylalanine, N-3-6-chloro-1-(3-methyl-4- NMDA Enhancer fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl 0095 NMDA enhancers suitable for use in certain meth N-methylglycine, N-3-6-chloro-1-(4-chlorophenyl)-1,3- ods of the present invention are well known to those of skill dihydroisobenzofuran-1-yl)-1-propyl-N-methylglycine, in the art. Suitable NMDA enhancers include, for example, N-3-6-chloro-1-(4-methylphenyl)-1,3-dihydroisobenzo but are not limited to D-alanine, a salt of D-alanine, an ester furan-1-yl)-1-propyl-N-methylglycine, N-3-6-chloro-1- of D-alanine, an alkylated D-alanine, a precursor of D-ala (4-methoxyphenyl)-1,3-dihydroisobenzofuran-1-yl)-1-pro nine, D-serine, a salt of D-serine, an alkylated D-serine, a pyl-N-methylglycine, N-3-5-fluoro-1-(4-chlorophenyl)-1, precursor of D-serine, D-cycloserine, a salt of D-cycloser 3-dihydroisobenzofuran-1-yl)-1-propyl-N-methylglycine, ine, an ester of D-cycloserine, a precursor of D-cycloserine, N-3-5-fluoro-1-(4-methoxyphenyl)-1,3-dihydroisobenzo an alkylated D-cycloserine, N,N-dimethylglycine, a salt of furan-1-yl)-1-propyl-N-methylglycine, N-3-5-trifluorom N,N-dimethylglycine, an ester of N,N-dimethylglycine, an ethyl-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1- alkylated N,N-dimethylglycine, and N.N.N-trimethylgly propyl-N-methylglycine, N-3-5-trifluoromethyl-1-(4- cine. fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl 0096. In certain embodiments the composition is substan N-methylalanine, N-3-5-cyano-1-(3-methyl-4- tially free of D-cycloserine when the agonist is D-alanine, a fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl salt of D-alanine, an ester of D-alanine, an alkylated D-ala N-methylglycine, N-3-(5-cyano-1-(4-cyanophenyl)-1,3- nine, or a precursor of D-alanine; and when the agonist is dihydroisobenzofuran-1-yl)-1-propyl-N-methylalanine, D-cycloserine, a salt of D-cycloserine, an ester of D-cyclos N-3-(5-cyano-1-(4-methoxyphenyl)-1,3-dihydroisobenzo erine, a precursor of D-cycloserine, or alkylated D-cyclos furan-1-yl)-1-propyl-N-methylglycine, N-3-(5-cyano-1- (4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-pro erine, the pharmaceutical composition comprises an amount pyl-N-methylglycine, N-(2-5-cyano-1-(4-fluorophenyl)- of the agonist equivalent to 105-500 mg of D-cycloserine. 1,3-dihydroisobenzofuran-1-yl)ethyl-N-methylglycine, N-3-5-Chloro-1-(4-chloro-phenyl)-indan-1-yl)-propyl Glycine Transporter Inhibitor. N-methylglycine, N-3-5-Chloro-1-(4-chloro-phenyl)-in 0097. Glycine transporter inhibitors suitable for use in the dan-1-yl)-propyl-N-methylalanine, N-3-3-cyclo-1-(4- methods of the present invention are well known to those of methylphenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl skill in the art. Suitable glycine transporter inhibitors N-methylglycine, N-3-(3.3-Dimethyl-1-phenyl-1,3- include, but are not limited to sarcosine (N-methylglycine), dihydro-benzoic thiophen-1-yl)-propyl-N-methylglycine, N-3-(4-fluorophenyl)-3-(4'-phenylphenoxy)propylsar N-3-(3.3-Dimethyl-1-phenyl-1,3-dihydro-benzoc thio cosine, (+)N3-(4-fluorophenyl)-3-(4'-phenylphenoxy)pro phen-1-yl)-propyl-N-methylalanine, N-3-1-(4-Fluoro pylsarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and phenyl)-3-dimethyl-1,3-dihydro-isobenzofuran-1-yl)-pro pyrazinyl piperidine compounds (see, e.g., WO/2005/ pyl-Nimethylglycine, N-3-5-Bromo-1-(4-chlorophenyl)- 094514, which is incorporated herein by reference, Pinard et 1,3-dihydroisobenzofuran-1-yl)-1-propyl-N- al. (2008) Bioorg Med Chem Leu. 18(18): 5134-5139; Bou methylglycine, N-(2-1-(4-Chloro-phenyl)-3.3 -dimethyl-1, lay et al. 92008) Pharmacol Biochem Behav. 91(1):47-58: 3-dihydro-isobenzofuran-1-yl-ethyl-N-methylglycine, Lindsley et al. (2006) Curr Top Med Chem. 6(17): 1883 N-3-(3-methyl-1-phenyl-1H-inden-1-yl)-propyl-N-meth 1896; Depoortere et al. (2005) Neuropsychopharmacology ylglycine, N-3-(5-Chloro-1-thiophen-2-yl-1,3-dihydro 30(11): 1963-1985; Brown et al. (2001) Bioorg Med Chem isobenzofuran-1-yl)-propyl-N-methylglycine, N-3-(5- Lett. 11(15): 2007-2009). Other glycine transporter inhibi Chloro-1-thiophen-2-yl-1,3-dihydro-isobenzofuran-1-yl)- tors include, but are not limited to N-3-5-Cyano-1-(4- propyl-N-methyl(1-ethyl)-glycine, N-3-(3-methyl-1- fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1- phenyl-1,3-dihydro-isobenzofuran-1-yl)-propyl-N- propylglycine ethyl ester, N-3-5-Cyano-1-(4- methylalanine, N-3-(3-methyl-1-phenyl- 1,3-dihydro fluorophenyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl)-N isobenzofuran-1-yl)-propyl-N-methyl(1-ethyl)-glycine, -methylglycine ethyl ester, N-3-5-Cyano-1-(4-fluorophe N-3-(3.3-Dimethyl-1-phenyl-1,3-dihydro-isobenzofuran-1- nyl)-1,3-dihydroisobenzofuran-1-yl)-1-propyl)glycine, yl)-ethyl-N-methylalanine, N-3-(3.3-Dimethyl-1-(4- US 2017/O181989 A1 Jun. 29, 2017 fluoro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-ethyl-N- herein by reference), or other non glycine-, N-methylgly methylalanine, N-3-(3.3-Dimethyl-1-phenyl-1,3-dihydro cine-structurally based inhibitors (see, e.g., Harsing et al. isobenzofuran-1-yl)-ethyl-N-methyl-(1-ethyl)glycine, (2006) Current Medicinal Chemistry, 13: 1017-1104). N-3-(3.3-Dimethyl-1-(4-fluoro-phenyl)-1,3-dihydro isobenzofuran-1-yl)-ethyl-N-methyl-(1-ethyl)glycine, Additional Active Agents. N-3-(3.3-Diethyl-1-phenyl-1,3-dihydro-isobenzofuran-1- 0098. In certain embodiments the methods can involve yl)-propyl-N-methyl alanine, N-3-(3,3-Diethyl-1-(4- administering additional neuropharmaceuticals and other chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl)-propyl-N- therapeutic agents instead of or in conjunction with the methylalanine, N-3-(3,3-Diethyl-1-(4-chloro-phenyl)-1,3- agents described above. dihydro-isobenzofuran-1-yl)-propyl-N-methylglycine, 0099. In certain embodiments such agents include, but N-3-(1-phenyl-1,3-dihydro-benzocthiophen-1-yl)-pro are not limited to diazepam, bromazepam, prazepam, pyl-N-methylalanine, N-3-1-(4-Chloro-phenyl)-3,3-dim Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, ethyl-indan-1-yl)-propyl-N-methylglycine, N-3-1-(4- Clonazepam, Temazepam, Triazolam, Alprazolam, Midazo Chloro-phenyl)-3,3-diethyl-1,3-dihydro-isobenzofuran-1- lam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, yl)-propyl-N-methyl-alanine, N-(2-(3-methyl-1-phenyl Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, indan-1-yl)-ethyl-amino)-N-methylalanine, N-3-(1- Zopiclone, Zaleplon, Chlorpromazine. Thioridazine, phenyl-(1H)-inden-1-yl)-propyl-N-methylalanine, N-3- Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, 1-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-1,3- Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, dihydro-isobenzofuran-1-yl)-propyl)-N-methyl-glycine, Risperidone, Olanzapine, Quetiapine, Haloperidol decano N-3-5-Chloro-1-(4-chloro-phenyl)-indan-1-yl)-propyl ate, Fluphenazine decanoate, Fluphenazine enanthate, N-methyl-glycine, N-3-5-Chloro-1-(4-chloro-phenyl)-in Risperdal Consta, Amitriptyline, Amoxapine, Bupropion, dan-1-yl)-propyl-N-methyl-alanine, N-3-1-(4-chloro Bupropion SR, Citalopram, S-Citalopram, Clomipramine, phenyl)-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-isobenzo Desipramine, Doxepin, Duloxetine, Milnacipran, Fluox furan-1-yl-ethyl-N-methyl-glycine, N-3-1-(4-Chloro etine, Fluvoxamine, Imipramine, Isocarboxazid, Lama phenyl)-5-(4-methyl-phenyl)-1,3-dihydro-isobenzofuran-1- trogine, Lithium, Topiramate, Gabapentin, Carbamazepine, yl-ethyl-N-methyl-glycine, N-3-1-(4-Chloro-phenyl)-5- Oxacarbazepine, Valporate, Maprotiline, Memantine, Mir (4-methoxy-phenyl)-1,3-dihydro-isobenzofuran-1- yl)- tazapine, Brofaromine, Gepirone, Moclobemide, Physostig ethyl-N-methyl-glycine, N-3-1-(4-Chloro-phenyl)-5-(2- mine, Nicotine, Huperzine Alpha, vitamine C. vitamine E. thiophenyl)-1,3-dihydro-isobenzofuran-1- yl-ethyl-N- Carotenoids, Ginkgo Biloba, Statins, Nefazodone, Nortrip methyl-glycine, N-3-1-(4-Chloro-phenyl)-5-(4-methyl tyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Pro phenyl)-1,3-dihydro-isobenzofuran-1-yl)-propyl-N- triptyline, Trimipramine. Amoxapine, isoniazid, iproniazid, methyl-glycine, N-3-1-(4-Chloro-phenyl)-5-(4-methoxy venlafaxine, Velafaxine XR, mianserin, reboxetine, Selegi phenyl)-1,3-dihydro-isobenzofuran-1-yl)-propyl-N- line, Tranylcypromine, Trazodone, Trimipramine, Venlafax methyl-glycine, N-3-1-(4-chloro-phenyl)-5-(4- ine, Velafaxine XR, Amphetamine, Modafinil, Desoxyn, trifluoromethyl-phenyl)-1,3-dihydro-isobenzofuran-1-yl)- Methamphetamine, arecoline, Dexmethylphenidate (Foca propyl-N-methyl-glycine, N-3-1-(4-Chloro-phenyl)-5- lin, Focalin XR), dextroamphetamine(Dexedrine, Dexedrine (4-chloro-phenyl)-1,3-dihydro-isobenzofuran-1-yl-ethyl SpanSules, Dextroamphetamine ER, Dextrostat), methyl N-methyl-glycine, N-(2-1-(4-Chloro-phenyl)-5-(5-chloro phenidate (Concerta, Daytrana, Metadate CD, Metadate ER, thiophen-2-yl)-1,3-dihydro-isobenzofuran-1-yl-ethyl-N- Methylin, Methylin ER, Ritalin, Ritalin-LA, Ritalin-SR), methyl-glycine, N-3-1-(4-Chloro-phenyl)-5-(3-methyl lisdexamfetamine dimesylate (Vyvanse), mixed salts phenyl)-1,3-dihydro-isobenzofuran-1-yl-ethyl-N-methyl amphetamine (Adderall. Adderall XR), Atomoxetine (Strat glycine, N-3-1-(4-Chloro-phenyl)-5-(2-methyl-phenyl)-1, tera), clonidine hydrochloride (Catapres), guanfacine hydro 3-dihydro-isobenzofuran-1-yl-ethyl-N-methyl-glycine, chloride (Tenex), cocaine, Pemoline, Donepezil, Tacrine, N-3-1-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-1,3-di Rivastigmine, Acetophenazine, Chlorprothixene, Droperi hydro-isobenzofuran-1-yl-ethyl-N-methyl-glycine, N-3- dol, Pimozide, Butaperazine, Carphenazine, Remoxipride, 1-(4-chloro-phenyl)-5-(3-trifluoromethyl-phenyl)-1,3-di Piperacetazine, Sulpiride, Ziprasidone, aripiprazole, Pali hydro-isobenzo furan-1-yl-ethyl-N-methyl-glycine, N-3- peridone, lamotrigine (LAMICTAL(R), memantine 1-(4-chloro-phenyl)-5-(3-trifluoromethyl-phenyl)-1,3- (AXURAR), AKATINOLOR, NAMENDAR, EBIXAR), dihydro-isobenzo furan- 1-yl)-propyl)-N-methyl-glycine, ABIXAR), arecoline, acamproSate, tetrabenazine N-3-1-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-1,3-di (XENAZINER, NITOMANR), RILUTEKR) (riluzole), and hydro-isobenzofuran-1-yl-ethyl-N-methyl-glycine, N-3- the like. 1-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-1,3-dihydro isobenzofuran-1-yl)-propyl-N-methyl-glycine, N-3-1-(4- Compound Formulations. Chloro-phenyl)-5-(3-methyl-phenyl)-1,3-dihydro isobenzofuran-1-yl)-propyl-N-methyl-glycine, N-3-1-(4- 0100. In certain embodiments, the agents described Chloro-phenyl)-5-(2-methyl-phenyl)-1,3-dihydro herein (e.g., benzoic acid, benzoic acid salt, or derivative isobenzofuran-1-yl)-propyl-N-methyl-glycine, N-3-1-(4- thereof and/or sorbic acid, sorbic acid salt, or derivative Chloro-phenyl)-5-(2,5-dichloro-phenyl)-1,3-dihydro thereof) and a neuropharmaceutical (e.g., as described isobenzofuran-1-yl)-propyl-N-methyl-glycine, N-3-1-(4- herein) are administered separately, either simultaneously or Chloro-phenyl)-5-(3,4-dichloro-phenyl)-1,3-dihydro sequentially. The agents are commercially available in Suit isobenzofuran-1-yl)-propyl-N-methyl-glycine, and N-3- able pharmaceutically acceptable formulations. 1-(4-chloro-phenyl)-5-(2-trifluoromethyl-phenyl)-1,3- 0101. In certain embodiments, however, the agents e.g., dihydro-isobenzo furan-1-yl)-propyl)-N-methyl-glycine benzoic acid, benzoic acid salt, benzoic acid ester, or other (see, e.g., U.S. Pat. No. 6,921,774, which is incorporated benzoic acid derivative and/or sorbic acid, sorbic acid salt, US 2017/O181989 A1 Jun. 29, 2017

sorbic acid ester, or other sorbic acid derivative, and neu EXAMPLES ropharmaceutical (e.g., antidepressant, antipsychotic, psy chostimulant, mood stabilizers, anxiolytic. ADHD therapeu 0108. The following examples are offered to illustrate, tic, Alzheimer's disease therapeutic, and other psychotropics but not to limit the claimed invention. etc.) are provided as a combined formulations for adminis Example 1 tration by any of a variety of modalities including, but not limited to oral administration, rectal administration, injec Introduction tion, transdermal administration, Subcutaneous depot admin istration, transnasal administration, and the like. Methods of 0109 Treatment by the agents enhancing N-methyl-D- preparing combined formulations are well known to those of aspartate neurotransmission have gained attention as an skill in the art (see, e.g., Remington's Pharmaceutical Sci alternative for patients not responding to available psycho ence, 15th ed., Mack Publishing Company, Easton, Pa. tropics including antipsychotic medication. However, the (1980), Remington: The Science and Practice of Pharmacy, efficacy of the individual NMDA-enhancement is limited at 21st Ed. 2005, Lippincott Williams & Wilkins, and the like). typical dosages. We believe a combination of NMDA 0102 For example, for oral administration, the active enhancing agents will render better clinical efficacy than an agent(s) (e.g., benzoic acid, Salt or derivative, and/or Sorbic individual agent alone. To evaluate this hypothesis, we acid, salt, or derivative, and antipsychotic) can be combined applied the combinational strategy in the best accepted with one or more excipients and used in the form of neurophysiological model of Schizophrenia in rodents, ingestible tablets, buccal tablets, troches, capsules, elixirs, startle habituation and prepulse inhibition (PPI). Suspensions, syrups, wafers, and the like. In wafer formu 0110. The startle response is comprised of a constellation lations, for example, different layers comprising the wafer of reflexes elicited by sudden relatively intense stimuli. It can contain different agents. Similarly time-release capsules offers many advantages as a behavioral measure of central can comprise multiple active agents. Such compositions and nervous system activity when elicited by acoustic (noise preparations are typically formulated to deliver the desired burst), electrical (cutaneous), tactile (air puff), or visual concentration of agent(s) over the desired time period. (light flash) stimuli. The startle reflex has served as a tool for 0103 Similarly, for injectables, the active agents can be studying fundamental properties of nervous function of combined into a single injectable formulation. complex behavioral states and cognitive processes. 0111. The forebrain modulates several forms of startle Kits plasticity including the habituation and PPI. Changes in 0104. In another embodiment this invention provides kits startle magnitude through repeated Stimulus presentations treating (e.g., mitigating one or more symptoms of) a habituation and sensitization-represent the simple forms of neuropsychiatric disorder. The kits preferably comprise a learning. Quantification of startle habituation and sensitiza container or containers containing the combinations of tion in rodent has direct physiological relevance to human active agents described herein, either a separate formula CNS function. In fact, the most well accepted animal tions or as a single “combined formulation. The agent(s) physiology models for schizophrenia are startle habituation can be provided in a unit dosage formulation (e.g. Supposi and PPI. tory, tablet, caplet, patch, etc.) and/or may be optionally 0112 Therefore, to test the hypothesis that combinational combined with one or more pharmaceutically acceptable NMDA-enhancing agent treatment has better efficacy than excipients. individual agent alone, we tested startle habituation and PPI 0105. In certain embodiments the kits comprise benzoic in animals receiving single NMDA-enhancing agents, sar acid, a benzoic acid salt, or a derivative thereof and/or sorbic cosine (N-methylglycine, a glycine transporter-1 inhibitor), acid, a Sorbic acid salt, or a derivative thereof, and a benzoate (a D-amino acid oxidase inhibitor), the combina neuropharmaceutical (e.g., an antipsychotic). The agents can tion of both agents or the vehicle. We also tested the be in separate containers or in the same container. hypothesis in a well accepted pharmacological model of 0106. In addition, the kits optionally include labeling Schizophrenia, amphetamine-disruption of startle habitua and/or instructional materials providing directions (i.e., pro tion and PPI. tocols) for the practice of the methods or use of the “thera peutics' or “prophylactics” of this invention. Preferred Method instructional materials describe the use of combinations of 0113 For the systematic investigation of the neurobio agents as described herein to mitigate symptom(s) of a logical systems that modulate sensorimotor inhibition, neuropsychiatric disorder and/or to prevent the onset or startle magnitude was investigated. Startle magnitude is increase of one or more of Such symptoms in an individual reduced when the pulse stimulus is preceded 30 to 500 msec at risk for Such a disorder. The instructional materials can by a weak prepulse. This inhibition (“gating”) of a motor also, optionally, teach preferred dosages/therapeutic regi response elicited by a weak sensory event, termed PPI, ment, counter indications and the like. provides an operational measure of sensorimotor gating. 0107 While the instructional materials typically com Prepulse stimuli of 3, 6, or 12 dB above the 70 dB back prise written or printed materials they are not limited to ground noise inhibit the startle response elicited by 120-dB Such. Any medium capable of storing Such instructions and pulse stimuli. Prestimuli used in intramodal studies of sen communicating them to an end user is contemplated by this Sorimotor gating of acoustic startle are by the delivery of a invention. Such media include, but are not limited to elec discrete acoustic prepulse several msec before the startle tronic storage media (e.g., magnetic discs, tapes, cartridges, pulse, with an intensity below startle threshold. Holding the chips), optical media (e.g., CD ROM), and the like. Such interval between the prepulse and pulse stimuli constant at media may include addresses to internet sites that provide 100 msec typically yields suitable levels of PPI, ranging Such instructional materials. from 20% to 80% inhibition. US 2017/O181989 A1 Jun. 29, 2017

0114 For habituation, we present six trials of a single corrected by either sarcosine (NMG) or benzoate (middle 2 acoustic stimulus to each mouse. To provide a consistent columns) and was best corrected by the combination treat acoustic environment and to mask external noises, maintain ment (right column). a continuous background noise level of 70 dB within each startle chamber. We collected the peak or average response Conclusion from each mouse on each of six trials, then averaged the six responses together for each mouse. Five more trials at the 0119. In the most accepted animal model of schizophre end of PPI were done. The results were averaged and nia, which tests the sensory gating, we found that combi compared to the original six trials. The difference of startle nation treatment improve the startle habituation and PPI responses between the initial six and the last five trials were significantly more than the individual agent alone. . The considered the amount of habituation. Analyses include the effect of benzoate was close to combination treatment in independent variable (e.g., vehicle or drug treatment) as a habituation. factor in analyses of variance (ANOVA) on the dependent measures (difference of the average of the first and last six Example 2 trials). 0115 There were a total of 36 trials in the experiments. Treatment of Schizophrenia by Sodium Benzoate, A The three prepulse stimuli were with a duration of 20 msec. D-Amino Acid Oxidase Inhibitor For each mouse the following metrics were determined: 1) Average response magnitude on pulse-only trials 1 to 6 and I0120 Schizophrenia is a devastating mental disorder 32 to 36; 2) Average response magnitude in each of the four with high morbidity and mortality, affecting about 1% of the trial types between trials 7 and 31 inclusively (i.e., ten population worldwide. Furthermore, care for schizophrenia pulse-only trials and five each of the three prepulse varia is extremely expensive in terms of direct and indirect costs. tions). The first block of pulse-only trials were analyzed as Clinical manifestation of schizophrenia consists of three measures of startle reactivity. The first and last blocks of domains: positive symptoms, negative symptoms, and neu pulse-only trials were analyzed together in a repeated mea ropsychological deficits that are poorly addressed today. sure ANOVA to assess habituation of acoustic startle across the test session. The four values (3, 6, or 12 dB above Therapeutic Need for Schizophrenia Beyond Clozapine background) derived from trials 7 to 31 were used to assess I0121 Pharmacotherapy of schizophrenia has been devel PPI which was calculated for each mouse as: Percentage oped for half century. Conventional antipsychotics, which score: PPI-100%x{pulse-only units-(prepulse-pulse blockade majority of D dopamine receptors only exerted units)/(pulse-only units)}. effects on positive symptoms. Newer atypical antipsychotics 0116 Male 129 SVE adult mice were first tested at targeting both dopamine D and serotonin 5HT receptors baseline. Four groups of 10 mice each were treated with have been Suggested to be Superior to conventional agents in sarcosine (200 mg/kg), benzoate (100 mg/kg), a combina terms of efficacy for positive symptoms, negative symptoms tion of both sarcosine and benzoate (same doses as the and cognitive deficits. Despite this, there were a consider individual treatment), or with vehicle for one week before able percentage of patients resistant or only partially respon the test. The mice continued to receive the drug until one sive to available medications. Moreover, side-effect profiles week later when amphetamatine (10 mg/kg) was adminis of second-generation antipsychotic agents are significant, tered 30 minutes before the experiments. including hypotension, seizure, sedation, weight gain, hyperglycemia, diabetes mellitus, hyperlipidemia, and Results hematological abnormalities, limit their clinical use. Lastly, most schizophrenic patients still suffer from lifelong illness 0117 We found that there was no difference in the and deteriorating function. habituation at baseline (when no drug had been adminis tered) across the groups (FIG. 1, left group). But combina Materials and Methods tion treatments induce a stronger habituation effect than benzoate or sarcosine treatment alone (FIG. 1, middle 0122) Subjects group). The effect of benzoate, however, was close to the I0123. The research protocol was approved by the Insti combination treatment. The same trend of habituation (com tutional Review Boards (IRB) of the institute. Patients were bination treatment>benzoated sarcosine) was evident when screened and evaluated by the research psychiatrists. After amphetamine was administered and disrupted the habitua complete description of the study to the subjects, written tion (FIG. 1, right group). The combination is better than the informed consent was obtained in line with the IRB's individual treatment in enhancing the habituation (FIG. 1, guidelines. The Structured Clinical Interview for DSM-IV middle). The combination treatment corrected the amphet was conducted for the diagnosis. Patients entered into this amine-induced disruption of habituation back to normal study if they 1) were physically healthy and had all labora state while single treatment of NMG or benzoate partially tory assessments (including urine/blood routine, biochemi correct the deficit (FIG. 1, right group). The effect of cal tests, and electrocardiograph) within normal limits, 2) benzoate, however, is better than sarcosine and close to aged 18-60 years, 3) satisfied DSM-IV criteria for schizo effect seen in the combination treatment. phrenia (2), 4) had no DSM-IV diagnosis of substance 0118 For PPI, we found that in general stronger prepulse (including alcohol) abuse or dependence, 5) consistently inhibited pulse response more (inhibition of 525 HZD487 symptomatic without fluctuation and the antipsychotic doses HZ>468 Hz) (FIG. 2). Amphetamine disrupted the inhibition were unchanged for at least 3 months, and 6) had a minimum in all treatments. This disruption by amphetamine is most baseline total score of 60 on the Positive and Negative pronounced in vehicle treated mice (left column), partially Syndrome Scale (PANSS) (3). US 2017/O181989 A1 Jun. 29, 2017

0.124 Study Design test. Only raters reaching the intraclass correlation coeffi 0.125. The dosing for the concurrent antipsychotics (all cients of 0.90 or higher during pre-study training were atypical antipsychotics), was an optimal dosing strategy allowed to rate the study patients. To maintain high interrater which minimize side effects, especially extrapyramidal side reliability and to prevent rater drift, raters met at least once effects (EPS), and can still yield favorable efficacy. After a month for training and reliability re-testing. To minimize having achieved optimal treatment response, patients antip interrater variability, individual patients were assessed by sychotic doses remained constant for at least three months the same research psychiatrist throughout the trial. Assess prior to the enrollment of the study and remained on the ments were completed at baseline and at the end of weeks 2, same antipsychotic regimens for the study period. All 4, and 6. patients are treated with atypical antipsychotics, risperidone I0132 Statistical Analysis in majority. I0133. The demographic and clinical characteristics of the 0126 All patients were then randomly assigned under patients, antipsychotic doses, response rate, and side effects double-blind conditions to receive a 6-week trial of placebo, among groups were compared by Kruskal Wallis tests (or or sodium benzoate (1 grams) daily. Patients were random ANOVA tests if the distribution was normal) for continuous ized in clusters of six Subjects, without stratification, through variables and by Chi-Square tests (or Fisher's Exact tests) a computer-generated randomization table to receive pla for categorical variables. cebo or active drugs in a 1:1 ratio. To ensure concealment of I0134. We applied multiple linear regression with the the randomization assignment, study medication was pro generalized estimating equation (GEE) method (10) for the vided in coded containers with Supply of identical-appearing treatment by time (0, 2, 4, 6 weeks) interaction analysis, capsules of placebo or either of active compounds. The which simultaneously compared the treatment groups using research pharmacist implemented random allocation and a single analysis and allowed controlling for baseline psy masked treatment assignment was communicated by tele chopathology. The results of GEE models were analyzed by phone to research staff. Patients, caregivers, and investiga the SAS/STAT (SAS Institute Inc, Cary, N.C.) “PROC tors (except for the investigational pharmacist) were all GENMOD procedure with AR (autoregressive) (1) work masked to the assignment. Patient’s compliance and safety ing correlation structure using the marginal model. Since were closely monitored by the research psychiatrists and the there are three comparison groups, the placebo group was inpatient nursing staff. selected to be compared with the two active treatment 0127. Measures groups. Because ANOVA and multiple linear regression can 0128. The primary outcome measures were psychopa be applied only if the distribution of the response values is thology changes measured by PANSS (3) and, Scales for the normal, we examined the distribution pattern using the Assessment of Negative symptoms (SANS) (4) total scores, “Kolmogorov D package in SAS/INSIGHT v8.2. All Quality of Life scale (10 items for inpatient use) (1, 5), and hypothesis tests were two sided and conducted at the 0.05 Global Assessment of Function (Axis V in DSM IV) (2). A alpha levels. To compare across the treatments, effect sizes secondary analysis aimed to explore whether the positive between endpoint and baseline were calculated. results (if any) from the PANSS or SANS were due to a 0.135 Results general effect on all components or to an effect on a specific 0.136. In this pilot, placebo-control, randomized, double component(s). blind trial (not yet published), we found that 1000-mg/day 0129. Factor analyses for PANSS revealed 5 components: Sodium benzoate adjunctive therapy (n=18) can significantly positive, negative, cognitive, depression and excitement (3). improve positive and negative symptoms and quality of life For the assessment of negative symptoms, we a priori chose than placebo (n=18) in schizophrenia patients (FIG. 3). SANS rather than PANSS-negative to avoid multiple com Benzoate also yielded good safety and tolerability. Treat parisons because SANS is more comprehensive, consisted ment-emergent side effects were also similar between ben of five Subscales: blunted affect, alogia, apathy, anhedonia/ Zoate and placebo groups. These side effects were all mild, asociality, and attention (4). Nevertheless, we also presented short-lived, and not warranting medical treatment. the findings in the PANSS-negative component. Of the 0.137 We had optimized the treatment of schizophrenia original 21 items on the Quality of Life scale (5), 10 (social by reconfirming the efficacy and safety of risperidone (ris)- activity, Social initiatives, social withdrawal, sense of pur benzoate combination (RBC). We found RBC was superior pose, motivation, curiosity, anhedonia, aimless inactivity, to risperidone (ris) (placebo add on) in all clinical domains, capacity for empathy, emotional interaction) are selected for including cognitive function and life quality and its safety is the inpatient setting (1). The Global Assessment of Function equal to ris (placebo addon) treatment. This beneficial (GAF, Axis V in DSM IV) includes symptoms in the anchors outcome will provide a new treatment for Schizophrenia and (2). The GAF raters were instructed to ignore the symptom markedly reduce the social cost for this severe mental components. disorder. 0130. Side-effect assessments included Simpson-Angus Rating Scale for EPS (6), Abnormal Involuntary Movement Example 3 Scale (AIMS) for dyskinesia (7), and Barnes Akathesia 0.138. Following acclimation at least 7 days in the animal Scale (8). Systemic side effects of treatments were evaluated facility prior to initiation of behavioral testing, the animals by means of routine physical and neurological examinations, (rats) were subjected to the forced swim test (FST). The laboratory tests, and reviewed by applying the Udvalg for method of the FST has been used in previous animal studies Kliniske Undersogelser (UKU) Side-effects Rating Scale of depression, which was modified by Cryan from the (9). Porsolt's FST. (Porsolt et al., 1977; Cryan et al., 2002). The 0131 Clinical ratings were performed by the research test was performed using a acrylic cylinder (diameter, 20 psychiatrists who were trained and experienced in the rating cm; height, 40 cm) filled to a height of 30 cm with 25°C. scales. Inter-rater reliability was analyzed with the ANOVA water. Rats were processed to a 15-min conditioning Swim. US 2017/O181989 A1 Jun. 29, 2017

Following 24 h after their first exposure, the rats were again applications cited herein are hereby incorporated by refer placed in the swim apparatus for 5 min. The behavior of rats ence in their entirety for all purposes. was observed 5 min after the administration of various drug 1-62. (canceled) treatments or 0.9% saline (control). All behavioral testing 63. A pharmaceutical composition for mitigating a symp was conducted between 1600-1800 h. On the study day, the tom associated with Schizophrenia, comprising: total periods of immobility during the 5-min testing period 500 milligrams to 10 grams of a first active ingredient, were recorded using the EthoVision Basic V 3.1 analysis which is benzoic acid, or a pharmaceutically acceptable program (Noldus, Wageningen, Netherlands). For the pres salt thereof, and an effective amount of a second active ingredient, which ent experiment, the immobility threshold was set at 15% and is selected from the group consisting of olanzapine, a fixed averaging interval of 1 second was chosen to Smooth aripiprazole, clozapine, amisulpride, chlorpromazine, the mobility parameter in EthoVision software. Below the flupenthixol, haloperidol, quetiapine fumarate, immobile threshold, the animal is considered immobile. Sulpiride, Ziprasidone, and Zotepine. Using the settings, the activity of all rats was analyzed 64. The pharmaceutical composition of claim 63, wherein automatically and quantitatively for mobility and numbers the ratio of the first active ingredient to the second active of crossing vertical central line in the FST. ingredient is greater than 2:1 (w/w). 65. The pharmaceutical composition of claim 64, wherein TABLE 1. the ratio of the first active ingredient to the second active ingredient is greater than 10:1 (w/w). Treatment effects for sodium benzoate and 66. The pharmaceutical composition according to claim potassium Sorbate in forced Swim test. 65, wherein the ratio of the first active ingredient to the Sodium Benzoate Potassium Sorbate second active ingredient is greater than 20:1 (w/w). Vehicle (500 mg/kg) (500 mg/kg) 67. The pharmaceutical composition of claim 63, which is Immobility time 46.94 - 4.6 40.17 3.3 27.64 - 6.2 formulated in a solid dosage form. (%) (p < 0.05) (p < 0.01) 68. The pharmaceutical composition of claim 63, wherein the first active ingredient is benzoic acid. 69. The pharmaceutical composition of claim 63, wherein 0139. The table indicates the scores on the behavioral the first active ingredient is a pharmaceutically acceptable scales of FST in three treatment groups. As can be seen, both salt of benzoic acid, which is selected from the group sodium benzoate and potassium Sorbate decrease the dura consisting of sodium benzoate, potassium benzoate, calcium tion of immobility significantly as compared to the vehicle benzoate, and lithium benzoate. control group. 70. The pharmaceutical composition of claim 63, wherein 0140. It is understood that the examples and embodi the second active ingredient is clozapine. ments described herein are for illustrative purposes only and 71. The pharmaceutical composition of claim 63, wherein that various modifications or changes in light thereof will be the first active ingredient is sodium benzoate. Suggested to persons skilled in the art and are to be included 72. The pharmaceutical composition of claim 71, wherein within the spirit and purview of this application and scope of the second active ingredient is clozapine. the appended claims. All publications, patents, and patent k k k k k