Time-dependent effects of dexamethasone plasma concentrations on glucocorticoid receptor challenge tests.
Glucocorticoid challenge tests such as the dexamethasone suppression test (DST) and the combined dexamethasone/corticotropin-releasing hormone (dex-CRH) test are considered to be able to sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in stress-related psychiatric and endocrine disorders. We used mass-spectrometry to assess the relationship of plasma dexamethasone concentrations and the outcome of these tests in two independent cohorts. Dexamethasone concentrations were measured after oral ingestion of 1.5mg dexamethasone in two cohorts that underwent a standard (dexamethasone at 23:00h) as well as modified (18:00h) DST and dex-CRH test. The first study population was a case/control cohort of 105 depressed patients and 133 controls in which peripheral blood mRNA expression was also measured. The second was a cohort of 261 depressed patients that underwent a standard dex-CRH test at baseline and after 12 weeks' treatment with cognitive-behavioral therapy or antidepressants. Dexamethasone concentrations explained significant proportions of the variance in the DST in both the first (24.6%) and the second (5.2%) cohort. Dexamethasone concentrations explained a higher proportion of the variance in the dex-CRH test readouts, with 41.9% of the cortisol area under the curve (AUC) in the first sample and 24.7% in the second sample. In contrast to these strong effects at later time points, dexamethasone concentrations did not impact cortisol or ACTH concentrations or mRNA expression 3hours after ingestion. In the second sample, dexamethasone concentrations at baseline and week 12 were highly correlated, independent of treatment type and response status. Importantly, a case/control effect in the Dex-CRH test was only apparent when controlling for dexamethasone concentrations. Our results suggest that the incorporation of plasma dexamethasone concentration or measures of earlier endocrine read-outs may help to improve the assessment of endocrine dysfunction in depression.
Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Wuerzburg, Fuechsleinstr. 15, Wuerzburg 97080, Germany; Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Andreas
A
Menke
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Janine
J
Arloth
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Johanna
J
Best
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Christian
C
Namendorf
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Tamara
T
Gerlach
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Darina
D
Czamara
Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
Susanne
S
Lucae
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA.
Boadie W
BW
Dunlop
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA.
Tanja Mletzko
TM
Crowe
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA.
Steven J
SJ
Garlow
Department of Psychiatry and Behavioral Sciences, University of Miami, Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
Charles B
CB
Nemeroff
Department of Clinical Pathology, Emory University, Atlanta, GA 30322, USA.
James C
JC
Ritchie
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA.
W Edward
WE
Craighead
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA.
Helen S
HS
Mayberg
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Monika
M
Rex-Haffner
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30307, USA. Electronic address: binder@psych.mpg.de.
Elisabeth B
EB
Binder
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, Munich 80804, Germany.
Manfred
M
Uhr
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003863:Depression / Q000097:blood / Q000378:metabolism; D003865:Major Depressive Disorder / Q000378:metabolism; D003907:Dexamethasone / Q000032:analysis / Q000097:blood / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors
D000928:Antidepressive Agents; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone
DST; Dex-CRH test; Dexamethasone; Gene expression; Glucocorticoid receptor; Major depression