Background
Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone
(DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of
the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in
depression. In the present study, we examined whether change in HPA system function
during the first weeks of hospitalization predicts response to antidepressant treatment
in major depression and thus constitutes a potential biomarker.
Methods
We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression,
once after study inclusion and a second time 2 to 3 weeks later while under continuous
antidepressant treatment.
Results
We found increased ACTH and cortisol responses to the first DEX/CRH test compared
with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of
the 50 patients showed an attenuated cortisol response, while 14 patients did not
display improvement or exhibited even aggravation of the altered HPA system function.
Improved HPA system regulation in the second DEX/CRH test was associated with beneficial
treatment response after 5 weeks and a higher remission rate at the end of hospitalization.
Conclusions
The results suggest that change in HPA system regulation assessed with repeated DEX/CRH
tests is a potential biomarker that may predict clinical outcome at follow-up. There
is consensus that the drug development process could be improved, once reliable biomarkers
become available that help to allow a judgement regarding the efficacy of a novel
drug candidate. The combined DEX/CRH test seems to be a promising candidate for such
a biomarker.
Key Words
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References
- Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association, Washington, DC1994
- Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression).Biol Psychiatry. 2006; 59: 696-701
- Modulation of glucocorticoid receptor gene expression by antidepressant drugs.Pharmacopsychiatry. 1996; 29: 12-22
- Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.Nat Genet. 2004; 36: 1319-1325
- A specific laboratory test for the diagnosis of melancholia.Arch Gen Psychiatry. 1981; 38: 15-22
- Statistical Power Analysis for the Behavioral Sciences. 2nd ed. Erlbaum, Hillsdale, New Jersey1988
- Stress and the brain: From adaptation to disease.Nat Rev Neurosci. 2005; 6: 463-475
- Pulse-dosing and conventional application of doxepin: Effects on psychopathology and hypothalamus-pituitary-adrenal (HPA) system.J Clin Psychopharmacol. 1997; 17: 156-160
- The combined dexamethasone/corticotropin-releasing hormone stimulation test is more closely associated with features of diurnal activity of the hypothalamo-pituitary-adrenocortical system than the dexamethasone suppression test.Biol Psychiatry. 1998; 43: 762-766
- Surrogate end points in clinical trials: Are we being misled?.Ann Intern Med. 1996; 125: 605-613
- Clinical outcome after trimipramine in patients with delusional depression–a pilot study.Pharmacopsychiatry. 2003; 36: 12-17
- Cortisol response to combined dexamethasone/CRH test in outpatients with a major depressive episode.J Psychiatr Res. 2004; 38: 553-557
- Psychiatric implications of basic and clinical studies with corticotropin-releasing factor.Am J Psychiatry. 1984; 141: 619-627
- Dexamethasone suppression tests in antidepressant treatment of melancholia.Arch Gen Psychiatry. 1983; 40: 493-500
- Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects.Am J Psychiatry. 1996; 153: 93-99
- The combined dexamethasone/CRH test: A refined laboratory test for psychiatric disorders.J Psychiatr Res. 1994; 28: 341-356
- The corticosteroid receptor hypothesis of depression.Neuropsychopharmacology. 2000; 23: 477-501
- Antidepressants and hypothalamic-pituitary-adrenocortical regulation.Endocr Rev. 1996; 17: 187-205
- Altered hypothalamic-pituitary-adrenocortical regulation in healthy subjects at high familial risk for affective disorders.Neuroendocrinology. 1995; 62: 340-347
- Repeated dexamethasone suppression test during depressive illness.J Affect Disord. 1982; 4: 93-101
- Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression.N Engl J Med. 1984; 311: 1127
- Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression.Biol Psychiatry. 1987; 22: 228-234
- Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment–neurobiological and psychometric assessment of course.J Psychiatr Res. 1994; 28: 381-399
- Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression.Psychiatry Res. 1991; 38: 163-171
- The combined dexamethasone/CRH test as a potential surrogate marker in depression.Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29: 1085-1093
- Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model.Neuropsychopharmacology. 2003; 28: 235-243
- Assessment of the dexamethasone/CRH test as a state-dependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: A multicenter study.Neuropsychopharmacology. 2006; 31: 212-220
- Combined Dex/CRH test among Japanese patients with major depression.J Psychiatr Res. 2004; 38: 123-128
- Pharmacological and non-pharmacological factors influencing hypothalamic-pituitary adrenocortical axis reactivity in acutely depressed psychiatric in-patients, measured by the Dex-CRH test.Neuropsychopharmacology. 2003; 28: 2169-2178
- Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region.J Neurosci. 2004; 24: 1478-1485
- Corticosteroid receptor function is decreased in depressed patients.Neuroendocrinology. 1997; 65: 216-222
- Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function.J Neuroendocrinol. 1995; 7: 841-845
- Pulsatile rhythms of adrenocorticotropin (ACTH) and cortisol in women with endogenous depression: Evidence for increased ACTH pulse frequency.J Clin Endocrinol Metab. 1987; 65: 962-968
- Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims.Arch Gen Psychiatry. 1988; 45: 577-579
- Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.Science. 1984; 226: 1342-1344
- Clinical and neurobiological effects of tianeptine and paroxetine in major depression.J Clin Psychopharmacol. 2003; 28: 155-168
- Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95
- Psychological, autonomic and neuroendocrine responses to acute stressors in the combined dexamethasone/CRH test: A study in healthy subjects.J Psychiatr Res. 2001; 35: 95-104
- The differential ACTH responses to combined dexamethasone/CRH administration in major depressive and dysthymic disorders.J Psychiatr Res. 2000; 34: 325-328
- Do antidepressants regulate how cortisol affects the brain?.Psychoneuroendocrinology. 2004; 29: 423-447
- Increased glucocorticoid receptor gene promoter activity after antidepressant treatment.Mol Pharmacol. 1992; 41: 1016-1022
- Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients.Neuroendocrinology. 1994; 60: 436-444
- When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.Am J Psychiatry. 2003; 160: 1554-1565
- Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse.Neuropsychopharmacology. 2003; 28: 126-132
- CSF corticotropin-releasing hormone in depressed patients and normal control subjects.Am J Psychiatry. 1987; 144: 641-645
- Neuroendocrine aspects of primary endogenous depression.Arch Gen Psychiatry. 1987; 44: 336
- The dexamethasone/corticotropin-releasing hormone test in depression in bipolar and unipolar affective illness.J Psychiatr Res. 1999; 33: 363-370
- Corticosteroids in depressive illness.Arch Gen Psychiatry. 1967; 17: 554-567
- Combined dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls. 1.Biol Psychiatry. 1995; 38: 797-802
- Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder.Neuropsychopharmacology. 1996; 15: 7-15
- Attenuation of hypothalamic-pituitary-adrenocortical hyperactivity in depressed patients by mirtazapine.Psychopharmacology (Berl). 2003; 166: 271-275
- Cortisol response to a combined dexamethasone-human corticotropin-releasing hormone challenge in patients with depression.J Neuroendocrinol. 1989; 1: 485-488
- Effect of age on the cortisol response to human corticotropin-releasing hormone in depressed patients pretreated with dexamethasone.Biol Psychiatry. 1991; 29: 1042-1050
- Hypothalamic-pituitary-adrenal axis function in patients with chronic depression.Psychol Med. 2002; 32: 1021-1028
- Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug.Biol Psychiatry. 1987; 22: 1340-1348
- HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures.Acta Psychiatr Scand. 2005; 112: 257-265
- Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: A prospective study.J Psychiatr Res. 2001; 35: 83-94
- Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression.Am J Psychiatry. 1999; 156: 949-951
Article info
Publication history
Published online: November 24, 2006
Accepted:
July 27,
2006
Received in revised form:
July 25,
2006
Received:
June 6,
2006
Identification
Copyright
© 2007 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
