@article{ada80d4dde5647c9a51cc6591bb34c5e,
title = "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 = "Bipolar disorder, Copy number variant, Genetics, Glycine decarboxylase, NMDAR hypofunction, Schizophrenia",
author = "Bodkin, {J. Alexander} and Coleman, {Michael J.} and Godfrey, {Laura J.} and Carvalho, {Claudia M.B.} and Morgan, {Charity J.} and Suckow, {Raymond F.} and Thea Anderson and Dost {\"O}ng{\"u}r and Kaufman, {Marc J.} and Lewandowski, {Kathryn E.} and Siegel, {Arthur J.} and Elliot Waldstreicher and Grochowski, {Christopher M.} and Javitt, {Daniel C.} and Dan Rujescu and Scott Hebbring and Richard Weinshilboum and Rodriguez, {Stephanie Burgos} and Colette Kirchhoff and Timothy Visscher and Alexander Vuckovic and Allison Fialkowski and Shane McCarthy and Dheeraj Malhotra and Jonathan Sebat and Goff, {Donald C.} and Hudson, {James I.} and Lupski, {James R.} and Coyle, {Joseph T.} and Uwe Rudolph and Levy, {Deborah L.}",
note = "Funding Information: We thank the individuals who participated in this trial. Their investment as collaborators was essential for the successful completion of these studies. The studies were done entirely on an outpatient basis, mostly by long distance, and required very substantial (and at times onerous) procedural and clinical oversight cooperation from these individuals. We thank Kim Holleran and Mytsie Thevenin for assisting in the pharmacy preparations and thank Jerry Crisp, Esther Vance, and Chris Tabor for clinical laboratory support. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported in part by National Institute of Mental Health Grant No. 1U24MH081810 (to C.M. Lajonchere). We also express special appreciation to Thomas Insel for having had the foresight to support this work. We dedicate this work to the memory of Philip S. Holzman, whose vision inspired the McLean Hospital Psychology Research Laboratory{\textquoteright}s focus on family and genetic studies, and to the memories of the loved ones of the subjects and researchers who passed away during the course of this work. Funding Information: This work was supported in part by National Institutes of Health (NIH) Grant Nos. R21 MH097470 and R21 MH105732 (to DLL), the Fuller Foundation (to DLL), the Ellison Foundation (to DLL, CMBC, and JRL), Anonymous Foundation (to DLL and JS), the Carmela and Menachem Abraham Fund (to DLL), and Team Daniel (DLL), NIH Grant No. R21 MH104505 (to UR), predoctoral National Heart, Lung, and Blood Institute (NHLBI) Training Grant No. T32HL079888 (to AF), National Institute of Neurological Disorders and Stroke Grant Nos. R01NS058529 and R35NS105078 (to JRL), National Institute of General Medical Sciences Grant No. R01GM106373 (to JRL), and a joint National Human Genome Research Institute/NHLBI grant (No. UM1HG006542 ) to the Baylor Hopkins Center for Mendelian Genomics (to JRL). Funding Information: This work was supported in part by National Institutes of Health (NIH) Grant Nos. R21 MH097470 and R21 MH105732 (to DLL), the Fuller Foundation (to DLL), the Ellison Foundation (to DLL, CMBC, and JRL), Anonymous Foundation (to DLL and JS), the Carmela and Menachem Abraham Fund (to DLL), and Team Daniel (DLL), NIH Grant No. R21 MH104505 (to UR), predoctoral National Heart, Lung, and Blood Institute (NHLBI) Training Grant No. T32HL079888 (to AF), National Institute of Neurological Disorders and Stroke Grant Nos. R01NS058529 and R35NS105078 (to JRL), National Institute of General Medical Sciences Grant No. R01GM106373 (to JRL), and a joint National Human Genome Research Institute/NHLBI grant (No. UM1HG006542) to the Baylor Hopkins Center for Mendelian Genomics (to JRL). We thank the individuals who participated in this trial. Their investment as collaborators was essential for the successful completion of these studies. The studies were done entirely on an outpatient basis, mostly by long distance, and required very substantial (and at times onerous) procedural and clinical oversight cooperation from these individuals. We thank Kim Holleran and Mytsie Thevenin for assisting in the pharmacy preparations and thank Jerry Crisp, Esther Vance, and Chris Tabor for clinical laboratory support. We gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families. AGRE is a program of Autism Speaks and is supported in part by National Institute of Mental Health Grant No. 1U24MH081810 (to C.M. Lajonchere). We also express special appreciation to Thomas Insel for having had the foresight to support this work. We dedicate this work to the memory of Philip S. Holzman, whose vision inspired the McLean Hospital Psychology Research Laboratory's focus on family and genetic studies, and to the memories of the loved ones of the subjects and researchers who passed away during the course of this work. JTC reports consulting relationships with Concert Pharm and BVF Partners. Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical genomics studies including chromosomal microarray analysis and clinical exome sequencing. JRL serves on the Scientific Advisory Board of Baylor Genetics. JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen Inc. and is a coinventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The other authors report no biomedical financial interests or potential conflicts of interest. ClinicalTrials.gov: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders; https://clinicaltrials.gov/ct2/show/NCT01720316; NCT01720316; Targeting a Genetic Mutation in Glycine Metabolism With D-cycloserine (DCS); https://clinicaltrials.gov/ct2/show/NCT02304432; NCT02304432. Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",
year = "2019",
month = oct,
day = "1",
doi = "10.1016/j.biopsych.2019.04.031",
language = "English (US)",
volume = "86",
pages = "523--535",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "7",
}