Advertisement

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene

      Abstract

      Background

      The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder.

      Methods

      We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one.

      Results

      Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials.

      Conclusions

      These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rees E.
        • Walters J.T.R.
        • Georgieva L.
        • Isles A.R.
        • Chambert K.D.
        • Richards A.L.
        • et al.
        Analysis of copy number variations at 15 schizophrenia-associated loci.
        Br J Psychiatry. 2014; 204: 108-114
        • Malhotra D.
        • Sebat J.
        CNVs: Harbinger of a rare variant revolution in psychiatric genetics.
        Cell. 2012; 148: 1223-1241
        • Marshall C.R.
        • Howrigan D.P.
        • Merico D.
        • Thiruvahindrapuram B.
        • Wu W.
        • Greer D.S.
        • et al.
        Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.
        Nat Genet. 2017; 49: 27-35
        • International Schizophrenia Consortium
        Rare chromosomal deletions and duplications increase risk of schizophrenia.
        Nature. 2008; 455: 237-241
        • Stefansson H.
        • Rujescu D.
        • Cichon S.
        • Pietilainen O.P.H.
        • Ingason A.
        • Steinberg S.
        • et al.
        Large recurrent microdeletions associated with schizophrenia.
        Nature. 2008; 455: 232-236
        • McCarthy S.
        • Makarov V.
        • Kirov G.
        • Addington A.
        • McClellan J.
        • Yoon S.
        • et al.
        Microduplications of 16p11.2 are associated with schizophrenia.
        Nat Genet. 2009; 41: 1223-1227
        • Cantor R.M.
        • Geschwind D.H.
        Schizophrenia: Genome, interrupted.
        Neuron. 2008; 58: 165-167
        • Weiss L.A.
        • Shen Y.
        • Korn J.M.
        • Arking D.E.
        • Miller D.T.
        • Fossdal R.
        • et al.
        Association between microdeletion and microduplication at 16p11.2 and autism.
        N Engl J Med. 2008; 358: 667-675
        • Mefford H.C.
        • Batshaw M.L.
        • Hoffman E.P.
        Genomics, intellectual disability, and autism.
        N Engl J Med. 2012; 366: 733-743
        • Heinzen E.L.
        • Neale B.M.
        • Traynelis S.F.
        • Allen A.S.
        • Goldstein D.B.
        The genetics of neuropsychiatric diseases: Looking in and beyond the exome.
        Ann Rev Neurosci. 2015; 38: 47-68
        • Kirov G.
        • Rees E.
        • Walters J.T.R.
        • Escott-Price V.
        • Georgieva L.
        • Richards A.L.
        • et al.
        The penetrance of copy number variations for schizophrenia and developmental delay.
        Biol Psychiatry. 2014; 75: 378-385
        • Kirov G.
        CNVs in neuropsychiatric disorders.
        Hum Mol Genet. 2015; 24: R45-R49
        • Sullivan P.F.
        • Daly M.J.
        • O’Donovan M.
        Genetic architectures of psychiatric disorders: The emerging picture and its implications.
        Nat Rev Genet. 2012; 13: 537-551
        • Geschwind D.H.
        • Flint J.
        Genetics and genomics of psychiatric disease.
        Science. 2015; 349: 1489-1494
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Sanders S.J.
        • He X.
        • Willsey A.J.
        • Ercan-Sencicek A.G.
        • Samocha K.E.
        • Cicek A.E.
        • et al.
        Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci.
        Neuron. 2015; 87: 1215-1233
        • Vacic V.
        • McCarthy S.
        • Malhotra D.
        • Murray F.
        • Chou H.-H.
        • Peoples A.
        • et al.
        Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.
        Nature. 2011; 471: 499-503
        • Brunetti-Pierri N.
        • Berg J.S.
        • Scaglia F.
        • Belmont J.
        • Bacino C.A.
        • Sahoo T.
        • et al.
        Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.
        Nat Genet. 2008; 40: 1466-1471
        • Mefford H.
        • Sharp A.J.
        • Baker C.
        • Itsara A.
        • Jiang Z.
        • Buysse K.
        • et al.
        Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
        N Engl J Med. 2008; 359: 1685-1699
        • Levinson D.F.
        • Duan J.
        • Oh S.
        • Wang K.
        • Sanders A.R.
        • Shi J.
        • et al.
        Copy number variants in schizophrenia: Confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications.
        Am J Psychiatry. 2011; 168: 302-316
        • Shinawi M.
        • Schaaf C.P.
        • Bhatt S.S.
        • Xia Z.
        • Patel A.
        • Cheung S.W.
        • et al.
        A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes.
        Nat Genet. 2009; 41: 1269-1271
        • Carvalho C.M.B.
        • Lupski J.R.
        Mechanisms underlying structural variant formation in genomic disorders.
        Nat Rev Genet. 2016; 17: 224-238
        • Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium
        Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways.
        Nat Neurosci. 2015; 18: 199-209
        • Parikshak N.N.
        • Gandal M.J.
        • Geschwind D.H.
        Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders.
        Nat Rev Genet. 2015; 16: 441-458
        • Pocklington A.J.
        • Rees E.
        • Walters J.T.R.
        • Han J.
        • Kavanagh D.H.
        • Chambert K.D.
        • et al.
        Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia.
        Neuron. 2015; 86: 1203-1214
        • Harrison P.J.
        Recent genetic findings in schizophrenia and their therapeutic relevance.
        J Psychopharmacol. 2015; 29: 85-96
        • Stessman H.A.
        • Bernier R.
        • Eichler E.E.
        A genotype-first approach to defining the subtypes of a complex disease.
        Cell. 2014; 156: 872-877
        • White J.
        • Beck C.R.
        • Harel T.
        • Posey J.E.
        • Jhangiani S.N.
        • Tang S.
        • et al.
        POGZ truncating alleles cause syndromic intellectual disability.
        Genome Med. 2016; 8: 3
        • Treadwell-Deering D.E.
        • Powell M.P.
        • Potocki L.
        Cognitive and behavioral characterization of the Potocki-Lupski syndrome (duplication 17p11.2).
        J Dev Behav Pediatr. 2010; 31: 137-143
        • Berg J.S.
        • Brunetti-Pierri N.
        • Peters S.U.
        • Kang S.-H.L.
        • Fong C.
        • Salamone J.
        • et al.
        Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region.
        Genet Med. 2007; 9: 427-441
        • Ben-Shachar S.
        • Lanpher B.
        • German J.R.
        • Qasaymeh M.
        • Potocki L.
        • Nagamani S.C.S.
        • et al.
        Microdeletion 15q13.3: A locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders.
        J Med Genet. 2009; 46: 382-388
        • Männik K.
        • Mägi R.
        • Macé A.
        • Cole B.
        • Guyatt A.L.
        • Shihab H.A.
        • et al.
        Copy number variations and cognitive phenotypes in unselected populations.
        JAMA. 2015; 313: 2044-2054
        • Lupski J.R.
        Clinical genomics: From a truly personal genome viewpoint.
        Hum Genet. 2016; 135: 591-601
      1. Scolnick EM (2010): 3rd Annual Report: January 2010—Executive Summary Version. Available at: https://www.broadinstitute.org/files/shared/psych/_StanleyCenterAnnualReportExecSum2009.pdf. Accessed August 14, 2016.

        • Bainbridge M.N.
        • Wiszniewski W.
        • Murdock D.R.
        • Friedman J.
        • Gonzaga-Jauregui C.
        • Newsham I.
        • et al.
        Whole-genome sequencing for optimized patient management.
        Sci Transl Med. 2011; 3: 87re83
        • Worthey E.A.
        • Mayer A.N.
        • Syverson G.D.
        • Helbling D.
        • Bonacci B.B.
        • Decker B.
        • et al.
        Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.
        Genet Med. 2011; 13: 255-262
        • Daly A.K.
        • Donaldson P.T.
        • Bhatnagar P.
        • Shen Y.
        • Pe’er I.
        • Floratos A.
        • et al.
        HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.
        Nat Genet. 2009; 41: 816-819
        • Loi S.
        • Haibe-Kains B.
        • Majjaj S.
        • Lallemand F.
        • Durbecq V.
        • Larsimont D.
        • et al.
        PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.
        Proc Natl Acad Sci U S A. 2010; 107: 10208-10213
        • Nathwani A.C.
        • Tuddenham E.G.D.
        • Rangarajan S.
        • Rosales C.
        • McIntosh J.
        • Linch D.C.
        • et al.
        Adenovirus-associated virus vector–mediated gene transfer in Hemophilia B.
        N Engl J Med. 2011; 365: 2357-2365
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
        American Psychiatric Association, Washington, DC1994
        • Malhotra D.
        • McCarthy S.
        • Michaelson J.J.
        • Vacic V.
        • Burdick K.E.
        • Yoon S.
        • et al.
        High frequencies of de novo CNVs in bipolar disorder and schizophrenia.
        Neuron. 2011; 72: 951-963
        • Grochowski C.M.
        • Gu S.
        • Yuan B.
        • TCW J.
        • Brennand K.J.
        • Sebat J.
        • et al.
        Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes.
        Hum Mutat. 2018; 39: 939-946
        • Mothet J.P.
        • Le Bail M.
        • Billard J.M.
        Time and space profiling of NMDA receptor co-agonist functions.
        J Neurochem. 2015; 135: 210-225
        • Olney J.W.
        • Farber N.B.
        Glutamate receptor dysfunction and schizophrenia.
        Arch Gen Psychiatry. 1995; 52: 998-1007
        • Coyle J.T.
        Glutamate and schizophrenia: Beyond the dopamine hypothesis.
        Cell Mol Neurobiol. 2006; 26: 365-384
        • Krystal J.H.
        • Anand A.
        • Moghaddam B.
        Effects of NMDA receptor antagonists: Implications for the pathophysiology of schizophrenia.
        Arch Gen Psychiatry. 2002; 59: 663-664
        • Goff D.C.
        • Coyle J.T.
        The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.
        Am J Psychiatry. 2001; 158: 1367-1377
        • Henderson G.
        • Johnson J.W.
        • Ascher P.
        Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor.
        J Physiol. 1990; 430: 189-212
        • Watson G.B.
        • Bolanowski M.A.
        • Baganoff M.P.
        • Deppeler C.L.
        • Lanthorn T.H.
        D-cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed in Xenopus oocytes.
        Brain Res. 1990; 510: 158-160
        • Overall J.
        • Gorham D.
        The Brief Psychiatric Rating Scale.
        Psychol Rep. 1962; 10: 799-812
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
        • Guy W.
        Clinical global impression (CGI) Scale.
        in: Guy W. ECDEU Assessment Manual for Psychopharmacology. Department of Health, Education, and Welfare, Rockville, MD1976: 125-126
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania: Reliability, validity and sensitivity.
        Br J Psychiatry. 1978; 133: 429-435
        • Posner K.
        • Brent D.
        • Lucas C.
        • Gould M.
        • Stanley B.
        • Brown G.
        • et al.
        Columbia–Suicide Severity Rating Scale (C-SSRS).
        Research Foundation for Mental Hygiene, New York2009
        • Simpson G.M.
        • Angus J.W.
        A rating scale for extrapyramidal side effects.
        Acta Psychiatr Scand. 1970; 212: 11-19
        • Guy W.
        Abnormal Involuntary Movement Scale (AIMS).
        in: Guy W. ECDEU Assessment Manual for Psychopharmacology, rev. Department of Health, Education, and Welfare, Rockville, MD1976: 118-119
        • Hahn R.G.
        Dose-dependent half-life of glycine.
        Urol Res. 1993; 21: 289-291
        • Heresco-Levy U.
        • Javitt D.C.
        • Ermilov M.
        • Mordel C.
        • Silipo G.
        • Lichtenstein M.
        Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 29-36
        • Heresco-Levy U.
        • Ermilov M.
        • Lichtenberg P.
        • Bar G.
        • Javitt D.C.
        High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia.
        Biol Psychiatry. 2004; 55: 165-171
        • Goff D.C.
        • Tsai G.
        • Levitt J.
        • Amico E.
        • Manoach D.
        • Schoenfeld D.
        • et al.
        A placebo-controlled trial of D-cycloserine added to conventional neuroleptics in patients with schizophrenia.
        Arch Gen Psychiatry. 1999; 56: 21-27
        • Goff D.C.
        • Tsai G.
        • Manoach D.S.
        • Flood J.
        • Darby D.G.
        • Coyle J.T.
        D-cycloserine added to clozapine for patients with schizophrenia.
        Am J Psychiatry. 1996; 153: 1628-1630
        • Hanngren H.
        • Hansson E.
        • Ullberg S.
        An autoradiographic study of the distribution of tritium-labeled cycloserine in mice.
        Antibiot Chemother. 1961; 12: 46-54
        • Hood W.F.
        • Compton R.P.
        • Monahan J.B.
        D-cycloserine: A ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics.
        Neurosci Lett. 1989; 98: 91-95
        • Emmett M.R.
        • Mick S.J.
        • Cker J.A.
        • Rao T.S.
        • Iyengar S.
        • Wood P.L.
        Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor site in vivo.
        Neuropharmacology. 1991; 30: 1167-1171
        • Chessell I.P.
        • Procter A.W.
        • Francis P.T.
        • Bowen D.M.
        D-cycloserine, a putative cognitive enhancer, facilitates activation of the N-methyI-D-aspartate receptor-ionophore complex in Alzheimer brain.
        Brain Res. 1991; 565: 345-348
        • Goff D.C.
        • Herz L.
        • Posever T.
        • Shih V.
        • Tsai G.
        • Henderson D.
        • et al.
        A six-month, placebo-controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients.
        Psychopharmacology (Berl). 2005; 179: 144-150
        • Gottlieb J.D.
        • Cather C.
        • Shanahan M.
        • Creedon T.
        • Macklin E.A.
        • Goff D.C.
        D-cycloserine facilitation of cognitive behavioral therapy for delusions in schizophrenia.
        Schizophr Res. 2011; 131: 69-74
        • Edgington E.S.
        • Onghena P.
        Randomization Tests.
        4th ed. Chapman & Hall, London2007
        • Cook S.P.
        • Galve-Roperh I.
        • Martínez del Pozo A.
        • Rodríguez-Crespo I.
        Direct calcium binding results in activation of brain serine racemase.
        J Biol Chem. 2002; 277: 27782-27792
        • Freudenreich O.
        • Goff D.C.
        Antipsychotic combination therapy in schizophrenia: A review of efficacy and risks of current combinations.
        Acta Psychiatr Scand. 2002; 106: 323-330
        • Cooper G.M.
        • Shendure J.
        Needles in stacks of needles: Finding disease-causal variants in a wealth of genomic data.
        Nat Rev Genet. 2011; 12: 628-640
        • Buchanan J.A.
        • Scherer S.W.
        Contemplating effects of genomic structural variation.
        Genet Med. 2008; 10: 639-647
        • Perakslis E.D.
        • Kohane I.S.
        Treating the enigmatic “exceptional responders” as patients with undiagnosed diseases.
        Sci Transl Med. 2016; 8: 340ed348
        • Goff D.C.
        Bitopertin: The good news and bad news.
        JAMA Psychiatry. 2014; 71: 621-622
        • Chau N.G.
        • Lorch J.H.
        Exceptional responders inspire change: Lessons for drug development from the bedside to the bench and back.
        Oncologist. 2015; 20: 699-701
        • Iyer G.
        • Hanrahan A.J.
        • Milowsky M.I.
        • Al-Ahmadie H.
        • Scott S.N.
        • Janakiraman M.
        • et al.
        Genome sequencing identifies a basis for everolimus sensitivity.
        Science. 2012; 338: 221
        • Petrovski S.
        • Wang Q.
        • Heinzen E.L.
        • Allen A.S.
        • Goldstein D.B.
        Genic intolerance to functional variation and the interpretation of personal genomes.
        PLoS Genet. 2013; 9e1003709
        • Liu P.
        • Gelowani V.
        • Zhang F.
        • Drory V.E.
        • Ben-Shachar S.
        • Roney E.
        • et al.
        Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication.
        Am J Hum Genet. 2014; 94: 462-469
        • Ramocki M.B.
        • Peters S.U.
        • Tavyev Y.J.
        • Zhang F.
        • Carvalho C.M.B.
        • Schaaf C.P.
        • et al.
        Autism and other neuropsychiatric symptoms are prevalent in individuals with MECP2 duplication syndrome.
        Ann Neurol. 2009; 66: 771-782
        • Carvalho C.M.B.
        • Ramocki M.B.
        • Pehliva D.
        • Franco L.M.
        • Gonzaga-Jauregui C.
        • Fang P.
        • et al.
        Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.
        Nat Genet. 2011; 43: 1074-1081
        • Tsai G.E.
        • Lin P.Y.
        Strategies to enhance N-methyl-D-aspartate receptor-mediated neurotransmission in schizophrenia: A critical review and meta-analysis.
        Curr Pharm Des. 2010; 16: 522-537
        • Singh S.P.
        • Singh V.
        Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia.
        CNS Drugs. 2011; 25: 859-885
        • Kirov G.
        • Pocklington A.J.
        • Holmans P.
        • Ivanov D.
        • Ikeda M.
        • Ruderfer D.
        • et al.
        De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.
        Mol Psychiatry. 2012; 17: 142-153
        • Raychaudhuri S.
        • Plenge R.M.
        • Rossin E.J.
        • Ng A.C.Y.
        • International Schizophrenia Consortium
        • Purcell S.M.
        • et al.
        Identifying relationships among genomic disease regions: Predicting genes at pathogenic SNP associations and rare deletions.
        PLoS Genet. 2009; 5e1000534
        • Hamdan F.F.
        • Gauthier J.
        • Araki Y.
        • Lin D.-T.
        • Yoshizawa Y.
        • Higashi K.
        • et al.
        Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
        Am J Hum Genet. 2011; 88: 306-316
        • Elia J.
        • Gai X.
        • Xie H.M.
        • Perin J.C.
        • Geiger E.
        • Glessner J.T.
        • et al.
        Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes.
        Mol Psychiatry. 2010; 15: 637-646
        • Yu Y.
        • Lin Y.
        • Takasaki Y.
        • Wang C.
        • Kimura H.
        • Xing J.
        • et al.
        Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility.
        Transl Psychiatry. 2018; 8: 12
        • Chang X.
        • Lima L.d.A.
        • Liu Y.
        • Li J.
        • Li Q.
        • Sleiman P.M.A.
        • et al.
        Common and rare genetic risk factors converge in protein interaction networks underlying schizophrenia.
        Front Genet. 2018; 9: 434
        • Kathiresan S.
        Developing medicines that mimic the natural successes of the human genome: Lessons from NPC1L1, HMGCR, PCSK9, APOC3, and CETP.
        J Am Coll Cardiol. 2015; 65: 1562-1566
        • Farrell M.
        • Lichtenstein M.
        • Crowley J.J.
        • Filmyer D.M.
        • Lázaro-Muñoz G.
        • Shaughnessy R.A.
        • et al.
        Developmental delay, treatment-resistant psychosis, and early-onset dementia in a man with 22q11 deletion syndrome and Huntington’s disease.
        Am J Psychiatry. 2018; 175: 400-407
        • Alexandre C.
        • Chaumette B.
        • Martinez G.
        • Christa L.
        • Dupont J.-M.
        • Kebir O.
        • et al.
        Paradoxical improvement of schizophrenic symptoms by a dopaminergic agonist: An example of personalized psychiatry in a CNV carrying patient.
        Biol Psychiatry. 2016; 80: e21-e23
        • Sakata Y.
        • Owada Y.
        • Sato K.
        • Kojima K.
        • Hisanaga K.
        • Shinka T.
        • et al.
        Structure and expression of the glycine cleavage system in rat central nervous system.
        Brain Res Mol Brain Res. 2001; 94: 119-130
        • Wolosker H.
        • Balu D.T.
        • Coyle J.T.
        The rise and fall of the D-serine-mediated gliotransmission hypothesis.
        Trends Neurosci. 2016; 39: 712-721
        • Kessler M.
        • Terramani T.
        • Lynch G.
        • Baudry M.
        A glycine site associated with N-methyl-D-aspartic acid receptors: Characterization and identification of a new class of antagonists.
        J Neurochem. 1989; 52: 1319-1328
        • Parsons C.G.
        • Danysz W.
        • Quack G.
        • Hartmann S.
        • Lorenz B.
        • Wollenburg C.
        • et al.
        Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: Electrophysiological, biochemical and behavioral characterization.
        J Pharmacol Exp Ther. 1997; 283: 1264-1275
        • Birch P.J.
        • Grossman C.J.
        • Hayes A.G.
        Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor.
        Eur J Pharmacol. 1988; 154: 85-87
        • Girirajan S.
        • Brkanac Z.
        • Coe B.P.
        • Baker C.
        • Vives L.
        • Vu T.H.
        • et al.
        Relative burden of large CNVs on a range of neurodevelopmental phenotypes.
        PLoS Genet. 2011; 7e1002334
        • O’Roak B.J.
        • Deriziotis P.
        • Lee C.
        • Vives L.
        • Schwartz J.J.
        • Girirajan S.
        • et al.
        Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
        Nat Genet. 2011; 43: 585-589
        • Dravid S.M.
        • Burger P.B.
        • Prakash A.
        • Geballe M.T.
        • Yadav R.
        • Le P.
        • et al.
        Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors.
        J Neurosci. 2010; 30: 2741-2754
        • Baran H.
        • Kepplinger B.
        D-cycloserine lowers kynurenic acid formation—New mechanism of action.
        Eur Neuropsychopharmacol. 2014; 24: 639-644
        • Lopes C.
        • Pereira E.F.
        • Wu H.Q.
        • Purushottamachar P.
        • Njar V.
        • Schwarcz R.
        • et al.
        Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.
        J Pharmacol Exp Ther. 2007; 322: 48-58
        • Hilmas C.
        • Pereira E.F.
        • Alkondon M.
        • Rassoulpour A.
        • Schwarcz R.
        • Albuquerque E.X.
        The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: Physiopathological implications.
        J Neurosci. 2001; 21: 7463-7473
        • Wu H.Q.
        • Pereira E.F.
        • Bruno J.P.
        • Pellicciari R.
        • Albuquerque E.X.
        • Schwarcz R.
        The astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex.
        J Mol Neurosci. 2010; 40: 204-210
        • Albuquerque E.X.
        • Schwarcz R.
        Kynurenic acid as an antagonist of α7 nicotinic acetylcholine receptors in the brain: Facts and challenges.
        Biochem Pharmacol. 2013; 85: 1027-1032
        • Freedman R.
        • Coon H.
        • Myles-Worsley M.
        • Orr-Urtreger A.
        • Olincy A.
        • Davis A.
        • et al.
        Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.
        Proc Natl Acad Sci U S A. 1997; 94: 587-592
        • Xu J.
        • Pato M.
        • Torre C.
        • Medeiros H.
        • Carvalho C.
        • Basile V.
        • et al.
        Evidence of linkage disequilibrium between the alpha 7-nicotinic receptor gene (CHRNA7) locus and schizophrenia in Azorean families.
        Am J Med Genet. 2001; 105: 669-674
        • Albuquerque E.X.
        • Pereira E.F.
        • Alkondon M.
        • Rogers S.W.
        Mammalian nicotinic acetylcholine receptors: From structure to function.
        Physiol Rev. 2009; 89: 73-120
        • MacDonald J.F.
        • Jackson M.F.
        • Beazely M.A.
        Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors.
        Crit Rev Neurobiol. 2006; 18: 71-84
        • Xu B.
        • Roos J.W.
        • Levy S.
        • van Rensburg E.J.
        • Gogos J.A.
        • Karayiorgou M.
        Strong association of de novo copy number mutations with sporadic schizophrenia.
        Nat Genet. 2008; 40: 880-885
        • Xu B.
        • Woodroffe A.
        • Rodriguez-Murillo L.
        • Roos J.L.
        • van Rensburg E.J.
        • Abecasis G.R.
        • et al.
        Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans.
        Proc Natl Acad Sci U S A. 2009; 106: 16746-16751
        • Georgieva L.
        • Rees E.
        • Moran J.L.
        • Chambert K.D.
        • Milanova V.
        • Craddock N.
        • et al.
        De novo CNVs in bipolar affective disorder and schizophrenia.
        Hum Mol Genet. 2014; 23: 6677-6682
        • Schwarcz R.
        • Bruno J.P.
        • Muchowski P.J.
        • Wu H.-Q.
        Kynurenines in the mammalian brain: When physiology meets pathology.
        Nat Rev Neurosci. 2012; 13: 465-477
        • Linderholm K.R.
        • Alm M.T.
        • Larsson M.K.
        • Olsson S.K.
        • Goiny M.
        • Hajos M.
        • et al.
        Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons.
        Neuropharmacology. 2016; 102: 42-47
        • Potter M.C.
        • Elmer G.I.
        • Bergeron R.
        • Albuquerque E.X.
        • Guidetti P.
        • Wu H.Q.
        • et al.
        Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior.
        Neuropsychopharmacology. 2010; 35: 1734-1742
        • Kozak R.
        • Campbell B.M.
        • Strick C.A.
        • Horner W.
        • Hoffmann W.E.
        • Kiss T.
        • et al.
        Reduction of brain kynurenic acid improves cognitive function.
        J Neurosci. 2014; 34: 10592-10602
        • Alexander K.S.
        • Wu H.-Q.
        • Schwarcz R.
        • Bruno J.P.
        Acute elevations of brain kynurenic acid impair cognitive flexibility: Normalization by the alpha 7 positive modulator galantamine.
        Psychopharmacology (Berl). 2012; 220: 627-637
        • Williams J.B.
        • Mallorga P.J.
        • Conn P.J.
        • Pettibone D.J.
        • Sur C.
        Effects of typical and atypical antipsychotics on human glycine transporters.
        Schizophr Res. 2004; 71: 103-112
        • Goff D.C.
        • Henderson D.C.
        • Evins A.E.
        • Amico E.
        A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia.
        Biol Psychiatry. 1999; 45: 512-514
        • Tanahashi S.
        • Yamamura S.
        • Nakagawa M.
        • Motomura E.
        • Okada M.
        Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes.
        Br J Pharmacol. 2012; 165: 1543-1555
        • Evins A.E.
        • Amico E.
        • Posever T.A.
        • Toker R.
        • Goff D.C.
        D-cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia.
        Schizophr Res. 2002; 56: 19-23
        • Heresco-Levy U.
        • Ermilov M.
        • Shimoni J.
        • Shapira B.
        • Silipo G.
        • Javitt D.C.
        Placebo-controlled trial of D-cycloserine added to convential neuroleptics, olanzapine, or risperidone in schizophrenia.
        Am J Psychiatry. 2002; 159: 480-482
        • Potkin S.G.
        • Jin Y.
        • Bunney B.G.
        • Costa J.
        • Gulasekaram B.
        Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia.
        Am J Psychiatry. 1999; 156: 145-147
        • Evins A.E.
        • Fitzgerald S.M.
        • Wine L.
        • Rosselli R.
        • Goff D.C.
        Placebo-controlled trial of glycine added to clozapine in schizophrenia.
        Am J Psychiatry. 2000; 157: 826-828
        • Tsai G.
        • Yang P.
        • Chung L.C.
        • Tsai C.W.
        • Coyle J.T.
        D-serine added to clozapine for the treatment of schizophrenia.
        Am J Psychiatry. 1999; 156: 1822-1825
        • Heresco-Levy U.
        • Javitt D.C.
        • Ermilov M.
        • Mordel C.
        • Horowitz A.
        • Kelly D.
        Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.
        Br J Psychiatry. 1996; 169: 610-617
        • Lin C.-H.
        • Lin C.-H.
        • Chang Y.-C.
        • Huang Y.-J.
        • Chen P.-W.
        • Yang H.-T.
        • et al.
        Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: A randomized, double-blind, placebo-controlled trial.
        Biol Psychiatry. 2018; 84: 422-432
        • Goff D.C.
        D-cycloserine in schizophrenia: New strategies for improving clinical outcomes by enhancing plasticity.
        Curr Neuropharmacol. 2017; 15: 21-34

      Linked Article