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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 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.

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References

  1. Licinio J, Wong ML . The pharmacogenomics of depression. Pharmacogenom J 2001; 1: 175–177.

    Article  CAS  Google Scholar 

  2. Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Berglund PA et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry 2003; 64: 1465–1475.

    Article  Google Scholar 

  3. Licinio J, Wong M-L . Pharmacogenomics: The Search for Individualized Therapies. Wiley-VCH: Weinheim (Germany), 2002 p 559.

    Book  Google Scholar 

  4. Perrin MH, Donaldson CJ, Ruoping C, Lewis KA, Vale WW . Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor. Endocrinology 1993; 133: 3058–3061.

    Article  CAS  Google Scholar 

  5. Wong ML, Licinio J, Pasternak KI, Gold PW . Localization of corticotropin-releasing hormone (CRH) receptor mRNA in adult rat brain by in situ hybridization histochemistry. Endocrinology 1994; 135: 2275–2278.

    Article  CAS  Google Scholar 

  6. Potter E, Sutton S, Donaldson C, Chen R, Perrin M, Lewis K et al. Distribution of corticotropin-releasing factor receptor mRNA expression in the rat brain and pituitary. Proc Natl Acad Sci USA 1994; 91: 8777–8781.

    Article  CAS  Google Scholar 

  7. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF . Cortisol production in depressive illness: a clinical and biochemical clarification. Arch Gen Psychiatry 1970; 23: 289–298.

    Article  CAS  Google Scholar 

  8. Carroll BJ, Feinberg M, Greden JF . A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 1981; 38: 15–22.

    Article  CAS  Google Scholar 

  9. Nemeroff CB, Wilderlov E, Bisette G, Walleus H, Karlsson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing-factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342–1344.

    Article  CAS  Google Scholar 

  10. Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 1984; 141: 619–627.

    Article  CAS  Google Scholar 

  11. Holsboer F, Muller OA, Doerr HG . ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: relationship to multi-steroid responses after ACTH stimulation and dexamethasone suppression. Psychoneuroendology 1984; 9: 147–160.

    Article  CAS  Google Scholar 

  12. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986; 314: 1329–1335.

    Article  CAS  Google Scholar 

  13. Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–330.

    Article  CAS  Google Scholar 

  14. Brady LS, Whitfield Jr HJ, Fox RJ, Gold PW, Herkenham M . Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest 1991; 87: 831–837.

    Article  CAS  Google Scholar 

  15. Brady LS, Gold PW, Herkenham M, Lynn AB, Whitfield Jr HJ . The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res 1992; 572: 117–125.

    Article  CAS  Google Scholar 

  16. Reul JM, Stec I, Soder M, Holsboer F . Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993; 133: 312–320.

    Article  CAS  Google Scholar 

  17. Gold PW, Chrousos GP . Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 2002; 7: 254–275.

    Article  CAS  Google Scholar 

  18. Michelson D, Galliven E, Hill L, Demitrack M, Chrousos G, Gold P . Chronic imipramine is associated with diminished hypothalamic-pituitary-adrenal axis responsivity in healthy humans. J Clin Endocrinol Metab 1997; 82: 2601–2606.

    Article  CAS  Google Scholar 

  19. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 2004; 13: 1353–1359.

    Article  CAS  Google Scholar 

  20. Bale TL, Vale WW . CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 2004; 44: 525–557.

    Article  CAS  Google Scholar 

  21. Bale TL, Picetti R, Contarino A, Koob GF, Vale WW, Lee KF . Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 2002; 22: 193–199.

    Article  CAS  Google Scholar 

  22. Schulz DW, Mansbach RS, Sprouse J, Braselton JP, Collins J, Corman M et al. CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors. Proc Natl Acad Sci USA 1996; 93: 10477–10482.

    Article  CAS  Google Scholar 

  23. American-Psychiatric-Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association: Washington, DC, 1994.

  24. Hazuda HP, Comeaux PJ, Stern MP, Haffner SM, Eifler CW, Rosenthal M . A comparison of three indicators for identifying Mexican Americans in epidemiologic research. Methodological findings from the San Antonio Heart Study. Am J Epidemiol 1986; 123: 96–112.

    Article  CAS  Google Scholar 

  25. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  Google Scholar 

  26. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA . Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002; 70: 425–434.

    Article  Google Scholar 

  27. Sebastiani P, Lazarus R, Weiss ST, Kunkel LM, Kohane IS, Ramoni MF . Minimal haplotype tagging. Proc Natl Acad Sci USA 2003; 100: 9900–9905.

    Article  CAS  Google Scholar 

  28. Hardy GH . Mendelian proportions in a mixed population. Section: ‘Discussion and Correspondence’. Science 1908; 28: 49–50.

    CAS  Google Scholar 

  29. Weinberg W . Über den Nachweis der Vererbung beim Menchen. Jahresh. Verein f. vaterl. Naturk Wüttemberg 1908; 64: 368–382.

    Google Scholar 

  30. Stern C . The Hardy–Weinberg law. Science 1943; 97: 137–138.

    Article  CAS  Google Scholar 

  31. Brady LS, Glowa J, Herkenham M . Electroconvulsive treatment induces long-term changes in corticotropin releasing hormone and tyrosine hydroxylase mRNA levels in rat brain. J Clin Invest 1994; 94: 1263–1268.

    Article  CAS  Google Scholar 

  32. Holsboer F, Barden N . Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996; 17: 187–205.

    Article  CAS  Google Scholar 

  33. Deak T, Nguyen KT, Ehrlich AL, Watkins LR, Spencer RL, Maier SF et al. The impact of the nonpeptide corticotropin-releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress. Endocrinology 1999; 140: 79–86.

    Article  CAS  Google Scholar 

  34. Holsboer F . Corticotropin-releasing hormone modulators and depression. Curr Opin Invest Drugs 2003; 4: 46–50.

    CAS  Google Scholar 

  35. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34: 171–181.

    Article  CAS  Google Scholar 

  36. Wong ML, Webster EL, Spokes H, Phu P, Ehrhart-Bornstein M, Bornstein S et al. Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress. Life Sci 1999; 65: L53–L58.

    Article  Google Scholar 

  37. Wong M-L, Licinio J . From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov 2004; 3: 136–151.

    Article  CAS  Google Scholar 

  38. Hamilton M . The assessment of anxiety states by ratings. Br J Med Psychol 1959; 32: 50–55.

    Article  CAS  Google Scholar 

  39. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M . Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998; 3: 508–511.

    Article  CAS  Google Scholar 

  40. Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E . Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20: 105–107.

    Article  CAS  Google Scholar 

  41. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23: 587–590.

    Article  CAS  Google Scholar 

  42. Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, di Bella D et al. Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156: 1450–1452.

    CAS  Google Scholar 

  43. Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 383–386.

    Article  CAS  Google Scholar 

  44. Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000; 11: 215–219.

    Article  CAS  Google Scholar 

  45. Serretti A, Zanardi R, Cusin C, Rossini D, Lorenzi C, Smeraldi E . Tryptophan hydroxylase gene associated with paroxetine antidepressant activity. Eur Neuropsychopharmacol 2001; 11: 375–380.

    Article  CAS  Google Scholar 

  46. Serretti A, Zanardi R, Rossini D, Cusin C, Lilli R, Smeraldi E . Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol Psychiatry 2001; 6: 586–592.

    Article  CAS  Google Scholar 

  47. Cusin C, Serretti A, Zanardi R, Lattuada E, Rossini D, Lilli R et al. Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int J Neuropsychopharmacology 2002; 5: 27–35.

    Article  CAS  Google Scholar 

  48. Wong ML, Khatri P, Licinio J, Esposito A, Gold PW . Identification of hypothalamic transcripts upregulated by antidepressants. Biochem Biophys Res Commun 1996; 229: 275–279.

    Article  CAS  Google Scholar 

  49. Wong M-L, Licinio J . Research and treatment approaches to depression. Nat Rev Neurosci 2001; 2: 343–351.

    Article  CAS  Google Scholar 

  50. Dantzer R, Wollman E, Vitkovic L, Yirmiya R . Cytokines and depression: fortuitous or causative association? Mol Psychiatry 1999; 4: 328–332.

    Article  CAS  Google Scholar 

  51. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

    Article  CAS  Google Scholar 

  52. Timonen M, Jokelainen J, Hakko H, Silvennoinen-Kassinen S, Meyer-Rochow VB, Herva A et al. Atopy and depression: results from the Northern Finland 1966 Birth Cohort Study. Mol Psychiatry 2003; 8: 738–744.

    Article  CAS  Google Scholar 

  53. Licinio J, Wong ML . Data from the Northern Finland 1966 Birth Cohort support an association between depression and immune function. Mol Psychiatry 2003; 8: 711–712.

    Article  CAS  Google Scholar 

  54. Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ, Gold PW et al. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci USA 1989; 86: 2374–2378.

    Article  CAS  Google Scholar 

  55. Chrousos GP . The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332: 1351–1362.

    Article  CAS  Google Scholar 

  56. Webster EL, Lewis DB, Torpy DJ, Zachman EK, Rice KC, Chrousos GP . In vivo and in vitro characterization of antalarmin, a nonpeptide corticotropin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996; 137: 5450–5747.

    Google Scholar 

  57. Webster EL, Barrientos RM, Contoreggi C, Isaac MG, Ligier S, Gabry KE et al. Corticotropin releasing hormone (CRH) antagonist attenuates adjuvant induced arthritis: role of CRH in peripheral inflammation. J Rheumatol 2002; 29: 1252–1261.

    CAS  PubMed  Google Scholar 

  58. Wlk M, Wang CC, Venihaki M, Liu J, Zhao D, Anton PM et al. Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum. Gastroenterology 2002; 123: 505–515.

    Article  CAS  Google Scholar 

  59. Leonard BE . The immune system, depression and the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 767–780.

    Article  CAS  Google Scholar 

  60. Connor TJ, Harkin A, Kelly JP, Leonard BE . Olfactory bulbectomy provokes a suppression of interleukin-1beta and tumour necrosis factor-alpha production in response to an in vivo challenge with lipopolysaccharide: effect of chronic desipramine treatment. Neuroimmunomodulation 2000; 7: 27–35.

    Article  CAS  Google Scholar 

  61. Castanon N, Leonard BE, Neveu PJ, Yirmiya R . Effects of antidepressants on cytokine production and actions. Brain Behav Immun 2002; 16: 569–574.

    Article  CAS  Google Scholar 

  62. Maes M, Vandoolaeghe E, Ranjan R, Bosmans E, Bergmans R, Desnyder R . Increased serum interleukin-1-receptor-antagonist concentrations in major depression. J Affect Disord 1995; 36: 29–36.

    Article  CAS  Google Scholar 

  63. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H . Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9: 853–858.

    Article  CAS  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/sj.mp.4001587

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