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.

Trial registration: ClinicalTrials.gov NCT01720316 NCT02304432.

Keywords: Bipolar disorder; Copy number variant; Genetics; Glycine decarboxylase; NMDAR hypofunction; Schizophrenia.

Conflict of interest statement

Disclosures:

JTC reports consulting relationships with Concert Pharm and BVF Partners. Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs clinical genomics studies including chromosomal microarray analysis and clinical exome sequencing. J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc. and is a co-inventor on multiple United States 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.

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

Figures

Figure 1.

Structure of the 9p24.1 duplication-triplication (A) and pedigree (B).

Figure 2.

Changes in total Brief Psychiatric Rating Scale (BPRS) score as a function of treatment with glycine or placebo in subject 5459 (A) and subject 3363 (B) during the short-term trials. Changes in total BPRS score during the interval between the short-term and long-term glycine trials and during long-term glycine treatment in subject 5459 (C) and subject 3363 (D).

Figure 3.

Changes in plasma glycine level as a function of short-term treatment with glycine or placebo in subject 5459 (A) and subject 3363 (B). Changes in plasma L-serine level as a function of short-term treatment with glycine or placebo in subject 5459 (C) and subject 3363 (D). All data are from the acute trials.

Figure 4.

Changes in total Brief Psychiatric Rating Scale (BPRS) score as a function of treatment with DCS or placebo in subject 5459 (A) and subject 3363 (B).

Figure 5.

Changes in plasma DCS level as a function of treatment with DCS or placebo in subject 5459 (A) and subject 3363 (B). Changes in plasma total serine level as a function of short-term treatment with DCS or placebo in subject 5459 (C) and subject 3363 (D).