D. Neavin,1 A. Taddei,1 B. Ray,1 J. Biernacka,1 H. Zhu,2 G. Jenkins,1 K. Kalari,1 T. Mushiroda,3 Y. Nakamura,4 M. Kubo,3 W. Matson,5 L. Wang,1 R. Kaddurah-Daouk,2 R. Weinshilboum1; 1Mayo Clinic, Rochester, MN, 2Pharmacometabolomics Research Network, Duke University School of Medicine, Durham, NC, 3RIKEN Center for Integrative Medicinal Sciences, Yokohama City, Japan, 4The University of Chicago, Chicago, IL, 5Bedford VA Medical Center, Bedford, MA
BACKGROUND: Major Depressive Disorder (MDD) is a debilitating disease impacting 20 million Americans annually. The balance of tryptophan (TRP) metabolism between the serotonin (5HT) and kynurenine (KYN) pathways has been implicated in MDD pathophysiology. Selective serotonin reuptake inhibitors (SSRIs) are used to treat MDD, but 30% of MDD patients do not respond. We set out to identify genes that lead to TRP pathway imbalance that may contribute to SSRI response.
METHODS: The Mayo SSRI Pharmacogenomics Study treated 800 MDD patients with citalopram or escitalopram over 8 weeks, collecting blood for genomic and metabolomic analyses at baseline, 4, and 8 weeks. These data were used to analyze 5HT and KYN pathway metabolite ratios associated with SSRI response. GWAS was performed to determine associations of SNPs with metabolite ratios to allow focus on pathway reactions.
RESULTS: Four metabolite ratios were related to SSRI response: 5HT/KYN, 5HT/TRP, 5HT/5-Hydroxyindole acetic acid (5HIAA), and 5HT/3-Hydroxykynureniune (3OHKYN). SNPs across and 3’ of superoxide dismutase 2 (SOD2) were highly associated with 4- and 8-week change in these metabolite ratios. For example, for change at 8 weeks:
5HT/KYN, rs199968457, p = 1.29E-06
5HT/TRP, rs199968457, p = 3.01E-07
5HT/5HIAA, rs199968457, p = 1.59E-06
5HT/3OHKYN, rs2842984, p = 1.83E-07.
In addition, some of the SNPs correlated to TRP metabolite ratio changes were eQTLs for SOD2. SOD2 knockdown in glioma cells increased expression of MAO A (4.7 + 0.58 fold, p = 4.3E-06) and IDO1 (5.8 + 0.78 fold, p = 1.5E-04). Both MAO A and IDO1 are TRP metabolism enzymes that contribute to the balance of 5HT and KYN pathways.
CONCLUSION: Our results suggest that SOD2 may be important in TRP metabolism balance and SSRI response, in part by effecting MAO A and IDO1 expression.