The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality1 as well as the treatment of depression2. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Molecular Psychiatry Open Access 06 October 2022
Molecular Psychiatry Open Access 14 September 2022
Nature Communications Open Access 18 August 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).
Nemeroff, C.B. & Owens, M.J. Treatment of mood disorders. Nat. Neurosci. 5, 1068–1070 (2002).
Holsboer, F. & Barden, N. Antidepressants and hypothalamic–pituitary–adrenocortical regulation. Endocr. Rev. 17, 187–205 (1996).
Nemeroff, C.B. The role of corticotropin–releasing factor in the pathogenesis of major depression. Pharmacopsychiatry 21, 76–82 (1988).
Nemeroff, C.B. et al. Elevated concentrations of CSF corticotropin–releasing factor–like immunoreactivity in depressed patients. Science 226, 1342–1344 (1984).
Nemeroff, C.B., Owens, M.J., Bissette, G., Andorn, A.C. & Stanley, M. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch. Gen. Psychiatry 45, 577–579 (1988).
Purba, J.S., Hoogendijk, W.J., Hofman, M.A. & Swaab, D.F. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch. Gen. Psychiatry 53, 137–143 (1996).
Timpl, P. et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin–releasing hormone receptor. Nat. Genet. 19, 162–166 (1998).
Muller, M.B. et al. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat. Neurosci. 6, 1100–1107 (2003).
Pariante, C.M. & Miller, A.H. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391–404 (2001).
Barden, N., Stec, I.S., Montkowski, A., Holsboer, F. & Reul, J.M. Endocrine profile and neuroendocrine challenge tests in transgenic mice expressing antisense RNA against the glucocorticoid receptor. Neuroendocrinology 66, 212–220 (1997).
Pratt, W.B. & Toft, D.O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997).
Cheung, J. & Smith, D.F. Molecular chaperone interactions with steroid receptors: an update. Mol. Endocrinol. 14, 939–946 (2000).
Schmidt, U. et al. Essential role of the unusual DNA-binding motif of BAG-1 for inhibition of the glucocorticoid receptor. J. Biol. Chem. 278, 4926–4931 (2003).
Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).
Schiene-Fischer, C. & Yu, C. Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Lett. 495, 1–6 (2001).
Davies, T.H., Ning, Y.M. & Sanchez, E.R. A new first step in activation of steroid receptors: hormone–induced switching of FKBP51 and FKBP52 immunophilins. J. Biol. Chem. 277, 4597–4600 (2002).
Denny, W.B., Valentine, D.L., Reynolds, P.D., Smith, D.F. & Scammell, J.G. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 141, 4107–4113 (2000).
Reynolds, P.D. et al. Glucocorticoid-resistant B-lymphoblast cell line derived from the Bolivian squirrel monkey (Saimiri boliviensis boliviensis). Lab. Anim. Sci. 48, 364–370 (1998).
Scammell, J.G., Denny, W.B., Valentine, D.L. & Smith, D.F. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen. Comp. Endocrinol. 124, 152–165 (2001).
Vermeer, H., Hendriks-Stegeman, B.I., van der Burg, B., van Buul-Offers, S.C. & Jansen, M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J. Clin. Endocrinol. Metab. 88, 277–284 (2003).
Heuser, I., Yassouridis, A. & Holsboer, F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J. Psychiatr. Res. 28, 341–356 (1994).
Wittchen, H. et al. Screening for mental disorders: performance of the Composite International Diagnostic – Screener (CID–S). Int. J. Methods Psychiatr. Res. 8, 59–70 (1999).
Zobel, A.W., Nickel, T., Sonntag, A., Uhr, M., Holsboer, F. & Ising, M. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study. J. Psychiatr. Res. 35, 83–94 (2001).
Fisher, R.A. Statistical Methods for Research Workers (Oliver and Boyd, London, 1932).
Dudbridge, F. & Koeleman, B.P. Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am. J. Hum. Genet. 75, 424–435 (2004).
Neale, B.M. & Sham, P.C. The future of association studies: gene-based analysis and replication. Am. J. Hum. Genet. 75, 353–362 (2004).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Lewontin, R.C. On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).
Holsboer, F., Lauer, C.J., Schreiber, W. & Krieg, J.C. Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology, 62, 340–347 (1995).
We thank G. Ernst, G. Gajeswski, J. Huber, C. Stallwanger and A. Tontsch for their excellent technical help and Dr. M.E. Keck for helpful discussions. This study was supported in part by the German Ministry of Education and Research (BMBF) within the National Genome Research Network (NGFN) and the Bavarian Ministry of Commerce.
The authors declare no competing financial interests.
Information on location of SNPs on the UCSC genome build version hg15, heterozygosity and Hardy-Weinberg equilibrium. (PDF 17 kb)
Association of confounding variables with response to antidepressant treatment and rs1360780 genotype. (PDF 4 kb)
Assessment of population stratification. (PDF 20 kb)
About this article
Cite this article
Binder, E., Salyakina, D., Lichtner, P. et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36, 1319–1325 (2004). https://doi.org/10.1038/ng1479
This article is cited by
Molecular Psychiatry (2023)
Burning down the house: reinventing drug discovery in psychiatry for the development of targeted therapies
Molecular Psychiatry (2023)
Child Psychiatry & Human Development (2023)
Association of SNPs in the FK-506 binding protein (FKBP5) gene among Han Chinese women with polycystic ovary syndrome
BMC Medical Genomics (2022)
Nature Communications (2022)