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. 2012 May;37(6):1455-64.
doi: 10.1038/npp.2011.331. Epub 2012 Jan 11.

Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients

Andreas Menke  1 , Janine Arloth, Benno Pütz, Peter Weber, Torsten Klengel, Divya Mehta, Mariya Gonik, Monika Rex-Haffner, Jennifer Rubel, Manfred Uhr, Susanne Lucae, Jan M Deussing, Bertram Müller-Myhsok, Florian Holsboer, Elisabeth B Binder
Affiliations

Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients

Andreas Menke et al. Neuropsychopharmacology. 2012 May.

Erratum in

  • Neuropsychopharmacology. 2012 Jul;37(8):1972

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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Figures

Figure 1
Figure 1
Alterations in cortisol and blood count of depressed cases and healthy volunteers: (a) dexamethasone intake resulted in a significant suppression of cortisol in healthy volunteers (n=31) and depressed patients (n=29) after 3 h (P<0.001). Cortisol levels at 1500 h the next day were significantly increased in patients compared with controls (P=0.039). (b) Dexamethasone led to a significant increase in granulocytes in cases (n=29; P<0.001) as well as controls (n=31; P<0.001). Lymphocytes and monocytes were significantly reduced by dexamethasone in both groups (P<0.001). When comparing healthy controls vs depressed cases, there was significantly less upregulation of granulocytes in cases (P=0.05) as well as baseline differences in granulocytes (P=0.067) and monocytes (P<0.001).
Figure 2
Figure 2
This heatmap illustrates the gene expression changes (poststimulation/prestimulation mRNA levels) of the 19 significant differentially regulated genes between cases and controls. Red indicates an upregulation following dexamethasone and blue a downregulation.
Figure 3
Figure 3
qPCR validation: mRNA expression (fold change poststimulation/prestimulation mRNA levels) of FKBP5, BEST1 and CEACAM4. Comparison of healthy controls vs depressed cases for cohort 1 and cohort 2: *significant interaction effects were observed for FKBP5 (cohort 1: P=0.005; cohort 2: P=0.007). #Significant main effects of dexamethasone were observed for FKBP5 (cohort 1: P<0.001; cohort 2: P<0.001) and CEACAM4 (cohort 1: P=0.001; cohort 2: P=0.001) and for BEST1, when analyzing the combined cohort (P=0.041 one-sided for interaction and P=0.028 for dexamethasone effects).
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