A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression
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In clinical practice, ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR (GRIN2B) is considered a promising candidate gene for MDD susceptibility.
The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients.
We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls.
Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G–T haplotype between the TRD and control groups (corrected P = 0.007), and the frequency of the G–T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR = 1.55, 95 % CI = 1.18–2.05, corrected P = 0.008).
These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients.
KeywordsGRIN2B Major depressive disorder Treatment-resistant depression Genetic predictor
We are deeply grateful to all the participants and the staff of the Division of Mood Disorders, Shanghai Mental Health Center, who assisted us in the implementation of the project. This work was supported by the National Natural Science Foundation of China (91232719), the “12th Five-year Plan” of National Key Technologies R&D Program (2012BAI01B04), the Shanghai Science & Technology Development Foundation (12140904200) and the National Key Clinical Disciplines at Shanghai Mental Health Center (OMA-MH2011-873). The authors thank Dr. Taylor Poor for her editorial help.
Conflict of interest
The authors declare no conflict of interest.
- Arnold PD, Macmaster FP, Hanna GL, Richter MA, Sicard T, Burroughs E, Mirza Y, Easter PC, Rose M, Kennedy JL, Rosenberg DR (2009) Glutamate system genes associated with ventral prefrontal and thalamic volume in pediatric obsessive-compulsive disorder. Brain Imaging Behav 3:64–76PubMedCentralPubMedCrossRefGoogle Scholar
- Fang Y, Yuan C, Xu Y, Chen J, Wu Z, Cao L, Yi Z, Hong W, Wang Y, Jiang K, Gao K, Cui X, Nierenberg AA (2010) Comparisons of the efficacy and tolerability of extended-release venlafaxine, mirtazapine, and paroxetine in treatment-resistant depression: a double-blind, randomized pilot study in a Chinese population. J Clin Psychopharmacol 30:357–364PubMedCrossRefGoogle Scholar
- Fang Y, Yuan C, Xu Y, Chen J, Wu Z, Cao L, Yi Z, Hong W, Wang Y, Jiang K, Cui X, Calabrese JR, Gao K (2011) A pilot study of the efficacy and safety of paroxetine augmented with risperidone, valproate, buspirone, trazodone, or thyroid hormone in adult Chinese patients with treatment-resistant major depression. J Clin Psychopharmacol 31:638–642PubMedGoogle Scholar
- Gonda X, Fountoulakis KN, Csukly G, Bagdy G, Pap D, Molnar E, Laszik A, Lazary J, Sarosi A, Faludi G, Sasvari-Szekely M, Szekely A, Rihmer Z (2011) Interaction of 5-HTTLPR genotype and unipolar major depression in the emergence of aggressive/hostile traits. J Affect Disord 132:432–437PubMedCrossRefGoogle Scholar
- Ibrahim L, Diaz Granados N, Jolkovsky L, Brutsche N, Luckenbaugh DA, Herring WJ, Potter WZ, Zarate CA Jr (2012) A randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. J Clin Psychopharmacol 32:551–557PubMedCentralPubMedCrossRefGoogle Scholar
- Li ZZ, Zhang YX, Wang ZW, Chen J, Fan JB, Guan YT, Zhang C, Yuan CM, Hong W, Wang Y, Wu ZG, Huang J, Hu YY, Cao L, Yi ZH, Cui DH, Yu SY, Fang YR (2013) The role of BDNF, NTRK2 gene and their interaction in development of treatment-resistant depression: Data from multicenter, prospective, longitudinal clinic practice. J Psychiatr Res 47:8–14PubMedCentralPubMedCrossRefGoogle Scholar
- Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28:631–637PubMedCrossRefGoogle Scholar
- Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M (2006) Acute and longer term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917PubMedCrossRefGoogle Scholar
- Souery D, Oswald P, Massat I, Bailer U, Bollen J, Demyttenaere K, Kasper S, Lecrubier Y, Montgomery S, Serretti A, Zohar J, Mendlewicz J (2007) Clinical factors associated with treatment resistance in major depressive disorder: Results from a European multicenter study. J Clin Psychiatry 68:1062–1070PubMedCrossRefGoogle Scholar
- Wang Z, Fan J, Gao K, Li Z, Yi Z, Wang L, Huang J, Yuan C, Hong W, Yu S, Fang Y (2013b) Neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene associated with treatment response to mood stabilizers in patients with bipolar i disorder. J Mol Neurosci 50:305–310PubMedCentralPubMedCrossRefGoogle Scholar