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.

• Authors: J Alexander Bodkin, Michael J Coleman, Laura J Godfrey, Claudia M B Carvalho, Charity J Morgan, Raymond F Suckow, Thea Anderson, Dost Öngür, Marc J Kaufman, Kathryn E Lewandowski, Arthur J Siegel, Elliot Waldstreicher, Christopher M Grochowski, Daniel C Javitt, Dan Rujescu, Scott Hebbring, Richard Weinshilboum, Stephanie Burgos Rodriguez, Colette Kirchhoff, Timothy Visscher, Alexander Vuckovic, Allison Fialkowski, Shane McCarthy, Dheeraj Malhotra, Jonathan Sebat, Donald C Goff, James I Hudson, James R Lupski, Joseph T Coyle, Uwe Rudolph, Deborah L Levy
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 86 Issue 7 Pg. 523-535 (10 01 2019) ISSN: 1873-2402 [Electronic] United States
• PMID: 31279534 (Publication Type: Case Reports, Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Glycine Agents
• Psychotropic Drugs
• Receptors, N-Methyl-D-Aspartate
• Glycine Dehydrogenase (Decarboxylating)
• Glycine

Topics

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