Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.
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.
Binder
Elisabeth B
EB
Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. ebinder@genetics.emory.edu
Salyakina
Daria
D
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P
Wochnik
Gabriele M
GM
Ising
Marcus
M
Pütz
Benno
B
Papiol
Sergi
S
Seaman
Shaun
S
Lucae
Susanne
S
Kohli
Martin A
MA
Nickel
Thomas
T
Künzel
Heike E
HE
Fuchs
Brigitte
B
Majer
Matthias
M
Pfennig
Andrea
A
Kern
Nikola
N
Brunner
Jürgen
J
Modell
Sieglinde
S
Baghai
Thomas
T
Deiml
Tobias
T
Zill
Peter
P
Bondy
Brigitta
B
Rupprecht
Rainer
R
Messer
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T
Köhnlein
Oliver
O
Dabitz
Heike
H
Brückl
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T
Müller
Nina
N
Pfister
Hildegard
H
Lieb
Roselind
R
Mueller
Jakob C
JC
Lõhmussaar
Elin
E
Strom
Tim M
TM
Bettecken
Thomas
T
Meitinger
Thomas
T
Uhr
Manfred
M
Rein
Theo
T
Holsboer
Florian
F
Muller-Myhsok
Bertram
B
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
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