Influence of genetic polymorphisms in homocysteine and lipid metabolism systems on antidepressant drug response

Abstract Background Chronic lesions of small blood vessels and capillaries may play a role in the pathogenesis of depression. As the genes associated with these vascular risk factors may be involved in depression, these genetic polymorphisms may affect the efficacy of antidepressants. This study was performed to investigate the roles of methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (ApoE), and apolipoprotein A4 (ApoA4) genetic polymorphisms in antidepressant response in depressive patients.Methods A total of 281 Han Chinese patients received a single antidepressant drug for at least 6 weeks. The Hamilton Depression Rating Scale (HAMD-17) was used to evaluate the severity of depressive symptoms and the therapeutic effects of the drug administered. Eight single nucleotide polymorphisms (SNPs) of MTHFR, ApoE, and ApoA4 genes were detected using gene chips. Differences in clinical variables between the responders and non-responders, as well as between remission and non-remission groups, were examined using the independent samples t test and Pearson’s χ 2 test. In addition, the associations of single loci and haplotypes with treatment response were analyzed.Results Among the eight SNPs in four genes, two SNPs (ApoA4 rs5101 and rs675) were eliminated as they had a MAF < 5%.Haplotype(C-A) in MTHFR (rsl801133 and rs1801131) was significantly associated with better antidepressant response in the 8-week antidepressant group overall ( P = 0.0007), and in the male subgroup ( P = 0.003), and serotonin norepinephrine reuptake inhibitor (SNRI) subgroup ( P = 0.001). The ApoE rs405509 C allele was significantly associated with poorer antidepressant response in the 6-week male subgroup ( P = 0.004), while the 405509 AA genotype was associated with better antidepressant efficacy in the 6-week antidepressant group overall ( P = 0.006) and male subgroup ( P = 0.002).Conclusions Genetic polymorphisms of MTHFR, ApoE, and ApoA4 may be associated with the efficacy of antidepressants, in which the haplotype (rs1801131-rs1801133) A–C type was associated with better antidepressant efficacy, especially in males and in patients using SNRIs. The efficacy of antidepressants may be better in ApoE rs405509 A allele and AA genotype carriers, but worse in ApoA4 rs5092 G allele and GG genotype carriers.