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

Bodkin, J. A., Coleman, M. J., Godfrey, L. J., Carvalho, C. M. B., Morgan, C. J., Suckow, R. F., Anderson, T., Ongur, D., Kaufman, M. J., Lewandowski, K. E., Siegel, A. J., Waldstreicher, E., Grochowski, C. M., Javitt, D. C., Rujescu, D., Hebbring, S., Weinshilboum, R., Rodriguez, S. B., Kirchhoff, C., Visscher, T., Vuckovic, A., Fialkowski, A., McCarthy, S., Malhotra, D., Sebat, J., Goff, D. C., Hudson, J. I., Lupski, J. R., Coyle, J. T., Rudolph, U., Levy, D. L. (May 2019) Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene. Biol Psychiatry, 86 (7). pp. 523-535. ISSN 0006-3223

URL: https://www.ncbi.nlm.nih.gov/pubmed/31279534
DOI: 10.1016/j.biopsych.2019.04.031

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.

Item Type: Paper
Subjects: diseases & disorders > mental disorders > schizophrenia
diseases & disorders > mental disorders > personality disorders > bipolar disorder
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants
CSHL Authors:
Communities: CSHL labs > Sebat lab
Depositing User: Matthew Dunn
Date: 9 May 2019
Date Deposited: 05 Aug 2019 15:46
Last Modified: 07 Oct 2019 19:32
Related URLs:
URI: https://repository.cshl.edu/id/eprint/38146

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