There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing 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=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1±4.5 vs 37.1±6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3±4.3 vs 51.2±6.0%, respectively, P=0.03). In those with lower-anxiety 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.org.
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 of patients respond differently to each drug, so that if multiple trials are conducted, eventually 85% of patients will respond.3 As there are no clinical or biomarker predictors of treatment response, the assignment of a depressed patient to a drug is based solely on chance or on attempts to minimize side effects that are more likely to occur with a specific medication. Efforts are therefore being made to identify genetic predictors of treatment response in depression.
Corticotropin-releasing hormone receptor type 1 (CRHR1) is a logical candidate gene for antidepressant-mediated responses.4, 5, 6 There is a long body of evidence indicating disruption of hypothalamic-pituitary-adrenal (HPA) axis function in depression, including the following key observations: increased 24-h elevations in cortisol production,7 lack of suppression of plasma cortisol levels by dexamethasone,8 increased concentrations of CRH in cerebrospinal fluid,9 dysregulation of HPA responses to exogenous CRH administration10, 11, 12 and loss of the negative correlation between plasma cortisol and continuously collected CSF CRH.13 Of particular relevance, it has been demonstrated that antidepressants of various classes suppress CRH gene expression14, 15, 16 in rodents and HPA activity in depressed17 and healthy humans.18 It has therefore been proposed that suppression of CRH activity is a common, final effect of antidepressant treatment.
Recently, Tantisira et al19 demonstrated that variants in the CRHR1 gene were associated with response to inhaled steroids in asthma. In the light of the findings that disruption of CRH function has long been implicated in depression and that variations of CRHR1 gene are associated with response to treatment of a human disease, we sought to investigate whether variations in CRHR1 sequence could predict response to antidepressants. As CRH and CRHR1 have been implicated not only in depression but also in anxiety,20, 21, 22 we hypothesized that the association of CRHR1 gene variations with antidepressant treatment response, if present, would be more evident in patients with both a diagnosis of major depression and higher levels of anxiety.
The study population consisted of 233 depressed subjects enrolled in an ongoing pharmacogenetic study of antidepressant treatment response to desipramine or fluoxetine. We report here data from the first 80 subjects who completed the protocol and for whom we had available genetic data. We also studied 251 age- and sex-matched control subjects who were recruited from the same Mexican-American community in Los Angeles, and studied by the same, bilingual, clinical research team at the Center for Pharmacogenomics and Clinical Pharmacology, Neuropsychiatric Institute, David Geffen School of Medicine at UCLA. Controls were in general good health but were not screened for medical or psychiatric illness, to avoid bias. All patients are Mexican-American men and women aged 21–68 years, with a current episode of major depression as diagnosed by the DSM-IV.23 In this study, all Mexican-American subjects had at least three grandparents born in Mexico.24 We used diagnostic and rating instruments that have been fully validated in English and in Spanish, and conducted all assessments in the subjects' primary language.
Inclusion criteria included DSM-IV diagnosis of current, unipolar major depressive episode, with a 21-Item Hamilton Depression Rating Scale (HAM-D)25 score of 18 or greater with item number 1 (depressed mood) rated 2 or greater. There was no anxiety threshold for inclusion. Subjects with any primary axis I disorder other than major depressive disorder (eg dementia, psychotic illness, bipolar disorder, adjustment disorder), electroconvulsive therapy in the last 6 months or previous lack of response to desipramine or fluoxetine were excluded. As anxiety can be a manifestation of depression, patients who met the criteria for depression and also anxiety disorders were not excluded. Exclusion criteria included active medical illnesses that could be etiologically related to the ongoing depressive episode (eg untreated hypothyroidism, cardiovascular accident within the past 6 months, uncontrolled hypertension or diabetes), current, active suicidal ideation with a plan and strong intent, pregnancy, lactation, current use of medications with significant central nervous system activity, which interfere with EEG activity (eg benzodiazepines) or any other antidepressant treatment within the 2 weeks prior to enrollment, illicit drug use and/or alcohol abuse in the last 3 months or current enrollment in psychotherapy.
All patients had an initial comprehensive psychiatric and medical assessment and, if enrolled, had 9 weeks of structured follow-up assessments. The study consists of two phases: a 1-week, single-blind placebo lead-in phase to eliminate placebo responders, followed, if subjects continue to meet the inclusion criteria after phase 1, by random assignment to one of the two treatment groups: fluoxetine 10–40 mg/day or desipramine 50–200 mg/day, administered in a double-blind manner for 8 weeks, with dose escalation based on clinical outcomes. The study population consisted of the first 80 subjects who completed the trial, with weekly data collection, and for whom we obtained genotype data.
Single-nucleotide polymorphism (SNP) genotyping methods
As reported previously,19 nine SNPs were assayed in CRHR1 corresponding to the following dbSNP identifiers: rs171440, rs1876828, rs1876829, rs1876831, rs242938, rs242939, rs242941, rs242949 and rs242950. The SNPs were genotyped via a SEQUENOM MassARRAY MALDI-TOF mass spectrometer (Sequenom, San Diego, CA, USA) for the analysis of unlabeled single-base extension minisequencing reactions with a semiautomated primer design program (SpectroDESIGNER, Sequenom). The protocol implemented the very short extension method,19 whereby sequencing products are extended by only one base for three of the four nucleotides and by several additional bases for the fourth nucleotide (representing one of the alleles for a given SNP), permitting clearly delineated mass separation of the two allelic variants at a given locus.
Haplotype scoring methods
Haplotype frequencies were imputed using EM algorithm-based estimation routine implemented in the S-PLUS software package Haplo.Stats. Version 126.96.36.199 on the entire group of depressed and control subjects; haplotypes were assigned to an individual based on maximal posterior probabilities. As a person can have more than one haplotype, the number and type of haplotypes for each subject was counted. A haplotype variable was created that had a value of 0, 1 or 2 for the count of haplotypes. Nine SNPs spanning 27 kb of the CRHR1 gene were successfully genotyped in both the depressed and control groups. Subsequently, we used a haplotype-tag approach27 to identify haplotype-tag single-nucleotide polymorphisms (htSNPs) for haplotypes with 5% of greater frequency. We chose a minimal subset of htSNPs that was identical for both depressed and controls. These SNPs were tested for haplotype association using Proc GLM in SAS program (SAS, version 8; Cary, NC, USA).
The primary phenotypic outcome measure HAM-D was converted to the percent change in HAM-D. The percent change in HAM-D was defined as
Similarly, the percent change in HAM-A was defined as:
In all, 80 subjects were divided into a low-anxiety (LA) group, with HAM-A score less than 18 at screening and a high-anxiety (HA) group, with HAM-A scores that were 18 or higher at screening. The inclusion criteria in the study included a HAM-D of 18 or higher. Therefore, HA subjects had HAM-D and HAM-A scores that were 18 or higher and LA subjects had a HAM-D that was 18 or higher and HAM-A score that was less than 18. Associations between haplotypes and antidepressant response were tested using generalized linear models (Proc GLM in SAS) under the assumption of an additive model. Demographics of the LA group and HA group were assessed for homogeneity using χ2 or t-tests, as appropriate.
Data deposition and data sharing
All data reported here are deposited in PharmGKB, the Pharmacogenetics and Pharmacogenomics Knowledge Base (www.pharmgkb.org). PharmGKB is a publicly available Internet research tool that is part of the nationwide collaborative research consortium, NIH Pharmacogenetics Research Network (PGRN). Its aim is to aid researchers in understanding how genetic variation among individuals contributes to differences in reactions to drugs.
Of 233 depressed patients who were genotyped, 198 had no missing data in the SNPs of interest, representing a genotype success rate of 85%. Of the 198 genotyped subjects, 80 completed the treatment trial and were included in this analysis. Among those 80 patients, there were 54 subjects in the HA group and 26 subjects in the LA group. Clinical and demographic variables are shown in Table 1. χ2 tests of sex, treatment, number of copies of haplotype 1 (GAG, see Table 2) and responder status showed no difference between HA and LA groups. HA and LA groups were also similar in age (P=0.326) and acculturation score (P=0.9). As expected, the average HAM-D score at week 0 of 23.0±4.2 in the HA group was significantly higher (P=0.0001) than in the LA group (19.6±1.9).
Haplotype frequencies were estimated using Haplo.Score, as shown in Table 2. No difference was found in the frequencies of haplotypes in depressed and control groups (P=0.9). Four common haplotypes comprised of 99.6% of the total haplotypic substructure for both depressed and control groups. The frequency of those haplotypes/subject in our population of all depressed and all controls is shown in Figure 1. Utilizing the htSNPs rs1876828, rs242939 and rs242941, we analyzed the rate of HAM-A and HAM-D improvements in patients with the GAG haplotype (haplotype 1), which had an allele frequency of 0.63197 in depressed and 0.66327 in controls (nonsignificant). Subjects' 8-week responses to daily antidepressant treatment (fluoxetine or desipramine) were stratified by CRHR1 GAG haplotype status, utilizing the htSNPs rs1876828, rs242939 and rs242941. In this group of 80 subjects, there were no individuals with zero copies of haplotype 1; therefore, patients were classified as being either homozygous (two copies of this haplotype) or heterozygous (one copy of this haplotype).
In the HA group (n=54), those who were homozygous for the GAG haplotype had a decrease in HAM-A of 63.1±4.5% (average±SEM); in those heterozygous for the GAG haplotype this rate was 37.1±6.9% (P=0.002). Thus, homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores in comparison to heterozygous.
In those with LA at screening (n=26), HAM-A scores decreased 29.9±19.5% in patients homozygous for haplotype 1 and 50.5±16.5% in those who were heterozygous for that haplotype (P=0.43, nonsignificant) (see Figures 2 and 3).
Of importance, in the HA group, homozygosity for the GAG haplotype was associated with a significant decrease in HAM-D of 67.3±4.3%; in those heterozygous for the GAG haplotype, the rate of decrease was significantly lower: 51.2±6.0% (P=0.03). This represents a relative 31% greater reduction in scores after treatment in homozygous compared to heterozygous.
In those with lower-anxiety levels at screening, HAM-D scores decreased 61.0±6.0% in those homozygous for haplotype 1 and 60.5±5.6% in heterozygous (P=0.95, nonsignificant).
Figure 3 summarizes the findings of a significant percent decrease in HAM-A and HAM-D in antidepressant-treated patients stratified by the level of anxiety and CRHR1 genotype. In the LA group, there was no significant association between number of copies of haplotype 1 and percent decrease in the HAM-A (or HAM-D). There was no difference between drugs in the association of clinical effects and CRHR1 genotype in this sample.
We examined genotype results at each htSNP to determine whether specific SNPs were driving the association of treatment response with haplotype 1. There was no association between each SNP and decreases in HAM-A or HAM-D in the entire group of 80 depressed (P=0.2). In the HA subgroup, we found nonsignificant trends for the association of treatment response and individual SNPs: In htSNP rs1876828A1, there was a trend for a difference (P=0.09) in the rate of HAM-A decrease in those with the G allele vs the A allele (56.0±4.6 and 38.2±9.6%, respectively). The frequency of the G allele was 42/52 and the A allele was 10/52. Genotyping of htSNP rs1876828A2 showed G in the entire group of 80 subjects. In htSNP rs242939, there was variation in the group of treated depressed subjects, who all had A (see Table 2). In htSNP rs242941A2, there was a trend for association between percent decrease in HAM-A and the G allele vs the T allele (57.0±4.4 and 39.5±9.9%, respectively, P=0.07). The frequency of the G allele was 39/42 and the T allele was 13/42. In htSNP rs242941A1, there was G in the entire group of 80 subjects.
Allele frequencies of htSNP rs1876828, rs242939 and rs242941A2 were in Hardy–Weinberg equilibrium, with no significant differences between actual and expected frequencies (Table 3).
In this study of treatment responses in depression, we find that treatment responses in a phenotypic subgroup of HA depressed patients there is stratification of response to antidepressant treatment according to a haplotype of CRHR1. Utilizing the htSNPs rs1876828, rs242939 and rs242941, we show here that homozygosity for the GAG haplotype was associated with a 70% greater reduction in HAM-A scores (63.1±4.5% in homozygous and 37.1±6.9% in heterozygous, P=0.002) and 31% greater reduction in HAM-D scores after treatment (67.3±4.3% in homozygous and 51.2±6.0% in heterozygous, P=0.03). CRHR1 haplotypes were not stratified by diagnosis of depression and were similarly distributed in depressed and control subjects.
In this study, we used a combined sample of patients taking either fluoxetine or desipramine, because both drugs have been shown to have equal effects on downregulating CNS CRH gene expression.14, 15 Based on extensively replicated work from several groups,14, 15, 16, 31, 32 it has been proposed that downregulation of CRH activity is a common, final effect of antidepressant treatment with tricyclic drugs, such as imipramine (or its metabolite desipramine),14, 16 selective serotonin reuptake inhibitors, such as fluoxetine,15 and also with nonpharmacologic treatment, such as electroconvulsion.31 Owing to the consensus on the role of CRHR1 in depression, CRHR1 antagonists22, 33 have been developed and successfully used in clinical research contexts as antidepressants,34, 35 without long-term effects on HPA responses to stress.36 It is consequently justifiable to group together patients taking desipramine and imipramine for the purposes of studying SNPs in this gene, because both of these drugs have effects on CRH function as a common, final pathway of action. Moreover, in our ongoing clinical study, we have not yet seen any differences between the two drugs in terms of antidepressant effectiveness (data not shown), which is consistent with previous findings.37
Our strategy was to identify a plausible candidate gene approach, based on the pathophysiology of a specific phenotypic subgroup. As CRHR1 antagonists are effective for amelioration of both depressive symptoms34, 35 and anxiety-like behaviors,22 we hypothesized that variants of the CRHR1 gene would be more likely to be associated with treatment responses in a subgroup of patients who met the diagnostic criteria for a current episode of major depression and who were also highly anxious. We therefore refined our phenotype to differentiate depressed subjects into two groups: HA and LA, as defined by their scores on the HAM-A, a validated rating scale for anxiety.38 Significant association of treatment response and a CRHR1 haplotype occurred only in the HA group and was not present in the LA group. The association was also not present when LA and HA subjects were grouped. These data suggest that the phenotype of antidepressant treatment response is heterogeneous and that variations in the CRHR1 gene may only be associated with a subgroup that has depression and HA levels, both depression and anxiety being mediated at least in part by CRH pathways. These results also indicate that the aggregation of all patients undergoing a treatment into one group may limit our ability to detect the effects of genetic variants on pathophysiologically defined subgroups.
The genetic substrate for the phenotype of antidepressant treatment response has been studied by several groups. The most consistent findings have been of associations between antidepressant treatment response with the insert/delete polymorphism of the upstream regulatory region of the serotonin transporter gene.39, 40, 41, 42, 43, 44 Other genes shown to be associated with antidepressant treatment response include tryptophan hydroxylase45, 46 and the serotonin 2A receptor.47
Antidepressants act on monoaminergic systems with pharmacological effects that are rapid and biochemically evident within hours of initial drug administration. Yet, clinical antidepressant effects only appear after daily treatment for 4–8 weeks. Moreover, drugs of various classes, which initially act on distinct monoamines such as serotonin or norepinephrine, have similar clinical antidepressant effects. Based on these facts, a working hypothesis in the field is that there are final, common pathways to antidepressant action that are activated after chronic treatment with monoaminergic drugs.48, 49 CRHR1 is considered to be part of one of such pathway. The findings reported here represent a new line of evidence that further strengthen the concept that CRH has a role in depression and that CRHR1 is involved in antidepressant response. Importantly, these findings suggest that specific variants of the CRHR1 gene may influence the efficacy of CRHR1 agonists or antagonists.22, 33, 34, 35
There are several limitations to this work. Our sample is small and represents one ethnic group, Mexican-Americans, studied in one geographical area: Los Angeles, California. The fact that only one group from one site is represented has advantages and makes the sample more informative and less biased than if the total n included a variety of ethnic groups and geographical sites. However, this type of approach requires replication in other groups. The necessary next steps in this work involve two parallel strategies: first, these findings need to be validated in a second group of antidepressant-treated Mexican-Americans, and then replicated in other populations; second, it would be justified to conduct genotyping of additional SNPs in the CRH pathway and in stress-related neuroendocrine-immune systems.
The finding that variants in CRHR1 appear to be associated with response to treatment in diseases as disparate as asthma and depression illustrates the fact that stress-inflammatory pathways are common to a variety of diseases and that pathways of relevance to pharmacogenetics cut across disease states. Additionally, in this case even though the diseases affect very distinct organs, lung and brain, they might represent different manifestations of immune dysfunction. The immunologic component of asthma is obvious. Depression also appears to have an immune substrate, which has been discussed extensively elsewhere.50, 51 Of interest, an association between depression and atopy has been recently reported in the Northern Finland 1966 Birth Cohort.52, 53
It is noteworthy that CRHR1 has a key role in inflammation,54, 55 and that CRHR1 antagonists, which have been used to treat depression,34, 35 also suppress peripheral inflammation.56, 57, 58 Antidepressants are known to modulate inflammatory responses after chronic administration, in a time course that is reminiscent of the time frame of antidepressant effects and they also confer protection against cytokine-induced depressive-like biological and behavioral changes.50, 51, 59, 60, 61 Moreover, concentrations of circulating immune mediators have been found to be elevated in depression.62, 63 Future studies should examine whether there is an interaction between the therapeutic effects of CRHR1 on inflammation and depression or if these are independent of each other.
Translational research on antidepressant pharmacogenetics might benefit from the use of phenotypically characterized subgroups in whom candidate genes can be selected based on a strong rationale for association, in a manner analogous to what we accomplished here by studying a gene involved in anxiety and depression in subjects who had high ratings both in depression and anxiety scales. In conclusion, we report in a small sample of depressed Mexican-Americans studied in Los Angeles an association between a CRHR1 haplotype and response to antidepressant treatment, but only in patients who were both depressed and highly anxious. Future studies should attempt to validate and replicate this finding.
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This work was supported by NIH Grants GM61394, HL65899, RR017365, MH062777, RR000865, K30HL04526, RR16996, HG002500, DK063240 and T32MH017140, and by an award from the Dana Foundation. We are grateful for the contributions of Israel Alvarado, Deborah L Flores, Lorraine Garcia-Teague, Patricia Reyes, Isabel Rodriguez, Gabriela Marquez and Gareth Holden.
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Licinio, J., O'Kirwan, F., Irizarry, K. et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol Psychiatry 9, 1075–1082 (2004) doi:10.1038/sj.mp.4001587
- corticotropin-releasing hormone
- corticotropin-releasing hormone receptor
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