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

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.

Figure 1

Overall research strategy and metabolomic statistical and pathway-based analyses. (A) Pharmacometabolomics-informed pharmacogenomic research strategy. (B) Sequential “flow” of metabolomic statistical and pathway-based regression analyses.

Figure 2

Glycine levels at zero time in MDD patient groups classified on the basis of response or remission status after SSRI therapy. P-values were calculated with Student’s t-test.

Figure 3

Glycine synthesis and degradation. The figure shows a schematic representation of glycine synthesis and degradation. SHMTs are the two serine hydroxymethyltransferase isoforms that catalyze the synthesis of glycine from serine, a reaction coupled with the conversion of tetrahydrofolate (THF) to 5,10-methylene THF. AMT, aminomethyltransferase; DLD, dihydrolipoamide dehydrogenase; GCSH, glycine cleavage system protein H and GLDC, glycine dehydrogenase, are components of the multiple-enzyme glycine cleavage system, the major pathway for glycine degradation.

Figure 4

The GLDC gene and its linkage disequilibrium relationships. (A) A region of chromosome 9 spanning the portion of the GLDC gene from which tag SNPs were selected for genotyping is shown. The box indicates a region around rs10975641 that was resequenced for purpose of fine-mapping. A Haploview (39) plot was generated using data from CEPH HapMap samples (CEU). (B) A “closer” view of the LD structure in the region of interest. Both genotyped (red) tag SNPs and SNPs identified during the resequencing effort (9) are plotted.

Figure 5

EMS assays for the rs10975641 SNP. Nuclear extract was prepared from three human brain-derived cell lines, glioblastoma U-87 MG, U-138 MG and U251 cell lines, as well as non-brain derived cell lines, human embryonic kidney 293T, HepG2 hepatocellular carcinoma cells and a pool of lymphoblastoid cells, and were used to perform EMS assays.