Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study.

BACKGROUND: The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in "pharmaco-epigenetic" approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. METHODS: The sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite- treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). RESULTS: Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110). CONCLUSIONS: Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.

Sympathetic activity relates to adenosine A(2A) receptor gene variation in blood-injury phobia.

Variation in the candidate genes adenosine A(2A) receptor (A(2A)R), catechol-O-methyl-transferase (COMT), and norepinephrine transporter (NET) has been suggested to influence vulnerability to panic disorder. We therefore investigated patients with another anxiety disorder with an even higher heritability, the blood-injury phobia, for association of these variants and used sympathetic measures during venipuncture, which serve as a naturalistic trigger of anxiety and autonomic hyperarousal, as an intermediate phenotype of anxiety. Patients homozygous for the A(2A)R 1976T allele as compared to patients carrying at least one 1976C allele exhibited a significantly increased respiratory rate with a trend towards elevated measures of systolic and diastolic blood pressure and respiratory minute volume. None of the sympathetic measures were influenced by the COMT or NET polymorphisms.This study provides preliminary data suggesting an influence of the A(2A)R 1976C/T polymorphism on sympathetic psychophysiological indicators of anxiety-related arousal in blood-injury phobia and thereby further supports a role of the A(2A)R gene in the pathogenesis of anxiety disorders.

Effects of pasture management and off-stream water on temporal/spatial distribution of cattle and stream bank characteristics in cool-season grass pastures.

A 2-yr grazing experiment was conducted to assess the effects of grazing management on cattle distribution and pasture and stream bank characteristics. Six 12.1-ha cool-season grass pastures in central Iowa were allotted to 1 of 3 treatments: continuous stocking with unrestricted stream access (CSU), continuous stocking with stream access restricted to 4.9-m-wide stabilized crossings (CSR), or rotational stocking with stream access restricted to a riparian paddock (RP). Pastures were stocked with 15 fall-calving Angus cows (Bos taurus L.) from mid-May to mid-October for 153 d in 2008 and 2009. A global positioning system (GPS) collar recording cow position every 10 min was placed on at least 1 cow per pasture for 2 wk of each month from May through September. Off-stream water was provided to cattle in CSU and CSR treatments during the second of the 2 wk when GPS collars were on the cattle. A black globe temperature relative humidity index (BGTHI) was measured at 10-min intervals to match the time of the GPS measurements. Each month of the grazing season, forage characteristics (sward height, forage mass, and CP, IVDMD, and P concentrations) and bare and fecal-covered ground were measured. Stream bank erosion susceptibility was visually scored in May, August, and October (pre-, mid-, and post-stocking). Cattle in RP and CSR treatments spent less time (P < 0.10) within the stream zone (0 to 3 m from stream center) in June and August and in the streamside zone (0 to 33 m from stream zone) in May through August and May through September, respectively, than cattle in CSU pastures. However, off-stream water had no effect on cattle distribution. Compared with the CSU treatment, the CSR treatment reduced the probability (P < 0.10) that cattle were within the riparian zone (0 to 36 m from stream center) at BGTHI of 50 to 100. Bare ground was greater (P < 0.10) in pastures with the CSU than CSR and RP treatments in the stream and streamside zones in September and October and in July and September. Streams in pastures with the CSU treatment had less stable banks (P < 0.10) mid- and post-stocking than RP or CSR treatments. Results show that time spent by cattle near pasture streams can be reduced by RP or CSR treatments, thereby decreasing risks of sediment and nutrient loading of pasture streams even during periods of increased BGTHI.