1. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.
- Author
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Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Pütz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Künzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Köhnlein O, Dabitz H, Brückl T, Müller N, Pfister H, Lieb R, Mueller JC, Lõhmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, and Muller-Myhsok B
- Subjects
- Adult, Analysis of Variance, Antidepressive Agents administration & dosage, Blotting, Western, Corticotropin-Releasing Hormone genetics, Depression drug therapy, Fluorescence, Gene Frequency, Genotype, Germany, HSP90 Heat-Shock Proteins metabolism, Humans, Lymphocytes metabolism, Neurophysins genetics, Protein Precursors genetics, Receptors, Glucocorticoid metabolism, Regression Analysis, Reverse Transcriptase Polymerase Chain Reaction, Vasopressins genetics, Antidepressive Agents therapeutic use, Depression genetics, HSP90 Heat-Shock Proteins genetics, Hypothalamo-Hypophyseal System metabolism, Pituitary-Adrenal System metabolism, Polymorphism, Single Nucleotide genetics, Receptors, Glucocorticoid genetics
- 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.
- Published
- 2004
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