Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics.
Major depressive disorder (MDD) is a common psychiatric disease. Selective serotonin reuptake inhibitors (SSRIs) are an important class of drugs used in the treatment of MDD. However, many patients do not respond adequately to SSRI therapy. We used a pharmacometabolomics-informed pharmacogenomic research strategy to identify citalopram/escitalopram treatment outcome biomarkers. Metabolomic assay of plasma samples from 20 escitalopram remitters and 20 nonremitters showed that glycine was negatively associated with treatment outcome (P = 0.0054). This observation was pursued by genotyping tag single-nucleotide polymorphisms (SNPs) for genes encoding glycine synthesis and degradation enzymes, using 529 DNA samples from SSRI-treated MDD patients. The rs10975641 SNP in the glycine dehydrogenase (GLDC) gene was associated with treatment outcome phenotypes. Genotyping for rs10975641 was carried out in 1,245 MDD patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and its presence was significant (P = 0.02) in DNA taken from these patients. These results highlight a possible role for glycine in SSRI response and illustrate the use of pharmacometabolomics to "inform" pharmacogenomics.
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Y
Y
Ji
S
S
Hebbring
H
H
Zhu
G D
GD
Jenkins
J
J
Biernacka
K
K
Snyder
M
M
Drews
O
O
Fiehn
Z
Z
Zeng
D
D
Schaid
D A
DA
Mrazek
R
R
Kaddurah-Daouk
R M
RM
Weinshilboum
D054316:Biomarkers, Pharmacological / Q000097:blood; D002460:Cell Line; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015283:Citalopram / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003865:Major Depressive Disorder / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D056726:Genetic Association Studies; D005998:Glycine / Q000097:blood* / Q000378:metabolism; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D055442:Metabolome / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
D054316:Biomarkers, Pharmacological; D015283:Citalopram; D004268:DNA-Binding Proteins; D005998:Glycine; D050841:Glycine Dehydrogenase (Decarboxylating); D009687:Nuclear Proteins; D017367:Selective Serotonin Reuptake Inhibitors