Abstract
Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor’s choice. In addition to the FKBP5 genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARKTM reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of FKBP5 gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the FKBP5 single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that FKBP5 and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development.
Highlights
Depression is a very serious and highly prevalent mental disorder
The same genetic variations increased the risk for adult depression [22,23] and for post-traumatic stress disorder [22,24] in individuals reporting early exposure to an adverse environment. These findings suggest the involvement of FKBP5 gene variants in depression risk and antidepressant treatment outcome; the role of FKBP5 gene expression is yet to be elucidated
Munich Antidepressant Response Signature (MARS) is a naturalistic open-label longitudinal treatment study with inpatients suffering from a depressive episode
Summary
Depression is a very serious and highly prevalent mental disorder. Epidemiological studies suggest an average annual prevalence rate of 5–6% across different cultures, which increases to10–15% over a lifetime [1]. Depression is a highly recurrent disorder with more than half of first-episode patients experiencing a second episode or more [2]. It is a highly disabling disorder, ranking third among all causes of time spent living in disability, with only low-back pain and headache disorders causing longer periods of disability [3]. As depression is a multifactorial disorder, genetic and environmental factors contribute substantially to depression risk and outcome development [4]. Twin and family studies suggest a 35–40% contribution of genetic factors to disease liability, while the remaining risk variance is best explained by individual environmental events and biographic circumstances [4,5]. Early adverse life experience has been frequently identified as an important environmental risk factor for adult depression [6,7], and severe and/or long-lasting stressors can trigger new disease episodes in vulnerable individuals [6,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
