title: Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.
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.
authors.affiliation: Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. ebinder@genetics.emory.edu
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.forename: Daria
authors.initials: D
authors.lastname: Salyakina
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Gabriele M
authors.initials: GM
authors.lastname: Wochnik
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.forename: Sergi
authors.initials: S
authors.lastname: Papiol
authors.forename: Shaun
authors.initials: S
authors.lastname: Seaman
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kohli
authors.forename: Thomas
authors.initials: T
authors.lastname: Nickel
authors.forename: Heike E
authors.initials: HE
authors.lastname: Künzel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fuchs
authors.forename: Matthias
authors.initials: M
authors.lastname: Majer
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfennig
authors.forename: Nikola
authors.initials: N
authors.lastname: Kern
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brunner
authors.forename: Sieglinde
authors.initials: S
authors.lastname: Modell
authors.forename: Thomas
authors.initials: T
authors.lastname: Baghai
authors.forename: Tobias
authors.initials: T
authors.lastname: Deiml
authors.forename: Peter
authors.initials: P
authors.lastname: Zill
authors.forename: Brigitta
authors.initials: B
authors.lastname: Bondy
authors.forename: Rainer
authors.initials: R
authors.lastname: Rupprecht
authors.forename: Thomas
authors.initials: T
authors.lastname: Messer
authors.forename: Oliver
authors.initials: O
authors.lastname: Köhnlein
authors.forename: Heike
authors.initials: H
authors.lastname: Dabitz
authors.forename: Tanja
authors.initials: T
authors.lastname: Brückl
authors.forename: Nina
authors.initials: N
authors.lastname: Müller
authors.forename: Hildegard
authors.initials: H
authors.lastname: Pfister
authors.forename: Roselind
authors.initials: R
authors.lastname: Lieb
authors.forename: Jakob C
authors.initials: JC
authors.lastname: Mueller
authors.forename: Elin
authors.initials: E
authors.lastname: Lõhmussaar
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Bertram
authors.initials: B
authors.lastname: Muller-Myhsok
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015153:Blotting, Western; D003346:Corticotropin-Releasing Hormone / Q000235:genetics; D003863:Depression / Q000188:drug therapy / Q000235:genetics*; D005453:Fluorescence; D005787:Gene Frequency; D005838:Genotype; D005858:Germany; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D009481:Neurophysins / Q000235:genetics; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014667:Vasopressins / Q000235:genetics
chemical_list: C438657:AVP protein, human; D000928:Antidepressive Agents; D018841:HSP90 Heat-Shock Proteins; D009481:Neurophysins; D011498:Protein Precursors; D011965:Receptors, Glucocorticoid; D014667:Vasopressins; D003346:Corticotropin-Releasing Hormone