Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder.

We examined genetic associations with duloxetine response in generalized anxiety disorder (GAD). Three pooled studies in patients with GAD receiving duloxetine 60-120 mg per day (N=164) or placebo (N=95) were used. Associations between 825 single-nucleotide polymorphisms (SNPs) in 61 candidate genes with change in Hamilton Anxiety Scale scores were examined with set-based testing (adjusted for the number of SNPs within each gene); sets with two-sided adjusted P≤0.05 were examined using repeated measure analysis. Follow-up analysis explored associations of these SNPs with change in Hamilton Rating Scale for Depression-Anxiety Subscale in a 6-week study in duloxetine-treated patients with major depressive disorder (MDD) (N=241). Variants in corticotropin-releasing hormone receptor 1 (CRHR1), dopamine receptor D3 (DRD3), nuclear receptor subfamily group C, member 1 (NR3C1) and phosphodiesterase 1A (PDE1A) were associated with duloxetine response in GAD. Only rs4792888 in CRHR1 showed modest evidence of association with duloxetine response in MDD (P=0.029 in GAD, P=0.054 in MDD). In conclusion, CRHR1 variation merits investigation in pathophysiology of anxiety and its treatment response.

Is reduced cell size the mechanism for shrinkage of the adrenal zona reticularis in aging?

In aging humans, corticosteroid production is preserved, or even increased, but there is an unexplained reduction in adrenal androgen secretion that likely has significant health implications. Preliminary analyses on adrenocortical morphology have revealed an age-associated reduction in the thickness of the zona reticularis (ZR), the cortical zone responsible for the majority of DHEA/DHEA sulfate production in the adult human, but no change in the overall thickness of the adrenal cortex. The ZR width could decrease in aging due to loss of ZR cells and/or to shrinkage of ZR cells. In the current study, we investigated whether there was a relation between thickness of the zona reticularis in young and old humans and the cell density in this zone. Paraffin-embedded sections of the adrenal cortex of 10 young (21-35 yr old) and 10 old (54-89 yr old) adults who had died suddenly as the result of trauma were stained with hematoxylin and eosin. These specimens were chosen from a larger cohort of samples for having a broad ZR in the young group and a narrower ZR in the older group. After determining the overall cortical thickness and the width of the ZR by use of computerized image analysis software, we counted the number of adrenocortical cells in two random high power fields of the ZR of each specimen. The ZR width of the older group (57 +/- 7 arbitrary units, Mean +/- SE) was significantly reduced compared to that of the young group (124 +/- 21), P < 0.001. On the other hand, the overall cortical width in the old group (232 +/- 17) was similar to that of the young adults (249 +/- 38). In the old group, the ZR comprised 24.7 +/- 3% of the total cortical width, whereas it was 50 +/- 2% of the cortical width in the young adrenals, P < 0.001. The cell density (cell number/60 x high power field) of the ZR of old adults (83 +/- 9) was similar to that of the young group (87 +/- 5). In summary, although the width of the ZR regresses with aging, cell size in this zone is preserved. Therefore, loss of trophic support for ZR cells would not appear to be the explanation for zonal shrinkage in aging. Rather, it is likely that aging effects may be due to increased cell loss in the ZR or else reduced rates of differentiation/migration of cells into this cortical zone.