J Alexander Bodkin1, Michael J Coleman1, Laura J Godfrey2, Claudia M B Carvalho3, Charity J Morgan4, Raymond F Suckow5, Thea Anderson2, Dost Öngür1, Marc J Kaufman1, Kathryn E Lewandowski1, Arthur J Siegel6, Elliot Waldstreicher7, Christopher M Grochowski3, Daniel C Javitt8, Dan Rujescu9, Scott Hebbring10, Richard Weinshilboum11, Stephanie Burgos Rodriguez2, Colette Kirchhoff12, Timothy Visscher13, Alexander Vuckovic1, Allison Fialkowski14, Shane McCarthy15, Dheeraj Malhotra16, Jonathan Sebat17, Donald C Goff18, James I Hudson1, James R Lupski3, Joseph T Coyle1, Uwe Rudolph1, Deborah L Levy1. 1. McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. 2. McLean Hospital, Belmont, Massachusetts. 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. 4. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: cjmorgan@uab.edu. 5. New York State Psychiatric Institute, New York. 6. McLean Hospital, Belmont, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. 7. Deceased. 8. Columbia University Medical Center, New York; Nathan Kline Institute, Orangeburg, New York. 9. Department of Psychiatry, Psychotherapy, and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany. 10. Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, Wisconsin. 11. Mayo Clinic, Rochester, Minnesota. 12. Bozeman-Deaconess Hospital, Bozeman, Montana. 13. Student Health Service, Montana State University, Bozeman, Montana. 14. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama. 15. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. 16. Hoffman-LaRoche Ltd., Basel, Switzerland. 17. Department of Psychiatry, University of California, San Diego, La Jolla, California. 18. Department of Psychiatry, New York University Langone Medical Center, New York; Nathan Kline Institute, Orangeburg, New York.
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.
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.
Authors: J Xu; M T Pato; C D Torre; H Medeiros; C Carvalho; V S Basile; A Bauer; A Dourado; J Valente; M J Soares; A A Macedo; I Coelho; C P Ferreira; M H Azevedo; F Macciardi; J L Kennedy; C N Pato Journal: Am J Med Genet Date: 2001-12-08
Authors: Y Sakata; Y Owada; K Sato; K Kojima; K Hisanaga; T Shinka; Y Suzuki; Y Aoki; J Satoh; H Kondo; Y Matsubara; S Kure Journal: Brain Res Mol Brain Res Date: 2001-10-19
Authors: Tim B Bigdeli; Ayman H Fanous; Yuli Li; Nallakkandi Rajeevan; Frederick Sayward; Giulio Genovese; Rishab Gupta; Krishnan Radhakrishnan; Anil K Malhotra; Ning Sun; Qiongshi Lu; Yiming Hu; Boyang Li; Quan Chen; Shrikant Mane; Perry Miller; Kei-Hoi Cheung; Raquel E Gur; Tiffany A Greenwood; David L Braff; Eric D Achtyes; Peter F Buckley; Michael A Escamilla; Douglas Lehrer; Dolores P Malaspina; Steven A McCarroll; Mark H Rapaport; Marquis P Vawter; Michele T Pato; Carlos N Pato; Hongyu Zhao; Thomas R Kosten; Mary Brophy; Saiju Pyarajan; Yunling Shi; Timothy J O'Leary; Theresa Gleason; Ronald Przygodzki; Sumitra Muralidhar; J Michael Gaziano; Grant D Huang; John Concato; Larry J Siever; Mihaela Aslan; Philip D Harvey Journal: Schizophr Bull Date: 2021-03-16 Impact factor: 9.306