Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment by Binder Elisabeth B, Salyakina Daria, Lichtner Peter, Wochnik Gabriele M, Ising Marcus, Pütz Benno, Papiol Sergi, Seaman Shaun, Lucae Susanne, Kohli Martin A, Nickel Thomas, Künzel Heike E, Fuchs Brigitte, Majer Matthias, Pfennig Andrea, Kern Nikola, Brunner Jürgen, Modell Sieglinde, Baghai Thomas, Deiml Tobias, Zill Peter, Bondy Brigitta, Rupprecht Rainer, Messer Thomas, Köhnlein Oliver, Dabitz Heike, Brückl Tanja, Müller Nina, Pfister Hildegard, Lieb Roselind, Mueller Jakob C, Lõhmussaar Elin, Strom Tim M, Bettecken Thomas, Meitinger Thomas, Uhr Manfred, Rein Theo, Holsboer Florian, Muller-Myhsok Bertram in Nature genetics (2004). PubMed

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.

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