Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response.
BACKGROUND
The corticotropin-releasing factor (CRF, or corticotropin-releasing hormone) and arginine vasopressin systems have been implicated in the pathophysiology of anxiety and depressive disorders and response to antidepressant treatment.


OBJECTIVE
To study the association of genetic variants in 10 genes that regulate the CRF and arginine vasopressin systems with treatment response to citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample (N = 1768).


METHODS
Pharmacogenetic association study derived from the STAR*D study, a multicenter, prospective, open, 12-week effectiveness trial.


METHODS
Outpatient primary care and psychiatric clinics. Patients Individuals with nonpsychotic major depressive disorder for whom DNA was available who were subsequently treated with citalopram hydrobromide for 4 to 12 weeks. Intervention Flexible doses of citalopram. Main Outcome Measure Association of genetic polymorphisms in genes encoding the CRF system with response and remission to citalopram treatment at exit visit.


RESULTS
One single-nucleotide polymorphism (SNP) (rs10473984) within the CRHBP locus showed a significant association with both remission (P = 6.0 x 10(-6); corrected, P = .0026) and reduction in depressive symptoms (P = 7.0 x 10(-7); corrected, P = .00031) in response to citalopram. The T allele of this SNP was associated with poorer treatment outcome in 2 of the 3 ethnic subsamples (African American and Hispanic), despite large differences in minor allele frequency. This association was more pronounced in patients with features of anxious depression (P = .008). The nonresponse allele was shown to be associated with overall higher plasma corticotropin levels and more pronounced dexamethasone suppression of corticotropin.


CONCLUSIONS
These data indicate that a genetic variant within the CRHBP locus affects response to citalopram in African American and Hispanic patients, suggesting a role for this gene and for the CRF system in antidepressant treatment response.
Binder
Elisabeth B
EB
Max-Planck Institute of Psychiatry, Kraepelinstr 2-10, 80804 Munich, Germany. ebinder@emory.edu
Owens
Michael J
MJ
Liu
Wei
W
Deveau
Todd C
TC
Rush
A John
AJ
Trivedi
Madhukar H
MH
Fava
Maurizio
M
Bradley
Bekh
B
Ressler
Kerry J
KJ
Nemeroff
Charles B
CB
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D015283:Citalopram / Q000627:therapeutic use*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005796:Genes / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D017483:Receptors, Vasopressin / Q000235:genetics / Q000502:physiology; D000099052:CRF Receptor, Type 1
D018687:Antidepressive Agents, Second-Generation; C101531:CRF receptor type 2; D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D017483:Receptors, Vasopressin; D015283:Citalopram; C067133:corticotropin releasing factor-binding protein; D000099052:CRF Receptor, Type 1; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone