Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

  • Nat Genet. 2004 Dec;36(12):1319-25. doi: 10.1038/ng1479.
Elisabeth B Binder  1 ,  Daria Salyakina ,  Peter Lichtner ,  Gabriele M Wochnik ,  Marcus Ising ,  Benno Pütz ,  Sergi Papiol ,  Shaun Seaman ,  Susanne Lucae ,  Martin A Kohli ,  Thomas Nickel ,  Heike E Künzel ,  Brigitte Fuchs ,  Matthias Majer ,  Andrea Pfennig ,  Nikola Kern ,  Jürgen Brunner ,  Sieglinde Modell ,  Thomas Baghai ,  Tobias Deiml ,  Peter Zill ,  Brigitta Bondy ,  Rainer Rupprecht ,  Thomas Messer ,  Oliver Köhnlein ,  Heike Dabitz ,  Tanja Brückl ,  Nina Müller ,  Hildegard Pfister ,  Roselind Lieb ,  Jakob C Mueller ,  Elin Lõhmussaar ,  Tim M Strom ,  Thomas Bettecken ,  Thomas Meitinger ,  Manfred Uhr ,  Theo Rein ,  Florian Holsboer ,  Bertram Muller-Myhsok
Affiliations
  • 1. Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. [email protected]
PMID: 15565110 DOI: 10.1038/ng1479
Abstract

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. 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.