Abstract
Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR-stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N=18 cases/18 controls) and a test cohort (N=11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of major depression, were found to be reliable markers of GR-activation. Using random forest analyses for classification, GR-stimulated gene expression outperformed baseline gene expression as a classifier for case and control status with a correct classification of 79.1 vs 41.6% in the test cohort. GR-stimulated gene expression performed best in dexamethasone non-suppressor patients (88.7% correctly classified with 100% sensitivity), but also correctly classified 77.3% of the suppressor patients (76.7% sensitivity), when using a refined set of 19 genes. Our study suggests that in vivo stimulated gene expression in peripheral blood cells could be a promising molecular marker of altered GR-functioning, an important component of the underlying pathology, in patients suffering from depressive episodes.
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Acknowledgements
The authors would like to thank A Sangl, M Asmus, G Ernst-Jansen, E Kappelmann, M Hartung and B Siegel for their excellent technical assistance. The study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481. Additionally, the study was supported by a grant of Neuronova G GmbH.
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Patent applications: Menke, Binder, Holsboer inventors: Means and methods for diagnosing predisposition for treatment emergent suicidal ideation (TESI). European application number: 08016477.5 International application number: PCT/EP2009/061575. Binder, Müller-Myhsok, Uhr, Holsboer inventors: FKBP5: a novel target for antidepressant therapy. International publication number: WO 2005/054500 Polymorphisms in ABCB1 associated with a lack of clinical response to medicaments. International application number: PCT/EP2005/005194. Elisabeth B Binder currently received grant support from NIMH, Doris Duke Charitable foundation, Behrens-Weise-Stiftung and PharmaNeuroBoost. Florian Holsboer is the founder and share holder of Affectis Pharmaceuticals and HolsboerMaschmeyer NeuroChemie GmbH. The other authors declare no conflict of interest.
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Parts of the data have been presented at the Society of Biological Psychiatry, May 2010, New Orleans, Louisiana, USA and at the Annual Meeting of the American College of Neuropsychopharmacology, December 2009, Hollywood, Florida, USA.
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
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Menke, A., Arloth, J., Pütz, B. et al. Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients. Neuropsychopharmacol 37, 1455–1464 (2012). https://doi.org/10.1038/npp.2011.331
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DOI: https://doi.org/10.1038/npp.2011.331
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