BackgroundThe dexamethasone–corticotropin releasing hormone (Dex–CRH) test may differentially predict which depressed patients will respond to antidepressant medication. However, a comprehensive analysis of the safety of this test in psychiatric patients has not previously been performed.
MethodsWe conducted a pooled analysis of depressed patients in four clinical studies. Observed and subjectively reported side-effects in 454 patients were collected for 90 minutes following CRH administration. Pre-test electrocardiograms were available in 250 patients to assess cardiac safety. Descriptive statistics were performed to evaluate these safety data.
ResultsEight-six (18.9%) subjects experienced no side-effects from the procedure. The mean number of side-effects per subject was 1.4±1.0. The most frequent adverse events were: flushing (n=216, 47.6%), feeling of warmth (144, 31.7%), hyperpnea/tachypnea (108, 23.8%), palpitations (37, 8.1%), and tachycardia (28, 6.2%). Side-effects were consistently mild and brief in duration. There were no serious adverse events.
ConclusionThe Dex–CRH test produces a mild, predictable side-effect profile, characterized by flushing, feelings of warmth, hyperpnea/tachypnea, palpitations, and tachycardia. These results provide reassurance that the Dex–CRH test is well tolerated in psychiatric patients.
Keywords:Cortisol, Corticotropin releasing factor, Predictor, Adverse event, HPA axis, Electrocardiogram
CrossRef | Scopus (3018)See all ReferencesKessler et al., 2003), but existing treatments induce remission in less than 50% of cases (Rush et al., 2008xRush et al., 2008Rush, A.J., Kilner, J., Fava, M., Wisniewski, S.R., Warden, D., Nierenberg, A.A. et al. Clinically relevant findings form STAR*D. Psychiatric Annals. 2008; 38: 188–193
CrossRef | Scopus (9)See all ReferencesRush et al., 2008). Currently, there are no predictive tests that can be used to select the best treatment for a given patient. Biological tests predictive of treatment response would shorten the duration of time a patient may remain ill, and reduce likelihood of side-effects.
One promising test for predicting treatment response in MDD is the dexamethasone–corticortopin releasing hormone (Dex–CRH) test (Holsboer et al., 1987xHolsboer et al., 1987Holsboer, F., von Bardeleben, U., Wiedemann, K., Muller, O.A., and Stalla, G.K. Serial assessment of corticotropin releasing hormone response after dexamethasone in depression: implications of pathophysiology of DST suppression. Biological Psychiatry. 1987; 22: 228–234
Abstract | Full Text PDF | PubMedSee all ReferencesHolsboer et al., 1987). The Dex–CRH test combines the administration of dexamethasone at 11 pm the night before the assessment, with intravenously administered CRH the following afternoon at 3 pm. CRH is administered as a fixed dose of 100μg of human CRH or 1 μg/kg of ovine CRH. Immediately prior to the CRH infusion, and at set intervals for the following 1–2 h, plasma cortisol and ACTH concentrations are measured. In healthy subjects, the CRH is unable to or only mildly overrides the HPA-suppressing effects of dexamethasone and therefore subjects do not exhibit a substantial increase of cortisol or ACTH concentrations after CRH administration. In contrast, many patients with MDD demonstrate elevated plasma ACTH and cortisol concentrations in response to this test, presumably, as a result of an impaired signaling of the glucocorticoid receptor (GR) and of an increased secretion of the hypothalamic neuropeptides CRH and vasopressin (AVP) (Heuser et al., 1994xHeuser et al., 1994Heuser, I., Yassouridis, A., and Holsboer, F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. Journal of Psychiatric Research. 1994; 28: 341–356
Abstract | Full Text PDF | PubMedSee all ReferencesHeuser et al., 1994). Reduced GR sensitivity attenuates the suppressive effects of dexamethasone at the pituitary and fails to inhibit CRH and AVP secretion from the paraventricular nuclei of the hypothalamus, which, in turn, enhances the stimulatory effects of the exogenous CRH in the combined Dex–CRH test (Holsboer, 2000xHolsboer, 2000Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000; 23: 477–501
CrossRef | PubMed | Scopus (1171)See all ReferencesHolsboer, 2000).
The test has also been studied in other psychiatric disorders, including bipolar disorder, post-traumatic stress disorder, panic disorder and alcohol dependence (Erhardt et al., 2006xErhardt et al., 2006Erhardt, A., Ising, M., Unschuld, P.G., Kern, N., Lucae, S., Putz, B. et al. Regulation of the hypothalamic–pituitary–adrenocortical system in patients with panic disorder. Neuropsychopharmacology. 2006; 31: 2515–2522
CrossRef | PubMed | Scopus (41)See all References, Hundt et al., 2001xHundt et al., 2001Hundt, W., Zimmerman, U., Pottig, M., Spring, K., and Holsboer, F. Combined dexamethasone-suppression/CRH stimulation test in alcoholics during and after acute withdrawal. Alcohol Clinical and Experimental Research. 2001; 25: 687–691
CrossRef | PubMedSee all References, Muhtz et al., 2008xMuhtz et al., 2008Muhtz, C., Wester, M., Yassouridis, A., Wiedermann, K., and Kellner, M. A combined dexamethasone/corticotropin-releasing hormone test in patients with chronic PTSD – first preliminary results. Journal of Psychiatric Research. 2008; 42: 689–693
Abstract | Full Text | Full Text PDF | PubMed | Scopus (10)See all References).
HPA axis dysregulation during a major depressive episode, and its normalization after recovery, has been confirmed in several studies using the Dex–CRH test (Hatzinger et al., 2002xHatzinger et al., 2002Hatzinger, M., Hemmeter, U.M., Baumann, K., Brand, S., and Holsboer-Trachsler, E. The combined DEX–CRH test in treatment course and long-term outcome of major depression. Journal of Psychiatric Research. 2002; 36: 287–297
Abstract | Full Text | Full Text PDF | PubMed | Scopus (63)See all References, Heuser et al., 1994xHeuser et al., 1994Heuser, I., Yassouridis, A., and Holsboer, F. The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. Journal of Psychiatric Research. 1994; 28: 341–356
Abstract | Full Text PDF | PubMedSee all References, Kunugi et al., 2006xKunugi et al., 2006Kunugi, H., Ida, I., Owashi, T., Kimura, M., Inoue, Y., Nakagawa, S. et al. 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
PubMedSee all References). MDD patients demonstrating sustained non-suppression of the HPA axis during the Dex–CRH test have a worse prognosis to respond to medication or psychotherapy treatments, compared to MDD patients with normalized Dex–CRH test profiles under therapy (Binder et al., 2009xBinder et al., 2009Binder, E.B., Kunzel, H.E., Nickel, T., Kern, N., Pfennig, A., Majer, M. et al. HPA-axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients. Psychoneuroendocrinology. 2009; 34: 99–109
Abstract | Full Text | Full Text PDF | PubMed | Scopus (52)See all References, Bschor et al., 2003xBschor et al., 2003Bschor, T., Baethge, C., Adli, M., Eichmann, U., Ising, M., Uhr, M. et al. Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. Journal of Psychiatric Research. 2003; 37: 135–143
Abstract | Full Text | Full Text PDF | PubMed | Scopus (16)See all References, Ising et al., 2005xIsing et al., 2005Ising, M., Künzel, H.E., Binder, E.B., Nickel, T., Modell, S., and Holsboer, F. The combined dexamethasone/CRH test as a potential surrogate marker in depression. Progress in Neuropsychopharmacology and Biological Psychiatry. 2005; 29: 1085–1093
CrossRef | PubMed | Scopus (170)See all References). Dex–CRH test results may also predict the risk of depressive relapse (Aubry et al., 2007xAubry et al., 2007Aubry, J.M., Gervasoni, N., Osiek, C., Perret, G., Rossier, M.F., Bertschy, G. et al. The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients. Journal of Psychiatric Research. 2007; 41: 290–294
Abstract | Full Text | Full Text PDF | PubMed | Scopus (30)See all References, Zobel et al., 1999xZobel et al., 1999Zobel, A.W., Yassouridis, A., Frieboes, R.M., and Holsboer, F. Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. American Journal of Psychiatry. 1999; 156: 949–951
PubMedSee all References).
Previous reports of the use of the Dex–CRH test have suggested that certain adverse events following CRH infusion are common, including flushing, tachypnea and tachycardia. These side-effects can be a direct result of peripheral CRH actions, as CRH receptors are present also in peripheral tissue including the myocardium (Wiley and Davenport, 2004xWiley and Davenport, 2004Wiley, K.E. and Davenport, A.P. CRF2 receptors are highly expressed in the human cardiovascular system and their cognate ligands urocortins 2 and 3 are potent vasodilators. British Journal of Pharmacology. 2004; 143: 508–514
CrossRef | PubMed | Scopus (54)See all ReferencesWiley and Davenport, 2004). Alternatively, these side-effects may also be explained indirectly by a CRH dependent activation of the sympathetic nervous system, which can be mediated by CRH receptors located at sympathetic ganglia (Udelsman et al., 1986xUdelsman et al., 1986Udelsman, R., Harwood, J.P., Millan, M.A., Chrousos, G.P., Goldstein, D.S., Zimlichman, R. et al. Functional corticotropin releasing factor receptors in the primate peripheral sympathetic nervous system. Nature. 1986; 319: 147–150
CrossRef | PubMed | Scopus (72)See all ReferencesUdelsman et al., 1986). Although EKG abnormalities have not been reported to be problematic in patients completing the Dex–CRH test, tachycardia resulting from the test presents a theoretical risk in patients with pre-existing cardiac disease.
To our knowledge, no serious adverse events (i.e. adverse events resulting or potentially resulting in death, hospitalization, or significant morbidity or disability) related to the Dex–CRH test in depressed patients have been reported previously. One potential serious adverse event requiring consideration is a possible anaphylactic reaction to the dexamethasone or CRH. Sustained use of glucocorticoids, including dexamethasone, is associated with several important adverse effects, including osteoporosis, hyperglycemia, gastrointestinal ulceration, increased intraocular pressure, and a wide array of psychiatric symptoms (Roxane Laboratories, 2007xRoxane Laboratories, 2007See all ReferencesRoxane Laboratories, 2007).
In the early 1980s, two groups studying the low-dose dexamethasone suppression test (DST) reported a temporal association of the test with subsequent suicide attempts (Asberg et al., 1981xAsberg et al., 1981Asberg, M., Varpila-Hansson, R., Tomba, P., Aminoff, A.-K., Martensson, B., Thoren, P. et al. Suicidal behavior and the dexamethasone suppression test. American Journal of Psychiatry. 1981; 138: 994–995
See all References, Beck-Friis et al., 1981xBeck-Friis et al., 1981Beck-Friis, J., Aperia, B., Kjellman, B., Ljunggren, J.-G., Petterson, U., Sara, V. et al. Suicidal behavior and the dexamethasone suppression test. American Journal of Psychiatry. 1981; 138: 993–994
PubMedSee all References). Five of 83 inpatients who underwent the DST attempted suicide (one completed) within 48 h of their dexamethasone dose. All 5 suicide attempters were women who had been considered at risk for suicide prior to the test, and two had prior suicide attempts. The authors of these reports did not assert there was a causal relationship between the DST and suicide attempts, but urged further evaluation of the test by other groups with larger DST datasets. Subsequently, two independent groups, which combined had studied the DST in 579 patients, found no association between the test and suicide attempts (Coryell, 1982xCoryell, 1982Coryell, W. Suicidal behavior and the DST: Lack of association. American Journal of Psychiatry. 1982; 139: 1214
PubMedSee all References, Kronfol et al., 1982xKronfol et al., 1982Kronfol, Z., Greden, J.F., Gardner, R., and Carroll, B.J. Suicidal behavior and the DST: Lack of association. American Journal of Psychiatry. 1982; 139: 1214–1215
PubMedSee all References).
Although prior studies reported minimal safety concerns in the use of the Dex–CRH test, the number of subjects in each study is relatively small. The increasing use of the Dex–CRH test in investigations of psychiatric illnesses require a greater understanding of the test’s safety profile, so we undertook a descriptive analysis of the safety data from four studies.
2. Methods and materials
2.1. Patients and study descriptions
Predictors of Response in Depression to Individual and Combined Treatments (PReDICT); the Emory CIDAR. Data from 53 patients, ages 18–65, were gathered from this ongoing Emory University study of predictors of response to medication or psychotherapy in treatment-naïve MDD patients in a current major depressive episode. Patients were required to have a 17-item Hamilton Depression Rating Scale (HDRS) score >=18. Patients were excluded if they had any of the following: lifetime history of OCD,bipolar disorder, or psychotic symptoms; substance dependence in the previous year, or substance abuse in the past 3 months.
Munich Antidepressant Response Signature project (MARS). This study is a naturalistic longitudinal clinical evaluation of HPA axis variables as predictive factors for antidepressant treatment response in depression (Hennings et al., 2009xHennings et al., 2009Hennings, J.M., Owashi, T., Binder, E.B., Horstmann, S., Menke, A., Kloiber, S. et al. Clinical characteristics and treatment outcome in a representative sample of depressed inpatients: findings from the Munich Antidepressant Response Signature (MARS) project. Journal of Psychiatric Research. 2009; 43: 215–229
Abstract | Full Text | Full Text PDF | PubMed | Scopus (74)See all ReferencesHennings et al., 2009). A total of 376 male and female inpatients, ages 18–75, in Southern Bavaria, Germany with a current MDE, either as part of MDD or Bipolar disorder underwent Dex–CRH testing. Severe medical conditions, lifetime alcohol dependence, illicit drug abuse depressive symptoms secondary to a medical or neurological condition, and the presence of manic, hypomanic or mixed affective symptoms were exclusionary to participation in this study.
Emory Conte Center for the Neuroscience of Mental Disorders (CONTE). This study explored the relationship between childhood trauma and the development of depression and anxiety later in life (Heim et al., 2009xHeim et al., 2009Heim, C., Bradley, B., Mletzko, T.C., Deveau, T.C., Musselman, D.L., Nemeroff, C.B. et al. Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Frontiers in Behavioral Neuroscience. 2009; 3: 1–10
CrossRef | PubMed | Scopus (70)See all ReferencesHeim et al., 2009). Eighty-five men and women, ages 21–45, were categorized by the presence or absence of a current major depressive episode, and presence or absence of childhood trauma (defined as abuse or neglect, or childhood loss prior to the age of 12). Of the 85 participants, 25 met criteria for current MDD and were included in the adverse event analysis. All participants with usable EKG data were included in the EKG analysis. Patients with any significant medical illness, current or lifetime psychotic symptoms or bipolar disorder, or a current eating disorder, illicit drug and/or alcohol abuse or current psychotropic medication were excluded.
Neurobiological and Hematological Correlates of Child Abuse in Adult Men (NARSAD). This study explored the long-term consequences of child abuse in adult men, focusing on endocrine, cardiovascular and behavioral systems. Adverse event data from the Dex–CRH test were not available for analysis, but twenty-six men, ages 18–55, with a diagnosis of current MDD had pre-test EKGs available for analysis. The inclusion/exclusion criteria were identical to the Conte Center study (Heim et al., 2008xHeim et al., 2008Heim, C., Mletzko, T., Purselle, D., Musselman, D.L., and Nemeroff, C.B. The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biological Psychiatry. 2008; 63: 398–405
Abstract | Full Text | Full Text PDF | PubMed | Scopus (123)See all ReferencesHeim et al., 2008).
2.1.1. Dex–CRH test
2.1.2. Adverse events
2.1.3. Electrocardiograms (EKGs)
2.1.4. Statistical analysis
3.1. Adverse events
The MARS study had significantly higher rates of adverse events than the studies conducted at Emory University. We believe this difference most likely arose from the difference in depression severity levels of the study samples. The patients in the MARS study were all inpatients; whereas, the other three studies evaluated outpatients. Moreover, the MARS sample included patients with bipolar depression and psychotic depression. Greater depression severity may reflect more severely disrupted HPA function, making patients more sensitive to physiological changes associated with the CRH infusion.
Consistent with the larger analyses of the low-dose DST (Coryell, 1982; Kronfol et al., 1982), we found no indication of increased suicidality with administration of the Dex–CRH test. The most significant adverse event occurred in a patient with asthma, who experienced a possible asthma attack after CRH infusion, successfully treated with the patient’s inhaled bronchodilator medication. The common experience of CRH-induced tachypnea may be interpreted by patients with asthma as an asthma attack, although there may be no reactive airway process actually occurring. CRH may be protective against asthma attacks through its central anti-inflammatory actions, with stimulation of the HPA axis and endogenous glucocorticoids. In a mouse model of asthma, CRH deficiency was associated with allergen-induced airway inflammation (Silverman et al., 2004xSilverman et al., 2004Silverman, E.S., Breault, D.T., Vallone, J., Subramanian, S., Yilmaz, A.D., Mathew, S. et al. Corticotropin-releasing hormone deficiency increases allergen-induced airway inflammation in a mouse model of asthma. Journal of Allergy and Clinical Immunology. 2004; 114: 747–754
Abstract | Full Text | Full Text PDF | PubMed | Scopus (41)See all ReferencesSilverman et al., 2004). In humans, a small study of patients with nocturnal asthma suggested intravenous CRH administration improved forced expiratory flow volumes (Georges et al., 1998xGeorges et al., 1998Georges, G., Kraft, M., Vianna, E.O., and Martin, R.J. Human corticotropin releasing hormone improves overnight FEV1 in nocturnal asthma. Journal of Asthma. 1998; 35: 261–265
CrossRef | PubMedSee all ReferencesGeorges et al., 1998). In the periphery, however, CRH may potentiate the immune response at sites of inflammation, possibly through inducing mast cell degranulation (Karalis et al., 1991xKaralis et al., 1991Karalis, K., Sano, H., Redwine, J., Listwak, S., Wilder, R.L., and Chrousos, G.P. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science. 1991; 254: 421–423
CrossRef | PubMedSee all References, Theoharides et al., 1995xTheoharides et al., 1995Theoharides, T.C., Spanos, C., Pang, X., Alferes, L., Ligris, K., Letourneau, R. et al. Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. Endocrinology. 1995; 136: 5745–5750
CrossRef | PubMedSee all References). Even though preclinical and some clinical evidence suggests the Dex–CRH test may not pose a danger to patients with asthma, the adverse event in the MARS study suggests caution in conducting the Dex–CRH test in such patients.
The high overall rate of EKG abnormalities in the sample is consistent with other studies suggesting autonomic disturbance is common in patients with MDD, or arises as a consequence of antidepressant treatment (Koschke et al., 2009xKoschke et al., 2009Koschke, M., Boettger, M.K., Schulz, S., Berger, S., Terhaar, J., Voss, A. et al. Autonomy of autonomic dysfunction in major depression. Psychosomatic Medicine. 2009; 71: 852–860
CrossRef | PubMed | Scopus (42)See all ReferencesKoschke et al., 2009). Analysis of EKGs obtained in the 1–2 weeks prior to Dex–CRH testing in 250 patients indicated that mild disturbances on EKG did not pose a health risk to patients undergoing the Dex–CRH test. Although a few patients with more serious cardiac conditions, such as previous myocardial infarction or left bundle branch block did safely complete the test, too few patients with these EKG findings were included to definitively conclude the safety of the test in these patients. Moreover, this analysis was performed post-hoc, and there were no post-test EKGs to analyze. Thorough assessment of cardiac risk would have required post-test EKGs to determine whether the procedure produced any significant changes. Important EKG changes, such as lengthening of the QT interval, may be clinically silent, yet contribute to cardiac risk.
In conclusion, the Dex-CRH test is well tolerated, with a predictable, short-duration side-effect profile. Non-acute EKG abnormalities do not appear to represent a contra-indication to the test. If the Dex–CRF test does demonstrate utility in predicting response and relapse in MDD or other conditions, its application in general clinical settings would be reasonable