Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

HPA axis genetic variation, cortisol and psychosis in major depression

Molecular Psychiatry volume 19, pages 220–227 (2014)Cite this article

Subjects

A Corrigendum to this article was published on 27 May 2014

Abstract

Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r2=0.288) and from 0100 to 0900 h (r2=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Anton RF . Urinary free cortisol in psychotic depression. Biol Psychiatry 1987; 22: 24–34.

    Article  CAS  PubMed  Google Scholar 

  2. Posener JA, DeBattista C, Williams GH, Kraemer HC, Kalehzan BM, Schatzberg AF . 24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression. Arch Gen Psychiatry 2000; 57: 755–760.

    Article  CAS  PubMed  Google Scholar 

  3. Belanoff JK, Kalehzan M, Sund B, Fleming Ficek SK, Schatzberg AF . Cortisol activity and cognitive changes in psychotic major depression. Am J Psychiatry 2001; 158: 1612–1616.

    Article  CAS  PubMed  Google Scholar 

  4. Keller J, Flores B, Gomez RG, Solvason HB, Kenna H, Williams GH et al. Cortisol circadian rhythm alterations in psychotic major depression. Biol Psychiatry 2006; 60: 275–281.

    Article  CAS  PubMed  Google Scholar 

  5. Lembke A, Gomez R, Tenakoon L, Keller J, Cohen G, Williams GH et al. The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression. Psychoneuroendocrinology 2012; 38: 115–121.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Evans DL, Burnett GB, Nemeroff CB . The dexamethasone suppression test in the clinical setting. Am J Psychiatry 1983; 140: 586–589.

    Article  CAS  PubMed  Google Scholar 

  7. Nelson JC, Davis JM . DST studies in psychotic depression: a meta-analysis. Am J Psychiatry 1997; 154: 1497–1503.

    Article  CAS  PubMed  Google Scholar 

  8. Schatzberg AF, Rothschild AJ, Stahl JB, Bond TC, Rosenbaum AH, Lofgren SB et al. The dexamethasone suppression test: identification of subtypes of depression. Am J Psychiatry 1983; 140: 88–91.

    Article  CAS  PubMed  Google Scholar 

  9. Rothschild AJ, Schatzberg AF, Rosenbaum AH, Stahl JB, Cole JO . The dexamethasone suppression test as a discriminator among subtypes of psychotic patients. Br J Psychiatry 1982; 141: 471–474.

    Article  CAS  PubMed  Google Scholar 

  10. Arana GW, Baldessarini RJ, Ornsteen M . The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Commentary and review. Arch Gen Psychiatry 1985; 42: 1193–1204.

    Article  CAS  PubMed  Google Scholar 

  11. Lupien SJ, Gillin CJ, Hauger RL . Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci 1999; 113: 420–430.

    Article  CAS  PubMed  Google Scholar 

  12. Gomez RG, Fleming SH, Keller J, Flores B, Kenna H, DeBattista C et al. The neuropsychological profile of psychotic major depression and its relation to cortisol. Biol Psychiatry 2006; 60: 472–478.

    Article  PubMed  Google Scholar 

  13. Leonard BE, Myint A . The psychoneuroimmunology of depression. Hum Psychopharmacol 2009; 24: 165–175.

    CAS  PubMed  Google Scholar 

  14. Hsu SY, Hsueh AJ . Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 2001; 7: 605–611.

    Article  CAS  PubMed  Google Scholar 

  15. De Kloet ER . Hormones and the stressed brain. Ann NY Acad Sci 2004; 1018: 1–15.

    Article  CAS  PubMed  Google Scholar 

  16. Turner JD, Alt SR, Cao L, Vernocchi S, Trifonova S, Battello N et al. Transcriptional control of the glucocorticoid receptor: CpG islands, epigenetics and more. Biochem Pharmacol Ann NY Acad Sci 2010; 80: 1860–1868.

    CAS  Google Scholar 

  17. Sanchez MM, Young LJ, Plotsky PM, Insel TR . Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 1999; 408: 365–377.

    Article  CAS  PubMed  Google Scholar 

  18. Keck ME, Kern N, Erhardt A, Unschuld PG, Ising M, Salyakina D et al. Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 1196–1204.

    Article  PubMed  Google Scholar 

  19. Liu Z, Zhu F, Wang G, Xiao Z, Wang H, Tang J et al. Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression. Neurosci Lett 2006; 404: 358–362.

    Article  CAS  PubMed  Google Scholar 

  20. Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 2008; 65: 190–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ressler KJ, Bradley B, Mercer KB, Deveau TC, Smith AK, Gillespie CF et al. Polymorphisms in CRHR1 and the serotonin transporter loci: gene x gene x environment interactions on depressive symptoms. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 812–824.

    CAS  PubMed  Google Scholar 

  22. Binder EB, Owens MJ, Liu W, Deveau TC, Rush AJ, Trivedi MH et al. Association of polymorphisms in genes regulating the corticotropin-releasing factor system with antidepressant treatment response. Arch Gen Psychiatry 2010; 67: 369–379.

    Article  CAS  PubMed  Google Scholar 

  23. van Winsen LM, Manenschijn L, van Rossum EF, Crusius JB, Koper JW, Polman CH et al. A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis. J Clin Endocrinol Metab 2009; 94: 2110–2114.

    Article  CAS  PubMed  Google Scholar 

  24. Koper JW, Stolk RP, de Lange P, Huizenga NA, Molijn GJ, Pols HA et al. Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. Hum Genet 1997; 99: 663–668.

    Article  CAS  PubMed  Google Scholar 

  25. van Rossum EF, van den Akker EL . Glucocorticoid resistance. Endocr Dev 2011; 20: 127–136.

    Article  CAS  PubMed  Google Scholar 

  26. El-Hage W, Phillips ML, Radua J, Gohier B, Zelaya FO, Collier DA et al. Genetic modulation of neural response during working memory in healthy individuals: interaction of glucocorticoid receptor and dopaminergic genes. Mol Psychiatry 2011; 18: 174–182.

    Article  PubMed  Google Scholar 

  27. Fortier ME, Sengupta SM, Grizenko N, Choudhry Z, Thakur G, Joober R . Genetic evidence for the association of the hypothalamic-pituitary-adrenal (HPA) axis with ADHD and methylphenidate treatment response. Neuromolecular Med 2013; 15: 122–132.

    Article  CAS  PubMed  Google Scholar 

  28. Krishnamurthy P, Romagni P, Torvik S, Gold PW, Charney DS, Detera-Wadleigh S et al. Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression. Horm Metab Res 2008; 40: 194–198.

    Article  CAS  PubMed  Google Scholar 

  29. van Rossum EF, Binder EB, Majer M, Koper JW, Ising M, Modell S et al. Polymorphisms of the glucocorticoid receptor gene and major depression. Biol Psychiatry 2006; 59: 681–688.

    Article  CAS  PubMed  Google Scholar 

  30. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36: 1319–1325.

    Article  CAS  PubMed  Google Scholar 

  31. Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel J et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch Gen Psychiatry 2011; 68: 901–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zimmermann P, Bruckl T, Nocon A, Pfister H, Binder EB, Uhr M et al. Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study. Am J Psychiatry 2011; 168: 1107–1116.

    Article  PubMed  Google Scholar 

  33. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008; 299: 1291–1305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1980; 23: 49–65.

    Google Scholar 

  35. Thase ME, Hersen M, Bellack AS, Himmelhoch JM, Kupfer DJ . Validation of a Hamilton subscale for endogenomorphic depression. J Affect Disord 1983; 5: 267–278.

    Article  CAS  PubMed  Google Scholar 

  36. Overall JE, Gorham DE . The brief psychiatric rating scale. Psychol Rep 1961; 10: 799–812.

    Article  Google Scholar 

  37. First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition. SCID-I/P, 1/2007 revision.

  38. Pettersson FH, Anderson CA, Clarke GM, Barrett JC, Cardon LR, Morris AP et al. Marker selection for genetic case-control association studies. Nat Protoc 2009; 4: 743–752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lomelin D, Jorgenson E, Risch N . Human genetic variation recognizes functional elements in noncoding sequence. Genome Res 2010; 20: 311–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.

    Article  CAS  PubMed  Google Scholar 

  41. De Bakker PI, Graham RR, Altshuler D, Henderson BE, Haiman CA . Transferability of tag SNPs to capture common genetic variation in DNA repair genes across multiple populations. Pac Symp Biocomput 2006; 478–486.

  42. Ballard DH, Cho J, Zhao H . Comparisons of multi-marker association methods to detect association between a candidate region and disease. Genet Epidemiol 2010; 34: 201–212.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Greenwood TA, Lazzeroni LC, Murray SS, Cadenhead KS, Calkins ME, Dobie DJ et al. Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. Am J Psychiatry 2011; 168: 930–946.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gauderman WJ, Murcray C, Gilliland F, Conti DV . Testing association between disease and multiple SNPs in a candidate gene. Genet Epidemiol 2007; 31: 383–395.

    Article  PubMed  Google Scholar 

  45. Kwee LC, Liu D, Lin X, Ghosh D, Epstein MP . A powerful and flexible multilocus association test for quantitative traits. Am J Hum Genet 2008; 82: 386–397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Claes S . Glucocorticoid receptor polymorphisms in major depression. Ann NY Acad Sci 2009; 1179: 216–228.

    Article  CAS  PubMed  Google Scholar 

  47. Kumsta R, Entringer S, Koper JW, van Rossum EF, Hellhammer DH, Wust S . Sex specific associations between common glucocorticoid receptor gene variants and hypothalamus-pituitary-adrenal axis responses to psychosocial stress. Biol Psychiatry 2007; 62: 863–869.

    Article  CAS  PubMed  Google Scholar 

  48. Sinclair D, Fullerton JM, Webster MJ, Shannon Weickert C . Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. PLoS ONE 2012; 7: e31720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schatzberg AF, Posener JA, DeBattista C, Kalehzan BM, Rothschild AJ, Shear PK . Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness. Am J Psychiatry 2000; 157: 1095–1100.

    Article  CAS  PubMed  Google Scholar 

  50. Garrett A, Kelly R, Gomez R, Keller J, Schatzberg AF, Reiss AL . Aberrant brain activation during a working memory task in psychotic major depression. Am J Psychiatry 2011; 168: 173–182.

    Article  PubMed  Google Scholar 

  51. Kelly R, Garrett A, Cohen J, Gomez RG, Lembke A, Keller J et al. Altered brain function underlying verbal memory encoding and retrieval in psychotic major depression. Psychiatry Res Neuroimaging 2012; 211: 119–126.

    Article  Google Scholar 

  52. Szczepankiewicz A, Rybakowski JK, Suwalska A, Hauser J . Glucocorticoid receptor polymorphism is associated with lithium response in bipolar patients. Neuro Endocrinol Lett 2011; 32: 545–551.

    CAS  PubMed  Google Scholar 

  53. Syed AA, Halpin CG, Irving JA, Unwin NC, White M, Bhopal RS et al. A common intron 2 polymorphism of the glucocorticoid receptor gene is associated with insulin resistance in men. Clin Endocrinol (Oxf) 2008; 68: 879–884.

    Article  CAS  Google Scholar 

  54. Kumsta R, Moser D, Streit F, Koper JW, Meyer J, Wust S . Characterization of a glucocorticoid receptor gene (GR, NR3C1) promoter polymorphism reveals functionality and extends a haplotype with putative clinical relevance. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 476–482.

    Article  CAS  PubMed  Google Scholar 

  55. Rovaris DL, Mota NR, de Azeredo LA, Cupertino RB, Bertuzzi GP, Polina ER et al. MR and GR functional SNPs may modulate tobacco smoking susceptibility. J Neural Transm 2013.

  56. Funk CK, O'Dell LE, Crawford EF, Koob GF . Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 2006; 26: 11324–11332.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Keller J, Shen L, Gomez RG, Garrett A, Solvason HB, Reiss A et al. Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression. Am J Psychiatry 2008; 165: 872–880.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ishitobi Y, Nakayama S, Yamaguchi K, Kanehisa M, Higuma H, Maruyama Y et al. Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 429–436.

    Article  PubMed  Google Scholar 

  59. Ray LA, Sehl M, Bujarski S, Hutchison K, Blaine S, Enoch MA . The CRHR1 gene, trauma exposure, and alcoholism risk: a test of G x E effects. Genes Brain Behav 2013; 12: 361–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ribbe K, Ackermann V, Schwitulla J, Begemann M, Papiol S, Grube S et al. Prediction of the risk of comorbid alcoholism in schizophrenia by interaction of common genetic variants in the corticotropin-releasing factor system. Arch Gen Psychiatry 2011; 68: 1247–1256.

    Article  PubMed  Google Scholar 

  61. Hsu DT, Mickey BJ, Langenecker SA, Heitzeg MM, Love TM, Wang H et al. Variation in the corticotropin-releasing hormone receptor 1 (CRHR1) gene influences fMRI signal responses during emotional stimulus processing. J Neurosci 2012; 32: 3253–3260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mahon PB, Zandi PP, Potash JB, Nestadt G, Wand GS . Genetic association of FKBP5 and CRHR1 with cortisol response to acute psychosocial stress in healthy adults. Psychopharmacology (Berl) 2013; 227: 231–241.

    Article  CAS  Google Scholar 

  63. Wasserman D, Sokolowski M, Rozanov V, Wasserman J . The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav 2008; 7: 14–19.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Aspects of this study were supported by grants from the Pritzker Foundation, NIH MH50604 to Alan Schatzberg, NIH MH19938 to Alan Schatzberg, and NIH/NCRR CTSA award number UL1 RR025744.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    A F Schatzberg, J Keller, L Tennakoon, A Lembke, J E Sarginson, L C Lazzeroni & G M Murphy

  2. Department of Medicine, Harvard Medical School and Brigham & Women’s Hospital, Boston, MA, USA

    G Williams

  3. Division of Endocrinology, Gerontology and Metabolism, VA Palo Alto Health Care System, Palo Alto, CA, USA

    F B Kraemer

  4. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    F B Kraemer

Authors
  1. A F Schatzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Tennakoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Lembke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F B Kraemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J E Sarginson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L C Lazzeroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G M Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A F Schatzberg.

Ethics declarations

Competing interests

In the last 3 years, Dr Alan Schatzberg has served as a consultant for the following companies: BrainCells, CeNeRx, Cervel, Eli Lilly, Forest Labs, GSK, Jazz, Lundbeck, Merck, Neuronetics, Novadel, Novartis, Pfizer, PharmaNeuroBoost, Sanofi-Aventis, Sunovion, Synosia, Takeda, Xhale, Xytis and Wyeth. He has held equity in the following companies: Amnestix, BrainCells, CeNeRx, Cervel, Corcept (co-founder), Delpor, Forest Labs, Merck, Neurocrine, Novadel, Pfizer, PharmaNeuroBoost, Somaxon, Synosia and Xhale. Dr Schatzberg is a named inventor on pharmacogenetic use patents on prediction of antidepressant response and glucocorticoid antagonists in psychiatry. Dr Greer Murphy has served as a consultant for Brain Resource, Ltd. Fredric B Kraemer has served as a consultant for BASF. Several authors have been named on a provisional use patent related to the findings in this manuscript, including Alan Schatzberg, Laura Lazzeroni, Greer Murphy and Jennifer Keller.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schatzberg, A., Keller, J., Tennakoon, L. et al. HPA axis genetic variation, cortisol and psychosis in major depression. Mol Psychiatry 19, 220–227 (2014). https://doi.org/10.1038/mp.2013.129

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2013.129

Keywords

This article is cited by

Search

Advanced search

Quick links