CRH test for major depression: A potentially useful diagnostic test

Psychiatry Research 208 (2013) 131–139

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The DEX/CRH test for major depression: A potentially useful diagnostic test Mohammadreza Mokhtari a,b,n, Cynthia Arfken a, Nash Boutros a a b

Department of Psychiatry and Behavioral Neurosciences, Wayne State University, 2751 East Jefferson Avenue, Suite 437, Detroit, MI 48207, USA Institute of Living, Hartford Hospital, 200 Retreat Avenue, Hartford, CT 06106, USA

a r t i c l e i n f o

abstract

Article history: Received 14 November 2011 Received in revised form 29 May 2012 Accepted 20 September 2012

The dexamethasone/corticotropin-releasing hormone (DEX/CRH) test has been proposed as a potential diagnostic test for major depressive disorder (MDD). A previously proposed four-step approach assesses the stage of development for a biological finding into a clinically useful diagnostic test. Using this approach, we evaluated the progress of the DEX/CRH test using meta-analysis as a part of step 1. A literature review identified 15 studies of the DEX/CRH test in patients with MDD and healthy controls. Meta-analysis estimated the effect size, heterogeneity, and confidence intervals using random effects models. Studies consistent with any step of the four-step approach were identified, and their characteristics were presented. Eleven studies reported significantly higher cortisol levels with the DEX/CRH test in patients with MDD, compared with the healthy controls (step 1). Eight eligible studies were included in meta-analysis, and had an effect size of 1.34 (95% confidence interval: 0.70–1.97). Most studies were step-1 studies (comparison of patients and healthy controls), and no step-4 studies (multicenter trials) were found. This review emphasizes that despite appearing as a promising test, the DEX/CRH has not been adequately studied for the required stages of development into a clinically useful laboratory test. Particularly, additional step-3 and step-4 studies are necessary. & 2013 Published by Elsevier Ireland Ltd.

Keywords: Major depressive disorder Dexamethasone Dexamethasone suppression test (DST) Corticotropin-releasing hormone Hypothalamic-pituitary-adrenal (HPA) axis

1. Introduction Among the efforts to utilize biological markers to establish ancillary laboratory tests to diagnose psychiatric disorders, one of the most popular and well-studied areas has been the hypothalamic– pituitary–adrenal (HPA) axis. The HPA axis is known to play a critical role in mammalian stress responses, especially during chronic stress (Checkley, 1996; Garcı´a et al., 2000). Alterations of this axis are postulated as key etiological factors in several psychiatric disorders, where dysregulations of the HPA axis are commonly observed (Ehlert et al., 2001; Simeon et al., 2007). This association is well defined in the case of HPA axis hyperactivity, which is believed to be the characteristic biological alteration found in a majority of patients with major depressive disorder (MDD) (Aubry et al., 2007). It is now more than four decades since the correlation between depression and HPA axis disinhibition was first demonstrated (Carroll et al., 1968; Carroll, 1982). The most frequently utilized test to assess HPA system function in psychiatric disorders is the dexamethasone suppression test (DST) (Sher, 2006). The DST is performed by measuring

n Corresponding author at: Institute of Living, Hartford Hospital, 200 Retreat Avenue, Hartford, CT 06106, USA. Tel.: þ 1 860 575 0091; fax: þ1 860 545 7403. E-mail address: [email protected] (M. Mokhtari).

0165-1781/$ - see front matter & 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.psychres.2012.09.032

cortisol levels following administration of a low dose of dexamethasone, normally suppressing cortisol through the negative feedback inhibition of the HPA axis. Impaired HPA function is expressed as non-suppression of cortisol following dexamethasone administration. The main mechanism of this alteration is hypothesized to be a down-regulation and reduced sensitivity of glucocorticoid receptors in the hippocampus and the cortex (Brooke et al., 1994; Modell et al., 1997; Pariante and Miller, 2001). For several years, the DST was widely accepted among researchers and even clinicians, particularly for the distinction between the so-called ‘‘melancholic’’ from the ‘‘neurotic’’ types of depression (Carroll, 1982; Green and Kane, 1983). However, after a decade of popularity, extensive research cast doubt on the DST as a diagnostic procedure in psychiatry (APA Task Force on Laboratory Tests in Psychiatry, 1987; Nierenberg and Feinstein, 1988; Berger et al., 1988). Even a large cohort study in the Netherlands (Vreeburg et al., 2009b) concluded that individuals with current major depressive disorder were more likely to be cortisol suppressors. The APA Task Force on Laboratory Tests in Psychiatry (1987) carried out an appraisal of the literature regarding the status of the DST in psychiatry. Methodological inconsistencies and interfering conditions were reported to contribute to the limited

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Table 1 Four-step approach (with permission, Arfken et al., 2009). Step Design

Purposes

Desired outcomes

1

Target group vs. healthy controls

1) Demonstration of significant deviance in the target group 2) Demonstration of test–retest reliability of finding

2

Target group vs. healthy and appropriate patient control groups Target vs. proper control groups (may include within target group sub-populations) Same as in step-3 but across centers, ideally in a multicenter design

Demonstration of significant differential prevalence of abnormality between illnesses that frequently need to be differentiated from one another Definition of test-performance characteristics

Provide evidence of a consistent biological abnormality in the target group Demonstration of potential clinical utility Defining clinical utility

3

4

Demonstration and standardization of clinical application

sensitivity and specificity of the test. Nierenberg and Feinstein (1988) suggested that the DST had not undergone the standard evaluation process necessary for diagnostic tests. They reviewed 84 published articles and concluded that the DST had limited utility in differentiating depression from similar comorbid conditions, yielding a range of specificities far below the stated value. Other sources of misinterpretation were low reliability of assays measuring plasma cortisol and variable bioavailability of dexamethasone, which was corroborated by additional studies (Ritchie et al., 1990; Guthrie, 1991). A multicenter World Health Organization (WHO) collaborative study (Gastpar et al., 1992) concluded that inconsistent methodologies and patient variables, such as sex and age, resulted in weak predictive power for describing symptom profiles among cortisol suppressors vs. non-suppressors. Several intervening conditions have also been identified to affect the DST, including weight loss, malnutrition, sleep, obesity, pregnancy, alcohol, infection, fever, dementia, diabetes mellitus, epilepsy, hypertension, and medications (Gaudiano et al., 2009). Another limitation of the DST was the pulsatile and circadian pattern of cortisol release, which was not reflected by the conventional test (Sherman et al., 1984; Deuschle et al., 1998). Addressing the limitations of the DST, a modified version of the test was proposed in 1989, namely the dexamethasone/ corticotropin-releasing-hormone (DEX/CRH) test, which examines the stimulating effects of CRH on ACTH (adrenocorticotropin hormone) and cortisol, under the suppressive action of dexamethasone (Bardeleben and Holsboer, 1989). Exogenously administered CRH normally overrides the dexamethasone suppression at the pituitary level, causing hypersecretion of ACTH and thereby cortisol. This effect is substantially enhanced in depressed patients, compared to control groups (Bardeleben and Holsboer, 1989; Holsboer-Trachsler et al., 1991; Kunugi et al., 2006). The mechanism is speculated to be an impaired signaling of glucocorticoid receptors, leading to increased endogenous CRH as well as arginine vasopressin (AVP), which is co-localized in the same hypothalamic neurons, and is demonstrated to synergize the effects of CRH at the pituitary level (Bardeleben and Holsboer, 1989; Ising et al., 2007). The DEX/CRH test is considered to be more closely associated with the HPA system than the standard DST (Deuschle et al., 1998). The DEX/CRH test has also been studied in other psychiatric disorders. In manic patients, it revealed dysregulated HPA-system activity (Schmider et al., 1995). However, the degree of HPAsystem dysfunction in schizophrenia patients seems to be less than in patients with affective disorders (Lammers et al., 1995). Superior sensitivity of the DEX/CRH test compared with the regular DST has been confirmed (Ising et al., 2007; Watson et al., 2006). Conversely, it has modest specificity in differentiating different kinds of stressors (Oshima et al., 2001). Furthermore, depressed patients with chronic disease, those in outpatient

Setting up standards for clinical application

settings, or those with atypical features did not show an increased response to the DEX/CRH test (Watson et al., 2002; Carpenter et al., 2009). Nevertheless, this test has been suggested to be a potential biomarker for treatment response in major depression in patients with an initially dysregulated HPA system (Ising et al., 2007). Major depressive disorder (MDD) is a serious illness that will soon be the world’s greatest public health burden, according to the World Health Organization (Boyle et al., 2005). However, no biological markers are available yet for inclusion in the diagnostic ¨ criteria of major depression (Mossner et al., 2007). To systematically translate biological parameters into clinically useful diagnostic tests, we proposed a four-step approach (Boutros et al., 2005, 2008; Boutros and Arfken, 2007; Arfken et al., 2009), based on the previously published guidelines for deciding the clinical usefulness of diagnostic tests (Sackett, 1991) and the criteria of the Standards for Reporting of Diagnostic Accuracy (STARD) (Bruns, 2003; Bossuyt et al., 2003). The fourstep approach was later further elaborated within each step (Arfken et al., 2009) to incorporate other guidelines, i.e. Appraisal of Guidelines for Research Evaluation (AGREE) (AGREE Collaboration, 2003) and evidence-based recommendations (Strauss, 2005). Characteristics of this step-wise approach are presented in Table 1. The current effort was undertaken to estimate the potential diagnostic value of the DST/CRH test. We categorized the published studies to date under our taxonomy and examined the effect size of the test in patients with MDD compared to health controls (step-1).

2. Methods 2.1. Inclusion and exclusion criteria Studies with the objective of comparing the results of the DEX/CRH test in individuals with MDD and healthy control subjects or other patient groups, which also met the criteria of the four-step approach, were initially selected. Studies not including a MDD group were excluded. Studies utilizing either sorely the DST or the CRH (not the combined test), studies measuring only baseline cortisol or ACTH (not in response to DEX/CRH), and studies probing a particular feature of depression (e.g. suicide) were also excluded. Review articles were not considered eligible for inclusion either. We also excluded the studies assessing the value of the DEX/CRH test only in treatment response (i.e. antidepressant efficacy or relapse prediction). While prediction of treatment response is undoubtedly a very important goal of laboratory testing, we elected to adopt this exclusion for two reasons. First the focus of the current review is on diagnosis. Secondly, our preliminary review of this literature suggested the number of reports using the exact same methodology (including testing prediction of response) was not adequate for a meaningful meta-analysis.

2.2. Literature search The review of the literature on this topic was aimed at including all the published articles that could be identified as compatible with one or more of the four steps. PubMed was the database searched; PsychInfo yielded very few articles which were also available in PubMed. The search strategy was seeking articles

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non-suppression as a cortisol level above either 40 ng/ml or 50 ng/ml, according to the two leading studies (Bardeleben and Holsboer, 1989; Carroll, 1982). Cortisol AUC scores were originally reported by different units (e.g. mg/l, mg/dl, ng/ml, nmol/l), in different studies, which were converted to a common unit, i.e. ng/ml. AUC scores showed a wide range of variability due to the following reasons: first, the ‘‘time interval’’ between the first and the last measurement of cortisol (the x axis of the AUC) varied from 1 h to 3 h in different studies. Second, the ‘‘time unit’’ used for calculation of AUC scores was different among the studies (e.g. 1 min, 15 min, or 1 h). Most of the studies did not report their time units for AUC calculation. Nonetheless, since the effect size can be calculated by having the differences of means/S.Ds. of patient and control groups, the observed AUC variability did not interfere with the meta-analysis. All studies utilized the same dosage of oral dexamethasone (1.5 mg) and intravenous CRH (100 mg). The only exception to this was the study of Oshima et al. (2000), which used a dexamethasone dosage of 1 mg, and hence was excluded from the meta-analysis.

3. Results 3.1. Characteristics of studies

Fig. 1. Flow chart process of selection of studies for review and meta-analysis.

with a combination of the following two main groups of keywords, using ‘‘AND’’ connector. The first group comprised the articles which had either of the following keywords/phrases, using ‘‘OR’’ connector, in any field: ‘‘dex/crh’’, ‘‘dex-crh’’, ‘‘dst/crh’’, ‘‘dst-crh’’, ‘‘dexamethasone/crh’’, ‘‘dexamethasone/corticotropin-releasinghormone’’, ‘‘‘‘dexamethasone suppression test’’ AND crh’’. The second group encompassed the articles indexed under MeSH major topic of these keywords/ phrases using ‘‘OR’’ connector: ‘‘depression’’, ‘‘major depressive disorder’’, ‘‘mood disorders’’. The search results were subsequently narrowed by limiting them to human subjects and English language. All the abstracts were reviewed for relevance to our study objective, and where appropriate, the full texts were reviewed for further clarification. Reference lists of the full-text articles were also reviewed for potential addition of articles which were not initially found. Articles on the same patients were excluded, except when the articles used different comparison groups (e.g. patients and healthy controls). The initial step in the literature review extracted two groups of articles. The first group consisting of all articles on DST or DEX/CRH tests, yielded 185 entries. The second group of all articles, indexed under the depressive or mood disorders MeSH topics produced 118,950 entries. Using the ‘‘AND’’ connector, 101 articles were identified. Review of the 101 abstracts and of the full texts, as well as review of included reference lists, yielded 15 articles meeting criteria for the study. This progressive elimination process is depicted graphically in Fig. 1. The full texts of the 15 included articles were thoroughly reviewed to assess the characteristics of each study. They were subsequently categorized based on the four-step criteria.

2.3. Statistical analysis We used the standardized mean difference (Cohen’s d) as the metric to summarize individual studies, since serum cortisol level is a continuous measure. For studies reporting standard errors, they were converted to standard deviations. The statistical software MIX 2.0 Professional was used for the analysis (Bax, 2010). Unfortunately, six studies did not report sufficient quantitative data for a meta-analysis, i.e. means or standard deviations (S.D.s) were not included. One study presented medians instead of means (Watson et al., 2002). Gervasoni et al. (2004) did not report means and S.D.s for the recurrent patient group. Four studies (Heuser et al., 1994; Watson et al., 2006; Carpenter et al., 2009; Veen et al., 2009) did not report means or medians for both patient and control groups. Inconsistent methodology in one of the articles resulted in exclusion from the meta-analysis. The remaining eight articles were included in the meta-analysis to estimate the effect size between MDD patients and healthy controls. All studies expressed the results of cortisol and ACTH suppression in response to CRH as Area Under Curve (AUC). However, only the AUC for cortisol was incorporated into our meta-analysis, since the abnormal DEX/CRH test is defined based only on the non-suppression of cortisol. The analyzed studies adopted the definition of

Table 2 summarizes the characteristics of 15 articles according to study groups, significance, and step-wise approach. There were common first authors in two pairs of the studies (Kunugi et al., 2004, 2006; Watson et al., 2002, 2006). Kunugi et al. conducted different studies. However, Watson et al. (2002) had the same study sample, but reported the test results in depressed patients in one article, and found the superior specificity and diagnostic utility of the DEX/CRH test compared with the DST for both depressed and bipolar patients in the other article (Watson et al., 2006). These articles were not included in the meta-analysis as they did not report means and standard deviations. Patient groups in two articles (Watson et al., 2002; Kunugi et al., 2004) comprised depressed patients only, whereas other articles had patients with other axis-I diagnoses as well. One article added individuals with dysthymic disorder (Oshima et al., 2000), one with schizophrenia (Heuser et al., 1994), two with panic disorder (Heuser et al., 1994; Erhardt et al., 2006), and eight with bipolar disorder; the latter group was divided into studies in which some of the patients with current depressive episodes had already been diagnosed with bipolar disorder (Bardeleben and Holsboer, 1989; Holsboer-Trachsler et al., 1991; Rybakowski and Twardowska, 1999; Gervasoni et al., 2004; Kunugi et al., 2006), and studies which assessed the bipolar and MDD groups separately (Heuser et al., 1994; Schmider et al., 1995; Watson et al., 2006). Except for one study which divided patients into pure depression and depression with comorbidity (Veen et al., 2009), other studies excluded depressed patients with most other psychiatric comorbidities and medical conditions or medications influencing the HPA axis. None of the articles included subjects with diagnoses of substance use or axis II disorders in their studies. Table 2 indicates the number of patients and healthy controls in each study, as well as the number of patients in subgroups with different disorders. Eleven studies showed significantly higher cortisol levels in response to the DEX/CRH test among the MDD subjects compared to the healthy controls. Cortisol non-suppression was defined as any level above the cut-off point (40 ng/ml or 50 ng/ml), according to the two leading studies (Bardeleben and Holsboer, 1989; Carroll, 1982). Except for one study (Carpenter et al., 2009), all others reported p-values, which are presented in Table 2. This table also indicates wherever cortisol non-suppression was significant for psychiatric disorders other than depression. All studies matched the age and gender of patient and control groups. Table 3 includes the age distribution in the reviewed studies. Some studies with MDD groups which also included patients with other psychiatric disorders reported the age range

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Table 2 Characteristics of reviewed studies based on groups, significance, and step-wise approach. Author/year

Groups

Significance

Step Additional findings and comments classification

Bardeleben and Holsboer (1989)

Significanta for patient group vs. controls p o 0.001

Step-1

DEX/CRH was not compared between BPAD and MDD, hence not step 2

Significant for patient group vs. controls p o 0.01

Step-1

DEX/CRH was not compared between BPAD and MDD, hence not step 2

Higher sensitivity of DEX/CRH (80%) than DST (25%) for MDD No differentiation between patient subgroups

Step-2

DEX/CRH did not differentiate between depressive and manic episodes

Modell et al. (1997)

HC ¼11 Major depressive episode ¼31 HC ¼29

Significant for all psychiatric disorders vs. controls p o 0.05 Significant for both patient groups vs. controls p o 0.05 Significant for patient group vs. controls p o 0.05 Significant for recurrent MDD vs. control p o 0.01 Non-significant p ¼ 0.17

Step-3

Schmider et al. (1995)

Major depressive episode ¼14 (first-episode ¼2, recurrent¼ 10, BPAD ¼2) HC ¼14 MDD ¼ 14 (first-episode ¼4, recurrent¼ 8, BPAD ¼2) HC ¼13 Psychiatric disorders¼ 140 (MDD ¼ 96, manic episode ¼11, panic disorder ¼9, schizophrenia ¼24) HC ¼82 MDD ¼ 11 Acute manic episode ¼11

Step-1

DEX/CRH was not compared between subgroups of patients, hence not step 2

Step-1

DEX/CRH was not compared between BPAD and MDD, hence not step 2

Step-2

DEX/CRH did not differentiate between MDD and dysthymia

Step-1

Only brief mention of higher sensitivity of DEX/CRH compared to DST, not quantitative, hence not step 3

Step-1

DEX/CRH was not compared between BPAD and MDD, hence not step 2

Step-1

Only brief mention of higher sensitivity of DEX/CRH compared to DST, not quantitative, hence not step 3

Step-2

DEX/CRH did not differentiate between MDD and panic disorder

Step-3

DEX/CRH had better specificity (71.4%) than DST (47.6%)

Step-1

DEX/CRH was not compared between BPAD and MDD, hence not step 2 multi-center, but not large sample, hence not step 4

Step-1

None

Step-2

DEX/CRH differentiated between pure MDD (significantly higher cortisol AUC) and MDD/comorbidity

HolsboerTrachsler et al. (1991) Heuser et al. (1994)

Rybakowski and Twardowska (1999) Oshima et al. (2000) Watson et al. (2002)

MDD ¼ 24 (first-episode ¼10, recurrent ¼ 14) BPAD ¼16 HC¼ 20 MDD ¼ 20 Dysthymic disorder ¼8 HC ¼12 Chronic MDD ¼ 29 HC ¼28

Non-significant, but with a trend p ¼ 0.052 Gervasoni et al. Major depressive episode ¼ 36 (previous Significant in patients (2004) episodes r 1¼ 21, Z2 ¼13, BPAD¼ 3) with Z2 episodes HC ¼20 p ¼ 0.0088 Kunugi et al. MDD ¼ 20 Significant for patient (2004) HC ¼30 group vs. controls p o 0.005 Erhardt et al. Major DEPRESSIVE episode ¼ 35 Significant for both Panic disorder ¼30 (2006) patient groups vs. controls p ¼ 0.001 HC ¼30 Watson et al. Mood disorders ¼82 Significant for both (MDD ¼ 29, BPAD¼ 53) (2006) patient groups vs. controls HC ¼28 p ¼ 0.031 Kunugi et al. Major depressive episode ¼61 (single, Significant for patient (2006) recurrent, BPAD) group vs. controls HC ¼57 p ¼ 0.036 Carpenter et al. MDD ¼ 34 Non-significant (2009) HC ¼34 p-Value not reported Veen et al. (2009) Pure MDD ¼ 36 Non-significant MDD þ comorbidity (anxiety/ p ¼ 0.32 somatoform disorders) ¼18 HC ¼43

BPAD: bipolar affective disorder; HC: healthy controls; MDD: major depressive disorder; S.D.: standard deviation. a

Significance relates to cortisol level, when it is above the cut-off point, which is defined as non-suppression.

of the whole patient group, and did not specifically report the age range of MDD patient subgroups. All studies made the diagnoses according to either the DSM-IV or DSM-III-R. Some studies specifically mentioned using the Structured Clinical Interview for DSM-IV (SCID) to arrive at diagnosis. To measure severity, 11 studies used the Hamilton Depression Rating Scale (HDRS). Two studies (Gervasoni et al., 2004; Veen ˚ et al., 2009) used the Montgomery-Asberg Depression Rating Scale (MADRS), and one study (Carpenter et al., 2009) used the Inventory of Depressive Symptomatology-Self Report (IDS-SR). Table 3 summarizes scores of severity scales and their correlation with the DEX/ CRH results. The treatment status of the patient groups is also included in Table 3. In six articles, depressed individuals were excluded if on anti-depressants. However, all or some of the patients were on

anti-depressant treatment at the time of the test in six studies. One study performed the test both before and after treatment (Rybakowski and Twardowska, 1999), and two articles did not report any treatment status of the patients (Bardeleben and Holsboer, 1989; Modell et al., 1997). Table 3 also shows the clinical settings of the subject recruitment in the studies. Patients in seven studies were recruited from an inpatient setting, while four studies were conducted in outpatient settings. The remaining four studies did not report their clinical settings. 3.2. Meta-analysis Table 4 shows means and standard deviations of AUC values for cortisol in depressed patients and healthy controls in studies included in the meta-analysis. The meta-analysis yielded a large

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Table 3 Age distribution, clinical and treatment status, severity scale and correlation of cortisol AUC scores with severity in the depressed patients. Author/year

Age

Medication status

Clinical setting

Severity Scale/score/correlation

Bardeleben and Holsboer (1989) Holsboer-Trachsler et al. (1991)

Heuser et al. (1994) Schmider et al. (1995) Modell et al. (1997) Rybakowski and Twardowska (1999)

MDD: 43.1(S.D. 79.2) HC: 40.4(S.D.7 15.1) MDD: 53.3(S.D. 79.3) HC: 53.2(S.D.7 11.8)

Not mentioned

Inpatient

HDRS

Majority of patients on medication

Inpatient

MDD: 57.4(S.D. 715.5) HC: 57(S.D.7 17.6) MDD: 39(S.D.7 17) HC: 38(S.D.7 15) MDD: 50.9(22–77) HC: 53(24–81) MDD: 46(21–61) HC: 30(22–52)

Subjects on medication excluded

Inpatient

HDRS Correlation with severity (r ¼0.45, p¼ 0.11) None

Subjects on medication excluded

Not mentioned

Not mentioned

Not mentioned

First-episodes not on medication Recurrents on medication

Inpatient

Oshima et al. (2000)

MDD: 40(S.D. 7 14.7) HC: 36.1(S.D.7 2.4)

Subjects on medication excluded

Outpatient

Watson et al. (2002)

MDD: 48.8(S.D. 79.6) HC: 49(S.D.7 9.4) MDD: 35.8(S.D. 711.5) HC: 32.8(S.D.7 11.6) MDD: 58(S.D.7 15) HC: 30(S.D. 7 6) MDD: 35.11(S.D. 76.02) HC: 34.17(S.D.7 8.8)

All patients on medication

Not mentioned

Subjects on medication excluded

Outpatient

All patients on medication

Inpatient

All patients on medication

Inpatient

MDD: 23–63 HC: 24–60 MDD: 30–82(S.D. 713) HC: 22–48(S.D. 77)

About half of patients on medication

Not mentioned

Majority of patients on medication

Inpatient

MDD: 40.5(S.D.7 12.7) HC: 39.7(S.D.7 12.1) MDD: 33.8(S.D. 711.2) HC: 33.9(S.D.7 12.3)

Subjects on medication excluded

Outpatient

Subjects on medication excluded

Outpatient

Gervasoni et al. (2004) Kunugi et al. (2004) Erhardt et al. (2006)

Watson et al. (2006) Kunugi et al. (2006)

Carpenter et al., 2009 Veen et al. (2009)

HDRS Mean: 30(S.D. 7 4.6) HDRS Mean: 27.8(21–40) HDRS Mean: 25.1(S.D.7 2.8) Correlation with severity (r ¼0.35, po 0.02) HDRS Mean: 17.1(S.D.7 4.5) No correlation with severity HDRS Mean: 23.0(S.D.7 7.0) MADRS Mean: 32(25–43) HDRS Mean: 28.4(S.D.7 11.6) HDRS Mean: 27.54(S.D. 74.73) Correlation with severity (r ¼0.342, p ¼0.044) HDRS Mean: 23.0(S.D.7 7.0) HDRS Excluded if o 15 Correlation with severity IDS-SR Mean: 36.0(S.D.7 10.24) MADRS Mean: 23.1(S.D.7 6.8)

˚ HDRS: Hamilton Depression Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; IDS-SR: Inventory of Depressive Symptomatology-Self Report; HC: healthy controls; MDD: major depressive disorder; S.D.: standard deviation. Table 4 Means and standard deviations of AUC scores for cortisol response to DEX/CRH in patient and control groups in studies included in the meta-analysis. Author

Year

MDD

HC

Mean (MDD)

S.D. (MDD)

Mean (HC)

S.D. (HC)

AUC Interval (h)

Bardeleben and Holsboer Holsboer-Trachsler et al. Schmider et al. Modell et al. Rybakowski and Twardowska Kunugi et al. Erhardt et al. Kunugi et al.

1989 1991 1995 1997 1999 2004 2006 2006

14 14 11 31 22 20 35 61

14 13 11 29 20 30 30 57

14,500 9400 5203.11 332 680 4730 2850.23 3650

4300 7600 11,276.12 95.4 468 3670 2414.37 3440

3100 3100 1673.47 103.8 545 1890 1123.73 1550

2400 3600 2294.73 33.4 398 1850 770.19 1310

2 3 3 1.25 2.5 1.25 1.25 1

AUC: area under curve; HC: healthy controls; MDD: major depressive disorder; S.D.: standard deviation. Unit of measurement for all values is ng/ml. (Time unit was not reported in most of the studies. Please see the text.)

effect size (Cohen’s d ¼1.34, with 95% confidence interval of 0.70–1.97) in a weighted random effects model. Heterogeneity was considerable (Q¼54.23, po0.001, I2 ¼87.09%). Exclusion sensitivity (deleting one study at a time) showed a range of large effect sizes from 1.02 to 1.49. However, prediction interval was from 0.89 to 3.53 (Fig. 2). 3.3. Four-step approach This approach was first proposed in view of some highly replicable abnormalities in psychiatry which can potentially be utilized as laboratory diagnostic tests (Boutros and Arfken, 2007).

Table 1 summarizes the characteristics of each step. In step 1, a biological variable is observed to be deviant from healthy controls in a particular patient population. An essential component of this step is the demonstration of test–retest reliability of the finding using blinding procedures. Replication of the finding by the same or collaborating groups is important, yet confirmation by independent groups is necessary for this particular test to move into the next stage. Referring to this approach, majority of the studies, nine out of 15, were compatible with step 1. Defining the strength of the biological observation in the target patient group as compared to healthy control subjects is an essential part of step 1 and is likely to be one of the eventual

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Fig. 2. Forest plot of effect sizes from the eight studies included in the meta-analysis.

determining factors of the actual clinical utility of the finding. Towards this point, a meta-analysis should be performed as part of assessing this step. What effect size will confidently predict the future performance of the test is not yet currently known. Our findings regarding the DEX/CRH test show an effect size of 1.34, which is considered relatively strong. Validation of the four-step approach will only come from examining the predictions of steps 1–3 about the eventual effectiveness of the test in wide clinical use. It is worth mentioning that meta-analysis or systematic review studies themselves are not considered eligible as studies with the four-step approach (Boutros and Arfken, 2007). Step 2 involves the demonstration of potential clinical usefulness of the specific finding of step 1 by showing a consistent difference between the target patient population and groups of patients with closely related diagnoses that commonly appear on the differential diagnostic lists of the target disorder. This step requires the biological abnormality to be differentially and significantly more prevalent in the target population. Four studies out of 15 were eligible as step-2 studies. They differentiated the depressed patients and those with other psychiatric illnesses in terms of response to the DEX/CRH test. Schmider et al. (1995) found no significant difference between two patient groups, i.e. those with acute manic episode and those with major depressive disorder. Erhardt et al. (2006) also reported an insignificant difference between subjects with panic disorder and major depressive disorder. In a comparison of depressed and dysthymic patients, Oshima et al. (2000) did not report any difference in cortisol levels of these two groups.

Veen et al. (2009) divided patients with major depressive disorder into pure and with comorbidities, i.e. anxiety and/or somatoform disorders. Significantly higher cortisol levels were reported in pure MDD compared to MDD/comorbidity patients. Modell et al. (1997), Gervasoni et al. (2004) and Kunugi et al. (2006) also had subjects with psychiatric disorders other than depression, yet none of them compared the test results of depressed patients with those of other diagnoses. Therefore, they are not considered step-2 studies. Step 3 demonstrates the performance characteristics of the biological marker, particularly, sensitivity, specificity, and positive and negative predictive values. These data should allow the estimation of the added diagnostic value resulting from incorporating the test into the work-up of a particular patient. The choice of the ‘‘gold standard’’ or reference test is an essential component of this step. Heuser et al. (1994) presented quantitative data on sensitivity of the DEX/CRH test, reporting a higher sensitivity thereof compared with the DST alone. Watson et al. (2006) described a similar superiority of the DEX/CRH in terms of specificity and overall diagnostic performance. Therefore, these two studies are considered step-3 studies in our review. Watson et al. (2002) and Kunugi et al. (2004) reported a higher sensitivity of the DEX/CRH test compared with the DST. However, they did not present quantitative data to support their statements. Thus, they cannot be considered step-3 studies. Step-4 studies require multicenter clinical trials and collaboration among research groups to define the clinical application of the test by standardization of laboratory procedures and

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collecting data on cost effectiveness and impact on both shortterm and long-term clinical outcomes. This step should develop larger normative databases that can eventually be used to examine an individual’s data. No study was found to have been conducted based on step 4 of this approach. Kunugi et al. (2006) recruited their subjects from different centers, yet this study does not meet the criteria for step 4 due to its small sample size within one country, as well as lacking the characteristics required for step-2 and step-3 studies.

4. Discussion Findings of this review reveal that despite a relatively considerable amount of research on the DEX/CRH test, there has not been a consistent approach to evaluate its clinical usefulness. This meta-analysis yields a relatively large effect size. Our extensive search of the literature failed to locate any metaanalysis on this topic, and to the best of our knowledge, this is the first meta-analysis of the DEX/CRH test in depressed patients vs. healthy controls. Even review articles on this particular subject are very few. Ising et al. (2005) concluded that elevated plasma cortisol responses to the combined DEX/CRH test could be observed in most studies with patients during an acute major depressive episode; and among psychiatric patients, most pronounced alterations of the HPA system are found in patients suffering from unipolar or bipolar affective disorders. Another review article asserts that depressed patients release significantly more cortisol after the DEX/CRH test in comparison with healthy controls (Sher, 2006). Among the 15 articles in our review, 11 studies concluded that there is a significantly higher rate of non-suppression in response to the DEX/CRH test in depressed patients compared to the healthy control subjects. However, there are some notable points about the articles with non-significant results. Oshima et al. (2000) administered a dexamethasone dosage lower than the conventional dosage for this test (1 mg instead of 1.5 mg), and also set a higher detection limit of cortisol, both of which could have contributed to the lack of significance in their data. Gervasoni et al. (2004) showed significantly higher cortisol levels in patients with recurrent depression, but not significantly in patients with only one previous major depressive episode. Watson et al. (2002) identified only a trend in favor of more patients than controls having an abnormal response to the DEX/CRH test. Nevertheless, the lack of significance of this study may be attributed to recruiting patients with only chronic subtype of major depressive disorder, who were stable on medication. A review by Ising et al. (2007) showed that the majority of the studies with significant results had reported a higher cortisol response only among the acutely depressed patients. This observation suggests that the abnormality is state rather than trait dependent. However, a number of articles reported the opposite finding, that HPA axis alterations are better explained as a trait factor, which can be considered as an endophenotype and a biological vulnerability for the development of depression. These articles, however, have utilized salivary cortisol levels upon awakening and in response to dexamethasone unaccompanied by CRH (Vreeburg et al., 2009a, 2010). A fundamental difference between a diagnostic test and an endophenotype is the need for the diagnostic test to be state dependent (i.e., indicating the illness state rather than the vulnerability to the illness) (Table 2, Arfken et al., 2009). A major problem in laboratory-based diagnostic procedures, particularly in psychiatry, is premature release of a test before the necessary stages of evaluation have been performed. Several biological markers have been suggested to be promising based

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on the studies in the literature, yet their accuracy for diagnostic application remains equivocal owing to such factors as heterogeneity of the disorder or methodological inconsistencies. The four-step approach was proposed to help propel promising biological variables towards developing into a clinically useful diagnostic test or screener along a described continuum. We have previously documented that this approach can be useful in determining the stage of development of a biological finding into a laboratory test (Boutros et al., 2005, 2008; Boutros and Arfken, 2007). Review of the literature according to this approach can illustrate which aspects of a test have been studied and which aspects have not been fully characterized. This can outline a prospect for future research, preventing duplicate studies without demonstrating further evidence of the clinical applicability of the test. The majority of the reviewed studies are considered step-1 studies, with fewer step-2 and step-3 studies, and no step-4 studies. This finding emphasizes the necessity of conducting more step-3 and step-4 studies on the DEX/CRH test. It would be thoughtful to propose a more universal guideline to perform this test, such that even more step-1 and step-2 studies can be conducted with higher methodological consistency.

4.1. Limitations We only included published articles in our review and metaanalysis. Unpublished studies may have differed substantially from those published. Our review is limited by the few articles published to date that could be included in the meta-analysis and the focus on the diagnostic possibility of the test. Obviously, there are other valid scientific issues to address with the test. A number of methodological variations were observed in the studies, including scales utilized to diagnose depression and its severity, treatment status of the patients, and the DEX/CRH procedure details such as cortisol sampling. This methodological inconsistency may complicate the generalization potential of the results. It also limited the number of articles that could be included in a meta-analysis. Furthermore, meta-analysis is best suited when the summary measure, in our analysis Cohen’s d, or the standardized mean difference, is a valid summary. Means and standard deviations may not be valid summaries of the cortisol AUC levels, and may obscure a different and more diagnostically useful summary.

4.2. Conclusion In summary, this review from the perspective of the four-step approach emphasizes that despite appearing promising, the DEX/ CRH test has not been adequately studied in terms of the required stages of development that a laboratory test needs to undergo before it can be declared as an applicable clinically useful procedure. More step-3 and step-4 studies are necessary, and more methodologically consistent step-1 and step-2 studies are required to facilitate this process. We strongly recommend this approach as a guideline for any biological marker that has been found to be replicable among the individuals with a particular disorder, yet has not been fully developed into an objective diagnostic test.

Acknowledgment The authors thank Dr. Marcus Ising for his expert advice.

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