The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients

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Abstract

Hypothalamo–pituitary–adrenal (HPA) system dysfunction is the most characteristic biological alteration found in a majority of depressed patients. Accumulating evidence suggests that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA system abnormalities. The aim of this study was to evaluate whether the DEX/CRH test has a predictive value for the risk of depressive relapse in outpatients who are in clinical remission from a major depressive episode. Thirty-eight depressed outpatients (23 women, 15 men) in remission (MADRS score ⩽8) underwent the DEX/CRH test and were followed up for 12 months regarding the occurrence of a new depressive episode. In parallel we recruited 24 controls (13 men and 11 women). The main result is a statistically significant difference concerning the delta and AUC numbers for cortisol plasmatic values between the group of patients who relapsed during the 1-year follow-up and control subjects, but not between the group of patients with prolonged remission and controls. These results suggest that in outpatients who are in clinical remission from a major depressive episode, high delta and AUC values in the DEX/CRH test compared to controls subjects can be associated with a higher risk of relapse.

Introduction

Patients with a major depressive episode have a 40–50% risk of experiencing subsequent episode(s) (Crown et al., 2002). Moreover, the risk of relapse increases with the number of episodes. Therefore, prevention of relapse has become an important target of depressive disorder treatment. A crucial aspect of relapse prevention concerns the identification of predictors of relapse. One domain of investigation that has generated a lot of interest is the role of the hypothalamo–pituitary–adrenocortical (HPA) axis in the pathophysiology of mood disorders (Holsboer, 1995, Plotsky et al., 1998), particularly dysfunctioning of this system in depression and whether it normalizes or not with clinical improvement. To date, compelling evidence has accumulated to show that the HPA system is hyperactive in major depression (Plotsky et al., 1998). To quantify the dysregulation of the HPA axis, the dexamethasone (DEX) suppression test (DST) has been studied most extensively (Carroll et al., 1981). However, the DST has only a limited sensitivity to depression (about 45%) (Arana et al., 1985) and also lacks specificity (Coppen et al., 1983). Subsequently, a refined laboratory test that combines the DST and corticotropin-releasing-hormone (CRH) challenge, the DEX/CRH test, has been introduced (Holsboer et al., 1987, von Bardeleben and Holsboer, 1989). In control subjects, pretreatment with DEX suppresses pituitary–adrenal responses to CRH but in hospitalized depressed patients, the same procedure has been reported to enhance ACTH and cortisol responses (Holsboer et al., 1987, von Bardeleben and Holsboer, 1989). Compared to the standard DST test, the combined DEX/CRH test has a higher sensitivity, of up to 80% (Heuser et al., 1994) and it has been shown that among various parameters such as weight, age and nicotine consumption, only female gender is weakly correlated with the neuroendocrine test response (Kunzel et al., 2003). It has also been reported that the kind of antidepressant treatment or intake of benzodiazepines do not affect the outcome of the test (Kunzel et al., 2003, Zobel et al., 2001). On the contrary, lithium and carbamazepine interfere with plasma ACTH and cortisol concentrations at baseline and under CRH stimulation (review in Kunzel et al., 2003).

Regarding the dexamethasone dose, the classical test performed by Holsboer et al. (1987) used 1.5 mg. Oshima used 1.0 mg in his two studies, arguing that Japanese depressives are reportedly more prone to dexamethasone suppression than Occidentals (Oshima et al., 2000, Oshima et al., 2001). In an inpatient study testing the glucocorticoid receptor hypothesis, Modell et al. (1997) tried three different DEX doses (0.75 mg/1.5 mg/3.0 mg) on 31 depressed patients and 29 controls. They concluded that doses of 0.75 mg and 1.5 mg are well suited to differentiate between controls and patients. As in our previous study with depressed outpatients (Gervasoni et al., 2004) we used the lower dosage (0.75 mg) proposed by Modell et al. (1997).

To date, there are only a few studies that have investigated the relationship between the DEX/CRH test and the occurrence of relapse. In two studies, subjects were inpatients and the follow-up period was only 6 months (Zobel et al., 1999, Zobel et al., 2001). These two studies concluded that the persistence of an exaggerated cortisol response, despite clinical remission, predicted relapse of depressive episodes. In a study evaluating the DEX/CRH test in treatment course and long-term (several years) outcome of major depression, Hatzinger et al. (2002) demonstrated that HPA system alterations increases in parallel with the number of previous episodes. Regarding outpatients, there is only one study that addressed this issue with the DEX/CRH test being performed before and after 8 weeks of antidepressant treatment (Appelhof et al., 2006). The authors concluded that higher post-treatment maximal cortisol levels on the DEX/CRH test were associated with relapse of major depression.

In the present study, we investigated whether the DEX/CRH test has a predictive value of relapse over 1-year follow-up of clinically remitted depressed outpatients.

Section snippets

Subjects

We recruited 38 remitted unipolar depressed patients (23 women, 15 men). Their mean age was 44.1 (SD ± 10.4). All patients had presented a major depressive episode defined as a MADRS score of at least 25, and were treated with antidepressants. To be included in the study, patients had to be in complete remission (MADRS  8) after a severe depressive episode, at two consecutive interviews (2 weeks between each interview). Pregnant women, patients with bipolar, schizo-affective or psychotic

Results

From 38 inclusions (15 men and 23 women), we had four drop outs during the 1-year follow-up. Two patients were also excluded from the analysis because they took lithium to potentiate their antidepressant treatment at study entry. Since it has been shown that lithium can influence the cortisol delta values (Kunzel et al., 2003), we decided not to include these two patients in the analysis. Therefore, we finally had 32 patients (18 women and 14 men) who either completed the one year follow-up

Discussion

Our study shows that, although they seem to be in complete remission regarding their clinical evaluation, some patients have an increased release of cortisol in the DEX/CRH test compared to controls. The issue of the DEX/CRH test and the prediction of relapse has been investigated in previous studies by Zobel et al., 1999, Zobel et al., 2001 showing that some depressed inpatients who have a higher cortisol response during the DEX/CRH test when they are in remission just before leaving the

Acknowledgements

We thank Christiane Gonzalez and Jacqueline Mange as well as Sandra Ter Pelle and Evgenia Daskalou for their expert technical assistance in the DEX/CRH test and for manuscript preparation, respectively. We also thank Marianne Gex-Fabry-Pun for her statistical expertise.

This work was supported by a grant from the Swiss National Fund for Research No. 32–64112.00 to Jean-Michel Aubry, G. Bondolfi and G. Bertschy.

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