Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder.

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers (minor allele homozygotes), independently from clinical variables. Furthermore minor allele homozygous carriers in all these three SNPs were associated with treatment response by various assessment such as HAM-D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four articles. In conclusion, this is the first study that reports a significant association of antidepressant response with rs10042486C/T and rs1364043T/G variants of HTR1A and also with rs10042486-rs6295-rs1364043 combination. This finding adds an important information for the pathway of detecting the genetics of antidepressant response even if results must be verified on larger samples.

The alpha 2A-adrenergic receptor gene polymorphism modifies antidepressant responses to milnacipran.

OBJECTIVE: The alpha 2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity. Recently, the functional defect of ADRA2A has been implicated as a cause of depression, attention deficit hyperactivity disorder, and Tourette syndrome. In this study, the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) was examined in depressed patients. METHOD: Ninety-three Japanese depressed patients were recruited in the present study, assigned randomly to paroxetine or milnacipran, and assessed by the Hamilton Rating Scale for Depression (HAM-D) scoring every 2 weeks before and after drug administration. The ADRA2A C-1297G polymorphism was considered in the association analysis with the efficacy of antidepressants. RESULTS: There were significant differences in the HAM-D percent score change over time (P = 0.019) among C/C, C/G, and G/G of the ADRA2A C-1297G polymorphism in the total subjects. The C allele carriers of the ADRA2A C-1297G polymorphism showed a significantly better improvement than G/G subjects at weeks 2, 4, and over time (P = 0.037) in the milnacipran group. DISCUSSION: Our findings suggest that ADRA2A plays an important role in depression therapy. The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs, especially milnacipran, although the functional change brought about by C-1297G polymorphism has not yet been fully identified in vivo and in vitro. CONCLUSIONS: The ADRA2A polymorphism could be a reasonable candidate to predict the response to milnacipran. Our results are still preliminary, and a large sample size will be required to confirm our findings. However, to the best of our knowledge, this study is the first to suggest a possible association of ADRA2A variants with the SNRI response.

Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients.

The G-protein beta3 subunit (GNB3) gene is a key modulator of signal transduction and is a major candidate for SSRIs response. The aim of the present study is to test a possible effect of the C825T polymorphism on the antidepressant response and intolerance to selective serotonin reuptake inhibitors (SSRIs) in 146 Japanese samples with major depression treated with paroxetine or fluvoxamine for 6 weeks. The severity of depression symptom was assessed using the 21-item Hamilton Rating Scale for Depression (HAM-D) and adverse drug reactions were evaluated bi-weekly. No association with SSRIs treatment response was observed in 107 completers also including HAM-D baseline scores, SSRI type or/and 5-HTTLPR variants in the model as covariates. Furthermore, no significant association could be observed with intolerance to SSRIs in the whole subjects. The result suggests that C825T variants of GNB3 cannot play a major role as a predictor of treatment response as well as intolerance to SSRIs in Japanese patients with major depression.

ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder.

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Multidrug resistance 1 (ABCB1, MDR1) gene encodes a blood-brain barrier transporter P-glycoprotein that plays an important role in controlling the passage of substances between the blood and brain. In the present study, we therefore examined the possible association of 3 functional ABCB1 polymorphisms (C3435T: rs1045642, G2677T/A: rs2032582 and C1236T: rs1128503) with response to paroxetine in a Japanese major depression sample followed for 6 weeks. Analysis of covariance at week 6 with baseline scores included in the model as covariate showed significant association of the non-synonymous SNP G2677T/A with treatment response to paroxetine (p=0.011). Furthermore, the wild variants haplotype (3435C-2677G-1236T) resulted associated with poor response (p=0.006). To our best knowledge, this study is the first suggestion of a possible association of ABCB1 variants with SSRIs response.