Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics

Clin Pharmacol Ther. 2011 Jan;89(1):97-104. doi: 10.1038/clpt.2010.250. Epub 2010 Nov 24.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Biomarkers, Pharmacological / blood
  • Cell Line
  • Chromosomes, Human, Pair 9 / genetics
  • Citalopram / therapeutic use*
  • DNA-Binding Proteins / metabolism
  • Depressive Disorder, Major / blood*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / genetics
  • Drug Monitoring / methods
  • Female
  • Genetic Association Studies
  • Glycine / blood*
  • Glycine / metabolism
  • Glycine Dehydrogenase (Decarboxylating) / genetics*
  • Humans
  • Introns / genetics
  • Linkage Disequilibrium
  • Male
  • Metabolome / drug effects
  • Nuclear Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*

Substances

  • Biomarkers, Pharmacological
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Glycine Dehydrogenase (Decarboxylating)
  • Glycine