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

Adult Affective Disorders, Psychotic / genetics DNA Copy Number Variations Double-Blind Method Drug Synergism Drug Therapy, Combination Female Glycine / administration & dosage Glycine Agents / administration & dosage Glycine Dehydrogenase (Decarboxylating) / genetics Humans Male Proof of Concept Study Psychotic Disorders / genetics Psychotropic Drugs / administration & dosage Random Allocation Receptors, N-Methyl-D-Aspartate Single-Case Studies as Topic
Bipolar disorder Copy number variant Genetics Glycine decarboxylase NMDAR hypofunction Schizophrenia

Journal

Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264

Informations de publication

Date de publication:
01 10 2019
Historique:
received: 21 09 2018
revised: 17 04 2019
accepted: 17 04 2019
pubmed: 8 7 2019
medline: 2 7 2020
entrez: 8 7 2019
Statut: ppublish

Résumé

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

Sections du résumé

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.

Identifiants

DOI: 10.1016/j.biopsych.2019.04.031 PMID: 31279534 PMC: PMC6745274
pubmed: 31279534
pii: S0006-3223(19)31330-7
doi: 10.1016/j.biopsych.2019.04.031
pmc: PMC6745274
mid: NIHMS1528958
pii:
doi:

Substances chimiques

Glycine Agents 0
Psychotropic Drugs 0
Receptors, N-Methyl-D-Aspartate 0
Glycine Dehydrogenase (Decarboxylating) EC 1.4.4.2
Glycine TE7660XO1C

Banques de données

ClinicalTrials.gov
['NCT01720316', 'NCT02304432']

Types de publication

Case Reports Clinical Trial Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

523-535

Subventions

Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM106373
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH105732
Pays : United States
Organisme : NIMH NIH HHS
ID : U24 MH081810
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS058529
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH097470
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL079888
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH104505
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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Auteurs

J Alexander Bodkin (JA)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Michael J Coleman (MJ)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Laura J Godfrey (LJ)

McLean Hospital, Belmont, Massachusetts.

Claudia M B Carvalho (CMB)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Charity J Morgan (CJ)

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: cjmorgan@uab.edu.

Raymond F Suckow (RF)

New York State Psychiatric Institute, New York.

Thea Anderson (T)

McLean Hospital, Belmont, Massachusetts.

Dost Öngür (D)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Marc J Kaufman (MJ)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Kathryn E Lewandowski (KE)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Arthur J Siegel (AJ)

McLean Hospital, Belmont, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Elliot Waldstreicher (E)

Deceased.

Christopher M Grochowski (CM)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Daniel C Javitt (DC)

Columbia University Medical Center, New York; Nathan Kline Institute, Orangeburg, New York.

Dan Rujescu (D)

Department of Psychiatry, Psychotherapy, and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.

Scott Hebbring (S)

Center for Human Genetics, Marshfield Clinic Research Institute, Marshfield, Wisconsin.

Richard Weinshilboum (R)

Mayo Clinic, Rochester, Minnesota.

Stephanie Burgos Rodriguez (SB)

McLean Hospital, Belmont, Massachusetts.

Colette Kirchhoff (C)

Bozeman-Deaconess Hospital, Bozeman, Montana.

Timothy Visscher (T)

Student Health Service, Montana State University, Bozeman, Montana.

Alexander Vuckovic (A)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Allison Fialkowski (A)

Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama.

Shane McCarthy (S)

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

Dheeraj Malhotra (D)

Hoffman-LaRoche Ltd., Basel, Switzerland.

Jonathan Sebat (J)

Department of Psychiatry, University of California, San Diego, La Jolla, California.

Donald C Goff (DC)

Department of Psychiatry, New York University Langone Medical Center, New York; Nathan Kline Institute, Orangeburg, New York.

James I Hudson (JI)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

James R Lupski (JR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Joseph T Coyle (JT)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Uwe Rudolph (U)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Deborah L Levy (DL)

McLean Hospital, Belmont, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Targeted Treatment of Individuals With...
questionsmedicales.fr › Troubles mentaux › Schizophrénie et troubles avec traits psychotiques › Troubles affectifs psychotiques › Targeted Treatment of Individuals With...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Variation structurale du génome › Variations de nombre de copies de segment d'ADN › Targeted Treatment of Individuals With...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Méthodologie en recherche épidémiologique › Méthode en double aveugle › Targeted Treatment of Individuals With...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Interactions médicamenteuses › Synergie des médicaments › Targeted Treatment of Individuals With...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Targeted Treatment of Individuals With...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Glycine › Targeted Treatment of Individuals With...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Agents neuromédiateurs › Agents glycinergiques › Targeted Treatment of Individuals With...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH2 group donors › Amino-acid oxidoreductases › Complexe de la glycine décarboxylase › Glycine dehydrogenase (decarboxylating) › Targeted Treatment of Individuals With...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeted Treatment of Individuals With...
questionsmedicales.fr › Disciplines des sciences naturelles › Science › Recherche › Étude de validation de principe › Targeted Treatment of Individuals With...
questionsmedicales.fr › Troubles mentaux › Schizophrénie et troubles avec traits psychotiques › Troubles psychotiques › Targeted Treatment of Individuals With...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents du système nerveux central › Psychoanaleptiques › Targeted Treatment of Individuals With...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Méthodologie en recherche épidémiologique › Répartition aléatoire › Targeted Treatment of Individuals With...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs ionotropes du glutamate › Récepteurs du N-méthyl-D-aspartate › Targeted Treatment of Individuals With...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études cliniques comme sujet › Essais cliniques comme sujet › Études de cas unique comme sujet › Targeted Treatment of Individuals With...