期刊
JOURNAL OF PSYCHOPHARMACOLOGY
卷 26, 期 3, 页码 360-367出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/0269881111434622
关键词
Pharmacogenetics; depressive disorder; treatment outcome; indoleamine-pyrrole 2, 3-dioxygenase; ID0; ID01; ID02
资金
- National Institute of Mental Health, NIH [N01MH90003]
- NARSAD
- Advanced Neuromodulation Systems, Inc.
- AstraZenica
- Best Practice Project Management, Inc.
- Cyberonics Inc.
- Eli Lilly Company
- Forest Pharmaceuticals Inc.
- Gerson Lehman Group
- GlaxoSmithKline
- Healthcare Technology Systems Inc.
- Jazz Pharmaceuticals
- Magellan Health Services
- Merck Co. Inc.
- National Institute of Mental Health
- Neuronetics
- Ono Pharmaceutical
- Organon USA Inc.
- Otsuka
- Pamlab
- Personality Disorder Research Corporation
- Pfizer Inc.
- Robert Wood Johnson Foundation
- Stanley Medical Research Institute
- Urban Institute
- Wyeth-Ayerst Laboratories Inc.
- Guilford Publications and Healthcare Technology Systems Inc.
- UT Southwestern Medical Center
- [K99MH085098-01]
The essential amino acid tryptophan is the precursor to serotonin, but it can also be metabolized into kynurenine through indoleamine-2,3-dioxygenase (ID0). Increased immune activation has long been associated with symptoms of depression and has been shown to upregulate the expression of ID0. The presence of additional ID0 directs more tryptophan down the kynurenine pathway, leaving less available for synthesis of serotonin and its metabolites. Kynurenine can be metabolized through a series of enzymes to quinolinic acid, a potent N-methyl-D-aspartate receptor agonist with demonstrated neurotoxic effects. We tested the hypothesis that ID0 plays a role in outcome of treatment with the selective serotonin reuptake inhibitor, citalopram. Patients consisted of 1953 participants enrolled in the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D). Genotypes corresponding to 94 single nucleotide polymorphisms (SNPs) in the genes ID01 and ID02, which encode ID0 and ID02, were extracted from a larger genome-wide set and analyzed using single marker tests to look for association with previously defined response, remission and QIDS-C score change phenotypes, with adequate correction for racial stratification and multiple testing. One SNP, rs2929115, showed evidence of association with citalopram response (OR = 0.64, p = 0.0005) after experiment-wide correction for multiple testing. Another closely associated marker, rs2929116 (OR = 0.64, p = 0.0006) had an experiment-wide significant result. Both implicated SNPs are located between 26 kb and 28 kb downstream of ID02. We conclude that common genetic variation in ID01 and ID02 may play a role in antidepressant treatment outcome. These results are modest in a genome-wide context and need to be replicated in an independent sample.
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