No abstract

There are well-replicated, independent lines of evidence supporting a role for corticotropinreleasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n ¼ 54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.174.5 vs 37.176.9%, respectively, P ¼ 0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.374.3 vs 51.276.0%, respectively, P ¼ 0.03). In those with loweranxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb. Keywords: corticotropin-releasing hormone; corticotropin-releasing hormone receptor; MexicanAmerican; Hispanic; depression; anxiety Major depression is a common and complex disorder of gene-environment interactions. 1 The specific genetic substrates and precipitating environmental factors have not yet been elucidated. The disorder affects 10% of males and 20% of females and has a point prevalence of 3%. Its cost to the US economy exceeds 100 billion dollars per year. 2 Over 20 drugs are approved by the US Food and Drug Administration for treatment of depression, each one with efficacy of approximately 60%. Various subgroups ...

To examine the association between lead exposure and both individual and geographic area indicators of socioeconomic position, the authors measured tibia lead concentration, a biomarker of cumulative lead exposure, using K x-ray fluorescence in a cross-sectional survey of 538 white males aged 50-92 years who were healthy when enrolled in the Normative Aging Study (Boston, Massachusetts) in the 1960s. Data on individual risk factors, education, occupation, and income were collected by questionnaire. Using subjects' residential addresses at the time of the tibia lead measurements, the authors obtained geographic area-specific measures of education, social class, and poverty by linking records to 1990 US Census block group data. In multivariate linear regression analysis controlling for age and cumulative smoking, tibia lead concentrations were 10.39 microg/g (95% confidence interval (CI) 7.80-12.97) higher in men who did not graduate from high school than in men with > or =4 years of college. Among the former men (non-high school graduates), living in an undereducated area was associated with a 9.28 microg/g (95% CI 1.59-16.97) increase in tibia lead level compared with living in a non-undereducated area; among the latter men (college graduates), no difference existed by residential area education (beta = 0.72, 95% CI -5.35 to 6.78). The authors conclude that the influence of individual socioeconomic position on cumulative lead exposure is modified by geographic area conditions.