Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

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 ...

A 40-basepair VNTR polymorphism in the dopamine transporter (DAT1) gene and the rapid response to antidepressant treatment

“…In a pharmacogenetic study in MexicanAmerican outpatients with depression, mean decrease in HDRS was about 30% after 3 weeks of treatment with either fluoxetine or desipramine. 21 In a similar study on the catechol-O-methyltransferase Val/Met polymorphism in patients treated with mirtazapine, patients had a mean decrease in HDRS-17 score of 38% after 3 weeks, 32 which is similar to our results. These comparisons show that our sample is a typical sample of moderately to severely depressed patients.…”

“…As primary parameter of response, reduction in HDRS during 3 weeks of treatment was calculated as (HDRS 1 -HDRS 21 )/ HDRS 1 *100, with HDRS 1 and HDRS 21 being the total score of the 21-item HDRS at day 1 (baseline) and day 21, respectively. 21 Response was defined as a decrease in HDRS of more than 50%, according to the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders.…”

“…21 Response was defined as a decrease in HDRS of more than 50%, according to the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders. 22 The number of responders in dependence of genotypes was calculated as secondary response parameter.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…Finally, pharmacogenomic evidence suggests a role for genetic variants in elements of the HPA axis, including the CRH receptor type 1 (CRHR1) in the response to antidepressants. 37,38 Given the abundant data supporting a role for CRH dysregulation in depression, CRH receptor antagonists have been developed as a new strategy for pharmacotherapy of depression. Such drugs have already been tested in clinical trials.…”

Relation of genes regulating the HPA-axis to major depression and suicidality: novel findings

“…Surprisingly little is known about influence of genetic variations in the CRHR1 gene in the context of stress and depression, since only a few such studies have been reported up to date (Licinio et al, 2004;Liu et al, 2007;Liu et al, 2006;Papiol et al, 2007;Wasserman et al, 2007). In fact, our group has been the first to study the genetic variation in the CRHR1 gene in connection to depression and stress among suicidal individuals (Wasserman et al, 2007).…”