Effects Of SLC6A5 Genetic Polymorphism On Antidepressant Treatment In Major Depressive Disorder

ObjectiveIn the process of synaptic transmission, neurotransmitter amino acids can be divided into two categories:excitatory amino acid neurotransmitters, such as glutamate, aspartate, and inhibitory amino acid neurotransmitters, such as γ- aminobutyric acid, glycine. In recent years, researchers were found that the systems of glutamate (Glu) and γ-aminobutyric acid (GABA) may be involved in the pathogenesis and antidepressant treatment in major depressive disorder. But they were deficient about researches of glycine and its receptors, transporters. The purpose of this study was to investigate the role of solute carrier family 6,member 5(SLC6A5) genetic polymorphisms in antidepressant efficacy.MethodsWe recruited 281 patients of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders-Ⅳ (DSM-Ⅳ).These patients received one single antidepressant drugs, of which were followed up for 8 weeks. The Hamilton Depression Scale 17 (17-item Hamilton depression rating scale, HAMD-17) was used to evaluate the severity of depressive symptoms and the therapeutic effects. Five single nucleotide polymorphisms(SNPs) of glycine transporter (SLC6A5) gene were detected using gene chips; In the treatment of 6 weeks, patients were enrolled into response group(reduction rate of HAMD’s baseline scores≥50%) and non-response group(reduction rate of HAMD’s baseline scores<50%); In the treatment of 8 weeks,patients were divided into the remission group(HAMD≤7) and non-remission group (HAMD> 7). Clinical variables between the responders and non-responders as well as the remitters and non-remitters were made the independent samples T test and Pearson’s χ2 test using SPSS 20.0 software package. The Hardy-Weinberg imbalance (HWE), the minor allele frequency (MAF), percentage of successful genotyping (%gene) and linkage disequilibrium (LD) were analyzed using haploview 4.0 software package. And the associations of single locus with treatment response were analyzed using Unphased 3.0.13 software.Results1, Clinical variables between the responders and non-responders as well as the remitters and non-remitters(1) After six weeks of antidepressant treatment, there were no significant differences of gender, age, years of education, family history, episode times, and antidepressant agents between responders and non-responders (all P>0.05), while the baseline scores of HAMD-17 was significantly different (t=2.891, P=0.004);(2) After eight weeks of antidepressant treatment, there were no significant differences of age, years of education, family history, episode times, baseline scores of HAMD-17, and antidepressant agents between remitters and non-remitters (both P>0.05), while proportion of male patients was significantly higher in non-remission group than in remission group (χ2=6.069, P=0.014).2, Associations of genotype of 5 SNPs in the SLC6A5 gene with treatment response between the responders and non-responders as well as the remitters and non-remitters(1) In 8 weeks’ total group,the rs1443551 AG genotype was associated with better antidepressant efficacy (χ2=4.699, P=0.03017),however the result failed to pass multiple permutation (P*=0.07999);rs3740870 GG genotype was associated with better antidepressant efficacy (χ2=4.216,P=0.04004), and passed multiple permutation for 10,000 test (P*=0.0395);(2) In 8 weeks’ SNRIs subgroup, rs 1805091 GG genotype was related to better response(χ2=6.031, P=0.01405), and 10,000 times by multiple displacement test is (P*=0.0126); in 8 weeks’ SSRIs subgroup, rs1443551 AG genotype was better (χ2= 4.566, P=0.03261), but failed to pass multiple permutation test (P*=0.07999);(3) In 8 weeks’ female subgroup, rs1443551 AG genotype was associated with better antidepressant efficacy (χ2=6.097, P=0.01354), and passed multiple permutation for 10,000 test(P*=0.0329);(4) In 8 weeks’ single episode subgroup, rs3740870 GG genotype was related to better response (χ2=6.687, P=0.009714), and passed multiple permutation for 10,000 test (P*=0.008199); 3, Associations of allele of 5 SNPs in the SLC6A5 gene with treatment response between the responders and non-responders as well as the remitters and non-remitters(1) In 8 weeks’ SNRIs subgroup, SLC6A5 rs1805091 G allele was related to better response (χ2=6.183, P=0.0129), and passed multiple permutation for 10,000 test (P *=0.0167);(2) In 8 weeks’ single episode subgroup, SLC6A5 rs3740870 G allele was related to better response(χ2=5.007, P=0.02524), and passed multiple permutation for 10,000 test(P*=0.015).4, The impact of the interaction of the genetic polymorphisms of SLC6A5 and environmental factors on antidepressant treatmentWith sex, age, and baseline of HAMD-17 scores as covariates, there wasn’t found the impact of the interaction of the genetic polymorphisms of SLC6A5 and environmental factors on antidepressant treatment carried Logistic regression analysis.Conclusion1, Compared with male patients, female patients with MDD received better antidepressant efficacy; 2, The genetic polymorphisms of glycine transporter gene (SLC6A5) may be associated with the efficacy of antidepressants; 3, The interaction of the genetic polymorphisms of SLC6A5 and negative life events/childhood trauma may not affect the efficacy of antidepressants.