Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is among the most consistent neuroendocrine abnormalities in major depressive disorder (MDD). The peptide adrenocorticotropin hormone (ACTH) mediates HPA axis function during stress and is encoded by the proopiomelanocortin (POMC) gene polycistronically. After screening 39 POMC polymorphisms, we evaluated the association of polymorphisms with susceptibility to MDD in 145 MDD patients and 193 normal subjects; in patients, we also evaluated the response to treatment with antidepressants. Additionally, we investigated the role of gene-environment interaction between POMC haplotypes and stressful life events (SLE) in the treatment response. Although genotypes and haplotypes were not significantly associated with the risk of MDD, non-remitters were more likely to carry haplotype 1 (ht1) and to have no ht2 than were remitters (corrected P = 0.010-0.035). Although observations were limited in patients without SLE, a significant haplotype-SLE interaction was observed (P = 0.020). Additionally, at 1, 2, and 8 weeks of treatment, the 21-item Hamilton Depression Rating scores of MDD subjects with POMC ht2 were significantly (P = 0.003-0.044) lower than those of patients with ht1 in subjects those did not experience SLE. MDD subjects possessing POMC ht2 achieved remission significantly (P = 0.013; survival analysis) faster than patients with ht1. This study suggests that POMC haplotypes, via an interaction with SLE, are associated with antidepressant treatment outcomes in MDD patients. Regarding SLE, haplotypes of the POMC gene could be useful markers for predicting the response to antidepressant treatment in MDD patients.

β-Arrestin 1 is known to be involved in the pathophysiology of major depressive disorder (MDD) and in the underlying mechanism of action of antidepressant therapies. After we screened 39 ARRB1 polymorphisms, we investigated the associations of seven ARRB1 single-nucleotide polymorphisms (SNPs) with the risk of MDD in 270 patients with MDD and 204 normal subjects, and with mirtazapine treatment response in patients with MDD. The genotype distributions of -132C>T and IVS1+85T>C showed significant deviations from Hardy-Weinberg equilibrium in patients with MDD but not in normal subjects. After four and 12 weeks of mirtazapine treatment, the proportion of haplotype 1 (ht1) carriers was significantly higher in remitters than in non-remitters after corrections for multiple comparisons (corrected p=0.006 and 0.014 at four and 12 weeks, respectively). After eight and 12 weeks of treatment, scores on the 21-item Hamilton Depression Rating Scale (HAMD21) were significantly lower in patients with MDD with ARRB1 ht1 than in those without ht1. Similarly, after 8 and 12 weeks of treatment, the percent reduction in HAMD21 scores was significantly higher in patients with MDD with ARRB1 ht1 than in those without ht1. The ARRB1 polymorphisms represent promising genetic markers for the prediction of treatment responses to mirtazapine.

Background/Aims: The genetic variations in serotonin-related genes may be associated with antidepressant treatment response in major depressive disorder (MDD). The tryptophan hydroxylase-1 (TPH1) gene and serotonin 5A receptor (HTR5A) gene are known to be involved in serotonin biosynthesis and signal transduction, respectively. The purpose of this study was to investigate a possible interaction between the TPH1 gene and the HTR5A gene in the treatment outcome of escitalopram in MDD. Methods: In total, 245 patients diagnosed with MDD were recruited, and their symptoms were evaluated using the 17-item Hamilton Depression Rating scale (HAMD-17). The association between the TPH1 218A/C and HTR5A 12A/T polymorphisms and the clinical outcomes (remission, response and changes in HAMD-17 score) was investigated after 2, 4 and 8 weeks of escitalopram treatment using multiple logistic regression or multiple linear regression analysis. Results: No significant associations of TPH1 or HTR5A gene polymorphisms were observed with either response rate or remission rate at 2, 4 and 8 weeks after escitalopram treatment. In addition, the gene-gene interaction between TPH1 and HTR5A genes was not associated with the treatment outcome. Conclusions: Our results suggest that TPH1 218A/C and HTR5A 12A/T polymorphisms cannot predict treatment response in major depression.