BIOL PSYCHIATRY 1990;28:193-202
193
Comorbidity in the Interpretation of Dexamethasone Suppression Test Results :in Children: A Review and Report Ronald Steingard, Joseph Biederman, Kate Keenan, and Cynthia Moore
The dexamethasone suppression test (DST) was administered as part of the initial clinical assessment to 83 children and adolescents who were consecutively referred for outpatient evaluation. All diagnoses were made clinically by a child psychiatrist according to DSM!11 criteria~ A weight-corrected dose of dexamethasone of 17 ttglkg was used. DSM-III diagnoses were made independent of DST results. Patients were stratified into four main diagnostic groups: "major depressive disorder (MDD) (N = 27); attention deficit disorder with hyperactivity (ADDH) (IV = 22); major depressive disorder plus auention deficit disorder with hyperactivity (MDD + ADDH) (N = 29); and psychiatric controls (PC) (N = 5). Rates of dexamethasone nonsuppression were found to be similarly elevated in children with MDD (29.6%), ADDH (22.7%), and MDD + ADDH (37.9%). All 5 psychiatric control patients had a normal pastdexamethasone suppression (0%). A similar pattern of results emerged in a reexamination of the literature on available studies of DST in juveniles which revealed that children with major affective disorders, attention deficit disorder (ADDH), and anxiety disorders had comparable DST results that were significantly higher than the 5.6% rate found in normal controls. These findings provide further support for similarities in DST results between ADDH and MDD in outpatients. Although these results suggest a lack of specificity of the DST as a laboratory aid for the diagnosis of juvenile affective disorders, they are also consistent with findings indicating that the DST may be an index of clinical severity and other findings suggesting a possible association between ADDH and MDD. Despite its limitations, the DST may provide potentially useful clinical and research information regarding the pathophysiology of psychiatric disorders and in alerting clinicians to the presence of serious psychiatric disorders. The findings also stress the relevance of assessing comorbidity in interpreting DST results.
Introduction The dexamethasone suppression test (DST) was initially introduced into psychiatry as a biological marker that could enhance diagnostic reliability in affective disorders (Carroll et al. 1976). The DST has been extensively studied in adult psychiatric populations (APA From the Pediatric PsychopharmacologyUnit, Massachusetts General Hospital, Boston, MA. Address reprint requests to Dr. Ronald Steingard, Pediatric PsychopharmacologyUnit, Massachusetts General Hospital, ACC-725, Boston, MA 02114. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
194
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
Task Force 1987; Arana et al. 1985) and findings have suggested that it could help define treatment parameters such as duration of treatment, predict response to pharmacological interventions, and identify individuals at risk for affective disorders (APA Task Force 1987). In a review of the literature regarding the use of the DST in adult psychiatric patients, the American Psychiatric Association Task Force on Laboratory Tests in Psychiatry (APA Task Force 1987) reported an overall sensitivity of the test of 50% to 60% for adult inpatients and 40% for outpatients, with a specificity ranging from 50% to 80%. The Task Force concluded that the DST may add to diagnostic reliability in patients suspected of having major depressive disorder (MDD). Studies of the DST in juvenile mood disorders have been generally optim.lsti¢ regarding the potential use of the test in clinical practice. In a recent review of 13 studies by Casat et al. (1989), the average rate of nonsuppression in children and adolescents with MDD was 81.7% for inpatients. Two of the reviewed studies examined DST results in outpatients meeting RDC criteria for MDDc Geller et al. (1983) reported a 10% (1/10) rate of nonsuppression whereas Poznansk ~. et al. (1982) reported a 56% (5/9) rate. These discrepant results could be attributed to the small sample size of each study, and to differences ;n methodology. Given the potential applicability of the DST as a laboratory aid in the differential diagnosis of juvenile mood disorders, we pursued an evalw, tion of the DST in children with depressive and dysphoric symptomatology in an outpatient child psychiatry clinic. As children with ADDH frequently show depres~b,~ and dysphoric symptomatology (Biederman et al. 1987; Bohline 1985; Brown et al. 1988; Jensen et al. 1988; Weinberg et al. 1989) and children with MDD frequently display psychomotor agitation as well as dysphoria, we expected that the DST would help in the differential diagnosis of these two highly prevalent disorders. Method The DST was administered to 83 children [boys N = 78, girls N = 5; mean age (+_ SD) = 11.2 ± 4.0 years] who were consecutively referred for outpatient psychiatric evaluation and who reported dysphoria and irritability as prominent presenting symptoms. There were 47 prepubertal children [45 boys, 2 girls; age range 4-12 years (mean = 8.1 _+ 2.4 years)] and 36 adolescents [33 boys, 3 girls; age range 13-16 years ..(mean = 15.3 _+ 1.8 years)]. All but 8.4% of 9articipating subjects iN = 7 (3 MDD, 4 ADD): 1 methylphenidate, 3 heterocyclic antidepressants, 1 propranolol, 1 alprazolam, 1 lithium] were medication-free at the time of the DST. Clinical interviews were conducted with each child and their p~_-t a_nd~!l diagnoses were based upon DSM-III criteria. PsychiaU~c diagnoses were made prior to, and independent of, the DST results. Because of the wide range of ages and corresponding weights in the participating children and adolescents, the dose of dexamethasone was corrected for weight. Using 0.125 mg (one-half tablet) increments, a dose as closely approximating 17 ttg/kg as possible was used, resulting in a dose of dexamethasone ranging from 14.5 to 20.8 I~g/kg [mean (_+ SD) = 18.2 _ 1.2 ttg/kg]. There were no statistical differences in the mean doses of dexamethasone used in the attention deficit disorder with hyperactivity (ADDH) (18.0 _ 1.5 ttg/kg), MDD (18.2 _+ 1.0 ttg/kg), M D D + A D D H (18.3 _+ 1.! ttg/kg), and psychiatric control (PC) (18.1 _+ 1.1 t~g/kg) groups. The weight-corrected dose of dexamethasone was administered at 11 PM on day 1 and blood samples were drawn at 4 PM on day 2 for serum cortisol determination. Cortisol levels were assayed using the Gamma Coat (1251) Radioimmunoassay Kit (Baxter Tray-
Comorbidity in the DST in Juveniles
195
BlOt. PSYCHIATRY 1990;28:193-202
Table I. Dexamethasone Suppression Test (DST) in an Outpatient Child Psychiatry Sample Abnormal DST
Cortisol (p,g/dl)
Diagnosis
N
N
%
Mean .4- SD
Mutually exclusive categories MDD ADDH MDD + ADDH PsF.hiatric controls
27 22 29 5
8 5 il 0
29.6 22.7 37.9 0
3.8 -," 4.0 __ 4.4 _ !.6.4-
Ncamutuaily exclusive Any MDD Any ADDH
56 51
19 16
33.9 31.4
4.1 +-- 3.7 4.2 .4- 4.0'
3.4 4.I 3.9' 0.2
Op < 0.05 versus psychiatric control by Mann-Whitney U test. Mutually exclusive categories: major depressive disorder (MDD); attention deficit disorder with hyperactivity (ADDH); MDD + ADDH. Nonmutually exclusive categories: any MDD: MDD with and without ADDH; any ADDH: ADDH with and without MDD. Psychiatric controls: anxiety disorder (N = 3); pervasive developmental disorder (N = 2).
enol Diagnostics, Cambridge, MA) following the procedure described in their instruction manual. This assay has a calculated sensitivity of 0.14 ttg/dl. A serum cortisol level greater than 5 ttg/dl was interpreted as indicative of postdexamethasone nonsuppression (APA Task Force 1987). DST assessments were done by laboratory personnel who were unaware of the clinical diagnosis of subjects or their diagnostic stratification. Patients were stratified into four mutually exclusive diagnostic groups: MDD (N = 27); ADDH without affective disorders (N = 22); MDD + ADDH (N = 29); and PC IN = 5 (anxiety disorder, N = 3; pervasive developmental disorder, N = 2)] (Table 1). There was limited additional comorbidity within these stratified groups. The co-occurrence of other affective disorders (i.e., dysthymia and cyclothymia) was limited to the MDD group (4 dysthymia) and the MDD + ADDH group (4 dysthymia, 1 cyclothymia). Other behavioral disorders occurred in the ADDH (2 oppositional disoraer) and the MDD + ADDH (1 conduct disorder) gr,~ups. Comorbid anxiety disorders were found in the MDD group (1 panic disorder) and the MDD + ADDH group (1 panic disorder, 1 generalized anxiety disorder). Data were also analyzed by stratifying the sample into nonmutuallyexclusive categories defined by the presence of MDD [with and without ADDH: any MDD, (N = 56)1 or ADDH [wit.h and without MDD: any ADDH (N = 51)1. Data were analyzed using rates of postdexamethasone nonsuppresslon and absolute postdexdmethasone cortisol levels. Data were distributed nonparametrically, therefore nonparametric statistical tests were used, including the Mann-Whitney U Test in the analysis of continuous variables, the Fisher Exact Test in the analysis of categorical variables, and the Spearman Rank Correlation Coefficient in the analysis of associations. All analyses were two-tailed and statistical significance was defined at the 0.05 level.
Results
Massachusetts General Hospital (MGH) Sample As shown in Table 1, no significant differences were found in rates of postdexamethasone nonsuppression in children with MDD (29.6%), ADDH (22.7%), and M D D + ADDH (37.9%), or in the nonmutually exclusive subgrot ps of any MDD (33.9%) and any ADDH
196
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
(3! .4%). Rates of nonsuppression were moderately elevated in children with MDD and ADDH, but all 5 patients with other disorders exhibited normal postdexamethasone cortisol suppression (0%) (Table 1). However, no statistical difference between the subgroups could be demonstrated (chi-square = 31, df = 3, ns), probably due to the small number of the psychia~c controls (N = 5). Of the 7 subjects who were on psychotropics at the time of the DST, 4 had positive and 3 had ~.egative DST results. Similar results were obtained when the analysis w:~sbased upon examination of mean ( _+SD) postdexamethasone cortisoi levels. Although the cortisol levels were significantly higher in the patients with MDD (3.8 ± 3.4 ~g/dl), ADDH (4.0 +_ 4.1 p.g/dl), MDD+ADDH (4.4 _+ 3.9 p,g/dl), any MDD (4.1 _+ 3.7 p,g/dl), and any ADDH (4.2 _+ 4.0 Ixg,'dl) than in psychiatric control patients (1.6 -+ 0.2 l~g/dl), a statistically significant difference could be established only for the MDD+ADDH subgroup (z = - 2 . 1 ; p = 0.04) and the any ADDH subgroup (z = - 2 . 0 , p = 0.045). A small negative, but statistically significant, correlation was found between postdexamethasone cortisol levels and age (Rho = -0.25; p = 0.02). Given the range of doses used in the study, the effect of the dose of dexamethasone on the results was examined in two ways. A correlation analysis failed to demonstrate a significant relationship between dose of dexamethasone and postdexamethasone cortisol levels (rho = 0.03, ns). Additionally, there was no statistically significant difference between the rate of nonsuppression in subjects receiving a dexamethasone dose above versus below the median (18 p,g/kg) (22.0% versus 35.7%, ns).
Review of the Literature A reexamination of the literature on available studies of DST in juveniles was undertaken. Using 4 PM results (whenever available, to permit cross-study comparison), or reported study results (when 4 PM data was not spec~3ed), comp~able DST results were found in children with major affective disorders (nonbipolar MDD: 55% inpatient, 34% outpatient, 51% overall; bipolar MDD: 52% inpatients only), attention deficit disorder (46% inpatient, 31% outpatient, 36% overall), and anxiety disorders (51% inpatients only). Statistical comparisons of overall results revealed that the rates of DST in these groups were significantly higher than the 5.6% rate found in normal controls (Weller et al. 1985) (by Fisher Exact Test, two-tailed p < 0.05) (Table 2). When comparisons were made between the MGH DST results and those reported in normal controls in the literature, the rates of dexamethasone nonsuppression in the any MDD and any ADDH subgroups were found to be significan".y higher than those of normal controls reported in the literature (by Fisher Exact test, both p = 9.93). However, for ~he n~utuallyexclusive diagnostic subgroups, a statistically significant difference could be established only for the MDD + ADDH subgroup (p = 0.008), whereas the results for the MDD subgroup approached statistical significance (p = 0.06). Discussion In a clinical sample of children and adolescents, the rates of postdexamethasone nonsuppression were found to be relatively high and comparable in l 'ttients with MDD (29.6%) and ADDH (22.7%). In contrast, although limited by small :'.ample size (N 5), the rate of postdexamethasone nonsuppression in subjects with pervasive developmental disorder (PDD) and anxiety disorders was 0%. However, the small size of tile
Comorbidity in the DST in Juveniles
toOLPSYCHIATRY
197
!990;28:193-202
Table 2. DST Results in Inpatient and Outpatient Child Psychiatry Populations Diagnosis
Study
MDD
Inpatient Cmmley et al. (1982) a'c Extein et al. (1982) b Hsu et -_I. (i983) b Robbins et al. (1983) b Targum and Capodanno (1983) b Ha et al. (1984) b Klee and Garfinkel (1984) b Livingston et ai. (1984) ° Petty et al. (1985) a Weller et al. (1985)" Doherty et al. (1986) b Emslie et al. (1987)'1 Evans and Nemeroff (1987) b Ki,'tan (1987) b Livingston et al. (1987) n Wood~ide et al. (1987) b Total Percent Outpatient Poznanski et d~ (1982)" Geller et al. (1983) ° Steingard et al. (1990)" Total Percent Overall Total Percent
11/23 8/15 9/14 4/16 7/17
Dysthymia
0/2
Bipolar disorder
ADDH
Conduct disorder
2/2
I/I
317
!/2
Anxiety disorder
4/26
7/38
Psychotic disorder
Normal controls
2/8 0/2 4/18
7/47
6/22 8/20 2/3 6/7 36/50 1 i/26 18/33 8/20
I/2 4/5
23/33 8i8 8,/10
I/6
173/317 54.6%
17/71 23.9%
I/I
4/6 I/2
!/! 2/3 1/18
4/18
2/5 3/8
0/4
! 15 7/14
3/22 3/13 2/18
17/22
11/24 45.8%
31/156 19.9%
23/45 51. ! %
10/39 25.6%
1/18 5.6%
31/156 19.9%
23/45 51. !%*
10/39 25.6%
1/18 5.6%
16/51
25/74 33.8%
! 6/5 ! 31.4% 17/71 23.9%
10/19 52.6%*
0/6
0/7
2/2 10/19 52.6%
1/15
!/3
5/9 1/9 19/56
198/391 50.6%*
I/4 8/I !
27/75 36%*
1/i
*By Fisher exact test (two-tailed) vs. DST rates in normal controls, p < 0.05. -~Reponreflects only 4 PM DST results. bReport reflects S AM, 4 eM, and | 1 PM DST results. ~Results reported for only I mg of dexamethasone.
psychiatric control group did not permit adequate statistical comparisons between all diagnostic groups. Though the rate of abnormal DST found in children with MDD is consistent with DST findings reported in outpatient samples of adults with MDD (APA Task Force 1987), it was striking to find a 22.7% rate of dexamethasone nonsuppression in an outpatient sample of children with ADDH. Several competing explanations can be considered in accounting for similarities in rates of DST results between ADDH and MDD. High rates of postdexamethasone nonsuppression in children with ADDH may suggest that the DST lacks specificity for mood disorders. Abnormalities in the DST are thought to reflect abnormalities in the limbic system, which is involved in regulating a wide range of human behaviors and functions
198
BIOL PSYCHIATRY 1090,28:193-202
R. Steingardet al.
(i.e., sleep, appetite, psychomotor activity, hedonic capacity, reward and reinforcement, motivation, memory, anger, and rage) (Carroll et al. 1976; Greden 1985). Therefore, it is not surprising to find DST abnormalities in a variety of psychopathological states and not only in MDD. In fact, abnormal DST results have also been reported in elderly patients (Fogel et al. 1985), in patients with alcoholism (Khan et ai. 1984), in patients with recent weight loss (Fichter and Pirke 1980), as well as in patients with schizophrenia (Tandon et al. 1989), anorexia (Brambilla et al. 1985), and bulimia (Mitchell et al. 1984). Our findings, therefore, may add to the unc~rtai~ntyof the role of the DST as a discriminatory tool in the diagnosis of mood disorders (Hirschfeld eta!. 1983) and shpport the claim that the in~oduction of the DST for this specific purpose may have been premature (Nierenberg and Feinstein 1988). However, lack of specificity is not without clinical relevance. DST studies in both adults and children have consistently reported higher rates of DST abnormalities in inpatients compared with outpatients, suggesting that the DST may be an index of clinical severity. If so, despite lack of specificity, the DST may be a potentially usefill laboratory aid in the assessment of severity of psychopathology. The use of nonspecific laboratory tests is common in medical practice. For example, despite lack of specificity, an elevated erythrocyte sedimentation rate can alert the physician to a potentially serious clinical problem or the need for further clinical evaluation. This clinical aspect is particularly relevant for child psychiatry. The differential diagnosis between an adjustment disorder and an incipient serious psychiatric dis~:~rdercan pose important clinical dilemmas. Such a dilemma can develop in the evaluation of juveniles with ADDH and associated depressive symptoms in the differential diagnosis between demoralization and major depression. In light of recent findings indicating that the comorbidity of ADDH and MDD may be a significant risk factor for adolescent suicide (Brent et al. 1988), the availability of a laboratory test, such as the DST, that can aid the clinician in assessing the severity of the clinical picture has clinical relevance. One component of clinical severity is the presence of comorbid disorders. Until recently, issues of comorbidity had received little attention in the evaluation of research and clinical findings in child psychiatry. Comorbidity has been found to be highly prevalent in clinical (Biederman et al. 1990; Munir et al. 1987) and epidemiological (Anderson et ai. 1987; Bird et al. 1988) samples of children. For example, symptomatic and diagnostic overlaps have been reported between attention deficit disorder (ADD) and conduct disorder, between ADD and affective disorders, between ADD and anxiety disorders, between depressive disorder and anxiety disorders, and between conduct disorder and substance abuse (Anderson et al. 1987; Biederman and Faraone 1988; Biederman and Faraone 1989; Bird et al. 1988; Rutter 1989). Zimmerman et al. (1986) have suggested that diagnostic heterogeneity may have contributed to the apparent lack of specificity of the DST in adults with MDD. DST studies in children have not adequately addressed comorbidity in accounting for DST results. In our sample, the nonmutually exclusive diagnostic groups of any ADDH and any MDD attained relatively higher rates of dexamethasone nonsuppression than those found in either ADDH or MDD alone. This finding reflects the inclusion of patients with comorbid MDD + ADDH, who exhibited the highest rate of dexamethasone nonsuppression (37.9%). Given the high rates of comorbidity found in clinical and epidemiological samples of children (Bird et al. 1988; Munir eta!. 1987), these findings further underscore the importance of assessing comorbidity in clinic and study populations in attempting to evaluate DST results.
Comorbidity in the DST in Juveniles
BIOL PSYCHIATRY 1990;28:193-202
199
We have reexamined the literature on available studies of DST in juveniles. This review also indicates that the presence Of comorbidity may be highly relevant in accounting for reported DST findings. As previously noted, comparable DST results were found in children with maior affective disorders, ADD, ~ d anxiety disorders which were significalltly higher than the 5.6% rate found in normal controls (Table 2). Although the available DST studies are limited by small sample size, our review of the literature indicates that, on the aggregate, inpatients with ADDH have a 46% rate of abnormal DST. This rate ~s as high as that found in inpatients with MDD. Our present findings provide further support for similarities in DST results between ADDH and MDD in outpatients by showing that the rate of DST abnormalities in some outpatient children with ADDH is as high as that found among outpatients with MDD. Our findings of high rates of nonsuppression in MDD and ADDH may also suggest that ADDH and MDD share a common pathophysiology. The possibility of a shared etiology is consistent with the recent findings suggesting an association between ADDH and MDD. Studies of high risk children of parents with affective disorders have found high rates of ADDH in the offspring (Orvaschel 1989). Family-genetic studies of ADDH children have found a significantly higher risk for affective disorders in ADDH children and their relatives compared with control children and their relatives (Biederman and Faraone 1988). Family studies of adopted children diagnosed with ADDH showed high rates of MDD in the probands and their biological relatives compared with their adoptive relatives and biological i~elatives of a normal control group (Deutsch et al. 1982). Recent case reports describe individuals with a childhood history of ADDH who subsequently developed major affective disorders (Dvoredsky and Stewart 1981). Based on concepts proposed by Pauls et al. (1986), Biederman and Faraone (1988) recently examined familial relationships between ADDH and MDD. Results of this analysis are consistent with the hypothesis that MDD and ADDH may share common genetic vulnerabilities. Specifically, this study found that (1) the rate of MDD among the relatives of ADDH children was significantly higher than the rate in relatives of a normal control group; (2) the rate of MDD was similar among the relatives of ADDH children with comorbid MDD and the relatives of ADDH chil&en without comorbid MDD; (3) ADDH and MDD did not cosegregate within families. Although not available to us at the time of our study, several methodological techniques have been recommended k help improve the implementation and interpretation or DST studies in clinical populatic..s. Those include the use of serum dexamethasone levels (APA Task Force 1987; Ritchie 1985), etandardization of assay techniques (Arana 1985; Maguire 1987), the use of new analytic approaches such as receiver operating characteristic analysis (Hsiao et al. 1989; Mossman and Somoza 1989a; Mossman and Somoza 1989b), and the use of a controlled low-stress environment (Puig-Antich et al. 1989). Studies that incorporate these techniques off,'- the potential of enhancing and refining the applicability of the DST as a research and cdnical tool in psychiatry. In summary, we found comparable rates of postdexamethasone nonsuppression in pediatric outpatients who met DSM-III criteria for MDD, ADDH, and comorbid MDD + ADDH. A review of the literature regarding DST results in juveniles also indicates comparable DST findings in MDD and ADDH patients. Several competing explanations can be considered in accounting for these findings: (i) the DST lack~ specificity for mood disorders; (2) ADDH and MDD share a common pathophysio!-~:',~: ~:-?~ r~ D ~'~ may be an index of clinical severity. Therefore, despite its limitat:,OnSo. ~.: ~-~~_ ~ ~°:, ~ro~i ~e potentially useful clinical and research information regarding the 7 -'~ ~"~ ':-~" ~"
200
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
certain psychiatric disorders, and may alert clinicians to the presence of serious psychiatric disorders. The findings also stress the relevance of assessing comorbidity in interp~,fing DST results.
References Anderson JC, Williams S, McGee R, Silva PA (1987): DSM-III Disorders in preadolescent chil&en: Prevalence in a large sample from the general population. Arch Gen Psychiatry 44:69-76. APA Task Force (1987): The dexamethasoi~e suppression test: An overview of its current status in psychiatry. The APA Task Force on Laboratory Tests in Psychiatry. Am J Psychiatry 144:12531262. Arana GW, Baldessarini RJ, Omsteen M (1985): The dexamethasone suppression test for diagnosis and prognosis in psychiatry: Commentary and review. Arch Gen Psychiatry 42:1193-1204. Biederman J, Faraone S (1988): Evidence of familial association between attention deficit disorder and major depressive disorder. American Psychiatric Association Annual Meeting, Montreal. Biederman J, Faraone S (1989): Familial association between attention deficit disorder and anxiety disolders. American Psychiatric Association Annual Meeting, San Francisco. Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT (1990): Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder. J Am Acad Child Adolesc Psychiatry (in press). Biederman J, Munir K, Knee D, et al (1987): High rate of affective disorders in probands with attention deficit disorder and in their relatives: A controlled family study. Am J Psychiatry 144:330o333. Bird HR, Canino G, Rubio-Stipec M, et al (1988): Estimates of the prevalence of childhood maladjustment in a community survey in Puerto Rico. Arch Gen Psychiatry 45:1120-1126. Bohline DS (1985): lntel]lectual and affective characteristics of attention deficit disordered children. J Learn Dis 18:604-608. Brambilla F, Cavagnini F, Invitti C, et al (1985): Neuroendocrine and psychopathological measures in anorexia nervosa: Resemblances to primary affective disorders. Psychiatry Res 16:165-176. Brent DA, Perper JA, Goldstein CE, et al (1988): Risk factors for adolescent suicide. A comparison of adolescent suicide v~ctims with suicidal inpatients. Arch Gen Psychiatry 45:581-588. Brown RT, Borden KA, Clingerman SR, Jenkins P (1988)" Depression in attention deficit-disordered and normal children and their parents. Child Psychiatry Hum Dev 18:119-132. Can'oll BJ, Curtis GC, Mendels J (1976): Neuroendocrine regulation in depression. I. Limbicadrenocortical dysfunction. Arch Gen Psychiatry 33:1039-1044. Casat CD, Arana GW, Powell KP (1989): The DST in children and adolescents with major depressive disorder. Am J Psychiatry 146:503-507. Crumley FE, Clevenger J, Steinfink D, Oldham D (1982): Preliminary report on the Dexamethasone Suppression Test for psychiatrically disturbed adolescents. Am J Psychiatry 139:1062-1064. Deutsch CK, Swanson JM, Bruell JM, Cantwell DP, Weinberg F, Baren M (1982): Overrepresentation of adoptees in children with the attention deficit disorder. Behav Genet 12:231-238. Doherty MB, Madansky D, Kraft J, Carter-Ake LL, Rosenthal PA, Coughlin BF (1986): Cortisol dynamics and test pe~,~rraancc of the dexamethasone suppression test in 97 psychiatrically hospitalized children aged 3-16 years. J Am Acad Child Adolesc Psychiatry 25:400-408. Dvoredsky A, Stewart M (1981): Hyperactivity followed by manic depressive disorder: Two case reports. J Clin Psychiatry 42:212-214. Emslie GJ, Weinberg WA, Rush AJ, Weissenburger J, P&-kin FL (1987): Depression and dexamethasone suppression testing in children and adolescents. J Child Neurol 2:31-37. Evans DL, Nemeroff CB (1987): The clinical use of the dexamethasone suppression test in DSMiii affective disorders: Correlation with the severe depressive subtypes of melancholia and psychosis. J Psychiatr Res 21:185-194.
Comorbidity in the DST in Juveniles
BIOLPSYCHIA'iRY 1990;28:193-202
201
Extein I, Rosenberg G, Pottash AL, Gold MS (1982): The dexamethasone suppression test ill depressed adolescents. Am J Psychiatry 139:1617-1619. Fichter MM, Pirke KM (1986): Effect of experimental and pathological weight loss upon the hypothalamo-pituital3,.adrenal axis. Psychoneuroendocrinology I 1:295-305. Fogel BS, Satel SL, Levy S (i985): Occurrence of high concentrations of postdexamethasone cortisol in elderly psychiatric inpatients. Psychiatry Re~ 15:85-90. Geller B, Rogol AD, Knitter EF (1983): Preliminary data on the dexamethasone suppression test in children with majo~ depressive disorder. Am J Psychiat~ 140:620-622. Greden JF (1985): Laboratory Tests in Psychiatry. In Kaplan HI, Sadock BJ (eds), Comprehensive Textbook of Psychiatry (ed 4). Baltimore: Williams and Wilkins, 2028-2033. Ha H, Kaplan S, Foley C (1984): The dexamethasone suppression test in adolescent psychiatric patients. Am J Psychiatry 141:421-423. Hirschfeld RM, Koslow SH, Kupfer DJ (1983): The clinical utility of the dexamethasone suppression tes~ in psychiatry: Summary of a National Institute of Mental Health workshop. JAMA 250:21722174. Hsiao JK, Bartko JJ, Potter WZ (1989): Diagnosing diagnoses: Receiver operating characteristic methods and psychiatry. Arch Gen Psychiatry 46:664-667. Hsu LK, Molcan K, Cashman MA, Lee S, Lohr J, Hindmarsh D (1983): The dexamethasone suppression test in adolescent depression. J Am Acad Child Adolesc Psychiatry 22:470--473. Jensen JB, Burke N, Garfinkel BD (1988): Depression and symptoms of attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 27:742-7. Khan A (1987): Biochemic~ profile of depressed adolescents. J Am Acad Child Adolesc Psychiatry 26:873-878. Khan A, Ciraulo DA, Nelson WH, Becker JT, Nies A, Jaffe JH (1984): Dexamethasone supp~ssion test in recently detoxified alcoholics: Clinical implications. J Clin Psychopharmacol 4:94-97. Klee SH, Garfinkel BD (1984): Identification of depression in chi!&en and adolescents: The role of the dexamethasone suppression test. J Am Acad Child Adolesc Psychiatry 23:410-415. Livingston R, Martin CC (1987): Depression, anxiety and the dexamethasone suppression test in hospitalized prepubertal children. Hillside J Clin Psychiatry 9:55-63. Livingston R, Reis CJ, Ringdahl IC (1984): Abnormal dexamethasone suppression test results in depressed and nondepressed children. Am J Psychiatry 141:106-108. Maguire KP, Schweitzer I, BiddJe N, Bridge S, Tiller JW (1987): The dexamethasone suppression test: Importance of dexamethasone concentrations. Biol Psychiatry 22:957-967. Mitchell JE, Pyle RL, Hatsukami D, Boutacoff LI (1984): The dexamethasone suppression test in patients with bulimia. J Clin Psychiatry 45:508-511. Mossman D, Somoza E (1989a): Assessing improvements in the dexamethasone suppression test using receiver operating characteristics enalysis. Biol Psychiatry 25:159-173. Mossman D, Somoza E (1989b): Maximizing diagnostic information from the dexamethasone suppression test. Arch Gen Psychiatry 46:653-660. Munir K, Biederman J, Knee D (i987): Psychiatric comorbidity in patients with attention deficit disorder: A controlled study. J Am Acad Child Adolesc Psychiatry 26:844-~48. Nierenberg AA, Feinstein AR (1988): How to evaluate a diagnostic marker test. Lessons from the rise and fall of dexamethasone suppression test. JAMA 259:1699-1702. Orvaschel H (1989): Comorbidity of attention deficit disorder and depress,on. Regional Meeting of the World Federation of Societies of Biological Psychiatry, Jerusalem, Israel. Pauls DL, Leckman JF, Towbin KE, Zalmer GE, Cohen DJ (1986): A possible genetic relationship exists between Tourette's syndrome and obsessive-compulsive disorder. Psychopharmacol BuU 22:730-733.
202
BIOLPSYCHIATRY 1990;28:193-202
R. Steingard et al.
Petty LK, Asamow JR, Carlson GA, Lesser L (1985): The dexamethasone suppression test in depressed, dysthymic, and nondepressed children. Am J Psychiatry 142:631-633. Poznanski EO, Carroll BJ, Banegas MC, Cook SC, Grossman JA (1982): The dexamethasone suppression test in prepubertal depressed children. Am g Psychiatry 139:321-324. Puig-Antich J, Dahl R, Ryan N, et al (1989): Cortisol secretion in prepubertal children with majoc depressive disorder: Episode and recovery. Arch Gen Psychiatry 46:801-809. Ritchie JC, Carroll BJ, Olton PR. et al ~1985): Plasma cortisol determination for the dexamethasone suppression test: Comparison of competitive protein-binding and commercial radioimmunoassay methods. Arch Gen Psychiatry 42:493--497. Robbins DR, Alessi NE, Yanchyshyn GW, Colfer MV (1983): The dexamethasone suppression test in psychiatrically hospitalized adolescents. J Am Acad Adolesc Child Psychiatry 22:467469. Rutter M (1989): Isle of Wight Revisited: Twenty-five years of child psychiatric epidemiology. J Am Acad Child Adolesc Psychiatry 28:633-653. Tandon R, Silk KR, Greden IF, et al (1989): Positive and negative symptoms in schizophrenia and the dexamethasone suppression test. Biol Psychiatry 25:788-792. Targum SD, Capodanno AE (1983): The dexamethasone suppression test in adolescent psychiatric inpatients. Am 3 Psychiatry 140:589-591. Weinberg WA, McLean A, Snider RL, Nuckols AS, Rintelmann ~0~t,Erwin PR (1989): Depression, learning disability and school behavior problems. Psychol Rep 64:275-283. Weller EB, Weller RA, Fristad MA, Preskom SH, Teare M (1985): The dexamethasone suppression test in prepubertal depressed children. J Clin Psychiatry 46:511-5!3. Woodside DB, Brownstone D, Fisman S (1987): _'~ae dexamethasone suppression test and the Children's Depression Inventory in psychiatric disorders in children. Can J Psychiatry 32:2-4. Zimmerman M, Coryell W, Pfohl B (1986): Validity of familial subtypes of primary unipolar depression. Arch Gen Psychiatry 43:1090-1096.
193
Comorbidity in the Interpretation of Dexamethasone Suppression Test Results :in Children: A Review and Report Ronald Steingard, Joseph Biederman, Kate Keenan, and Cynthia Moore
The dexamethasone suppression test (DST) was administered as part of the initial clinical assessment to 83 children and adolescents who were consecutively referred for outpatient evaluation. All diagnoses were made clinically by a child psychiatrist according to DSM!11 criteria~ A weight-corrected dose of dexamethasone of 17 ttglkg was used. DSM-III diagnoses were made independent of DST results. Patients were stratified into four main diagnostic groups: "major depressive disorder (MDD) (N = 27); attention deficit disorder with hyperactivity (ADDH) (IV = 22); major depressive disorder plus auention deficit disorder with hyperactivity (MDD + ADDH) (N = 29); and psychiatric controls (PC) (N = 5). Rates of dexamethasone nonsuppression were found to be similarly elevated in children with MDD (29.6%), ADDH (22.7%), and MDD + ADDH (37.9%). All 5 psychiatric control patients had a normal pastdexamethasone suppression (0%). A similar pattern of results emerged in a reexamination of the literature on available studies of DST in juveniles which revealed that children with major affective disorders, attention deficit disorder (ADDH), and anxiety disorders had comparable DST results that were significantly higher than the 5.6% rate found in normal controls. These findings provide further support for similarities in DST results between ADDH and MDD in outpatients. Although these results suggest a lack of specificity of the DST as a laboratory aid for the diagnosis of juvenile affective disorders, they are also consistent with findings indicating that the DST may be an index of clinical severity and other findings suggesting a possible association between ADDH and MDD. Despite its limitations, the DST may provide potentially useful clinical and research information regarding the pathophysiology of psychiatric disorders and in alerting clinicians to the presence of serious psychiatric disorders. The findings also stress the relevance of assessing comorbidity in interpreting DST results.
Introduction The dexamethasone suppression test (DST) was initially introduced into psychiatry as a biological marker that could enhance diagnostic reliability in affective disorders (Carroll et al. 1976). The DST has been extensively studied in adult psychiatric populations (APA From the Pediatric PsychopharmacologyUnit, Massachusetts General Hospital, Boston, MA. Address reprint requests to Dr. Ronald Steingard, Pediatric PsychopharmacologyUnit, Massachusetts General Hospital, ACC-725, Boston, MA 02114. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
194
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
Task Force 1987; Arana et al. 1985) and findings have suggested that it could help define treatment parameters such as duration of treatment, predict response to pharmacological interventions, and identify individuals at risk for affective disorders (APA Task Force 1987). In a review of the literature regarding the use of the DST in adult psychiatric patients, the American Psychiatric Association Task Force on Laboratory Tests in Psychiatry (APA Task Force 1987) reported an overall sensitivity of the test of 50% to 60% for adult inpatients and 40% for outpatients, with a specificity ranging from 50% to 80%. The Task Force concluded that the DST may add to diagnostic reliability in patients suspected of having major depressive disorder (MDD). Studies of the DST in juvenile mood disorders have been generally optim.lsti¢ regarding the potential use of the test in clinical practice. In a recent review of 13 studies by Casat et al. (1989), the average rate of nonsuppression in children and adolescents with MDD was 81.7% for inpatients. Two of the reviewed studies examined DST results in outpatients meeting RDC criteria for MDDc Geller et al. (1983) reported a 10% (1/10) rate of nonsuppression whereas Poznansk ~. et al. (1982) reported a 56% (5/9) rate. These discrepant results could be attributed to the small sample size of each study, and to differences ;n methodology. Given the potential applicability of the DST as a laboratory aid in the differential diagnosis of juvenile mood disorders, we pursued an evalw, tion of the DST in children with depressive and dysphoric symptomatology in an outpatient child psychiatry clinic. As children with ADDH frequently show depres~b,~ and dysphoric symptomatology (Biederman et al. 1987; Bohline 1985; Brown et al. 1988; Jensen et al. 1988; Weinberg et al. 1989) and children with MDD frequently display psychomotor agitation as well as dysphoria, we expected that the DST would help in the differential diagnosis of these two highly prevalent disorders. Method The DST was administered to 83 children [boys N = 78, girls N = 5; mean age (+_ SD) = 11.2 ± 4.0 years] who were consecutively referred for outpatient psychiatric evaluation and who reported dysphoria and irritability as prominent presenting symptoms. There were 47 prepubertal children [45 boys, 2 girls; age range 4-12 years (mean = 8.1 _+ 2.4 years)] and 36 adolescents [33 boys, 3 girls; age range 13-16 years ..(mean = 15.3 _+ 1.8 years)]. All but 8.4% of 9articipating subjects iN = 7 (3 MDD, 4 ADD): 1 methylphenidate, 3 heterocyclic antidepressants, 1 propranolol, 1 alprazolam, 1 lithium] were medication-free at the time of the DST. Clinical interviews were conducted with each child and their p~_-t a_nd~!l diagnoses were based upon DSM-III criteria. PsychiaU~c diagnoses were made prior to, and independent of, the DST results. Because of the wide range of ages and corresponding weights in the participating children and adolescents, the dose of dexamethasone was corrected for weight. Using 0.125 mg (one-half tablet) increments, a dose as closely approximating 17 ttg/kg as possible was used, resulting in a dose of dexamethasone ranging from 14.5 to 20.8 I~g/kg [mean (_+ SD) = 18.2 _ 1.2 ttg/kg]. There were no statistical differences in the mean doses of dexamethasone used in the attention deficit disorder with hyperactivity (ADDH) (18.0 _ 1.5 ttg/kg), MDD (18.2 _+ 1.0 ttg/kg), M D D + A D D H (18.3 _+ 1.! ttg/kg), and psychiatric control (PC) (18.1 _+ 1.1 t~g/kg) groups. The weight-corrected dose of dexamethasone was administered at 11 PM on day 1 and blood samples were drawn at 4 PM on day 2 for serum cortisol determination. Cortisol levels were assayed using the Gamma Coat (1251) Radioimmunoassay Kit (Baxter Tray-
Comorbidity in the DST in Juveniles
195
BlOt. PSYCHIATRY 1990;28:193-202
Table I. Dexamethasone Suppression Test (DST) in an Outpatient Child Psychiatry Sample Abnormal DST
Cortisol (p,g/dl)
Diagnosis
N
N
%
Mean .4- SD
Mutually exclusive categories MDD ADDH MDD + ADDH PsF.hiatric controls
27 22 29 5
8 5 il 0
29.6 22.7 37.9 0
3.8 -," 4.0 __ 4.4 _ !.6.4-
Ncamutuaily exclusive Any MDD Any ADDH
56 51
19 16
33.9 31.4
4.1 +-- 3.7 4.2 .4- 4.0'
3.4 4.I 3.9' 0.2
Op < 0.05 versus psychiatric control by Mann-Whitney U test. Mutually exclusive categories: major depressive disorder (MDD); attention deficit disorder with hyperactivity (ADDH); MDD + ADDH. Nonmutually exclusive categories: any MDD: MDD with and without ADDH; any ADDH: ADDH with and without MDD. Psychiatric controls: anxiety disorder (N = 3); pervasive developmental disorder (N = 2).
enol Diagnostics, Cambridge, MA) following the procedure described in their instruction manual. This assay has a calculated sensitivity of 0.14 ttg/dl. A serum cortisol level greater than 5 ttg/dl was interpreted as indicative of postdexamethasone nonsuppression (APA Task Force 1987). DST assessments were done by laboratory personnel who were unaware of the clinical diagnosis of subjects or their diagnostic stratification. Patients were stratified into four mutually exclusive diagnostic groups: MDD (N = 27); ADDH without affective disorders (N = 22); MDD + ADDH (N = 29); and PC IN = 5 (anxiety disorder, N = 3; pervasive developmental disorder, N = 2)] (Table 1). There was limited additional comorbidity within these stratified groups. The co-occurrence of other affective disorders (i.e., dysthymia and cyclothymia) was limited to the MDD group (4 dysthymia) and the MDD + ADDH group (4 dysthymia, 1 cyclothymia). Other behavioral disorders occurred in the ADDH (2 oppositional disoraer) and the MDD + ADDH (1 conduct disorder) gr,~ups. Comorbid anxiety disorders were found in the MDD group (1 panic disorder) and the MDD + ADDH group (1 panic disorder, 1 generalized anxiety disorder). Data were also analyzed by stratifying the sample into nonmutuallyexclusive categories defined by the presence of MDD [with and without ADDH: any MDD, (N = 56)1 or ADDH [wit.h and without MDD: any ADDH (N = 51)1. Data were analyzed using rates of postdexamethasone nonsuppresslon and absolute postdexdmethasone cortisol levels. Data were distributed nonparametrically, therefore nonparametric statistical tests were used, including the Mann-Whitney U Test in the analysis of continuous variables, the Fisher Exact Test in the analysis of categorical variables, and the Spearman Rank Correlation Coefficient in the analysis of associations. All analyses were two-tailed and statistical significance was defined at the 0.05 level.
Results
Massachusetts General Hospital (MGH) Sample As shown in Table 1, no significant differences were found in rates of postdexamethasone nonsuppression in children with MDD (29.6%), ADDH (22.7%), and M D D + ADDH (37.9%), or in the nonmutually exclusive subgrot ps of any MDD (33.9%) and any ADDH
196
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
(3! .4%). Rates of nonsuppression were moderately elevated in children with MDD and ADDH, but all 5 patients with other disorders exhibited normal postdexamethasone cortisol suppression (0%) (Table 1). However, no statistical difference between the subgroups could be demonstrated (chi-square = 31, df = 3, ns), probably due to the small number of the psychia~c controls (N = 5). Of the 7 subjects who were on psychotropics at the time of the DST, 4 had positive and 3 had ~.egative DST results. Similar results were obtained when the analysis w:~sbased upon examination of mean ( _+SD) postdexamethasone cortisoi levels. Although the cortisol levels were significantly higher in the patients with MDD (3.8 ± 3.4 ~g/dl), ADDH (4.0 +_ 4.1 p.g/dl), MDD+ADDH (4.4 _+ 3.9 p,g/dl), any MDD (4.1 _+ 3.7 p,g/dl), and any ADDH (4.2 _+ 4.0 Ixg,'dl) than in psychiatric control patients (1.6 -+ 0.2 l~g/dl), a statistically significant difference could be established only for the MDD+ADDH subgroup (z = - 2 . 1 ; p = 0.04) and the any ADDH subgroup (z = - 2 . 0 , p = 0.045). A small negative, but statistically significant, correlation was found between postdexamethasone cortisol levels and age (Rho = -0.25; p = 0.02). Given the range of doses used in the study, the effect of the dose of dexamethasone on the results was examined in two ways. A correlation analysis failed to demonstrate a significant relationship between dose of dexamethasone and postdexamethasone cortisol levels (rho = 0.03, ns). Additionally, there was no statistically significant difference between the rate of nonsuppression in subjects receiving a dexamethasone dose above versus below the median (18 p,g/kg) (22.0% versus 35.7%, ns).
Review of the Literature A reexamination of the literature on available studies of DST in juveniles was undertaken. Using 4 PM results (whenever available, to permit cross-study comparison), or reported study results (when 4 PM data was not spec~3ed), comp~able DST results were found in children with major affective disorders (nonbipolar MDD: 55% inpatient, 34% outpatient, 51% overall; bipolar MDD: 52% inpatients only), attention deficit disorder (46% inpatient, 31% outpatient, 36% overall), and anxiety disorders (51% inpatients only). Statistical comparisons of overall results revealed that the rates of DST in these groups were significantly higher than the 5.6% rate found in normal controls (Weller et al. 1985) (by Fisher Exact Test, two-tailed p < 0.05) (Table 2). When comparisons were made between the MGH DST results and those reported in normal controls in the literature, the rates of dexamethasone nonsuppression in the any MDD and any ADDH subgroups were found to be significan".y higher than those of normal controls reported in the literature (by Fisher Exact test, both p = 9.93). However, for ~he n~utuallyexclusive diagnostic subgroups, a statistically significant difference could be established only for the MDD + ADDH subgroup (p = 0.008), whereas the results for the MDD subgroup approached statistical significance (p = 0.06). Discussion In a clinical sample of children and adolescents, the rates of postdexamethasone nonsuppression were found to be relatively high and comparable in l 'ttients with MDD (29.6%) and ADDH (22.7%). In contrast, although limited by small :'.ample size (N 5), the rate of postdexamethasone nonsuppression in subjects with pervasive developmental disorder (PDD) and anxiety disorders was 0%. However, the small size of tile
Comorbidity in the DST in Juveniles
toOLPSYCHIATRY
197
!990;28:193-202
Table 2. DST Results in Inpatient and Outpatient Child Psychiatry Populations Diagnosis
Study
MDD
Inpatient Cmmley et al. (1982) a'c Extein et al. (1982) b Hsu et -_I. (i983) b Robbins et al. (1983) b Targum and Capodanno (1983) b Ha et al. (1984) b Klee and Garfinkel (1984) b Livingston et ai. (1984) ° Petty et al. (1985) a Weller et al. (1985)" Doherty et al. (1986) b Emslie et al. (1987)'1 Evans and Nemeroff (1987) b Ki,'tan (1987) b Livingston et al. (1987) n Wood~ide et al. (1987) b Total Percent Outpatient Poznanski et d~ (1982)" Geller et al. (1983) ° Steingard et al. (1990)" Total Percent Overall Total Percent
11/23 8/15 9/14 4/16 7/17
Dysthymia
0/2
Bipolar disorder
ADDH
Conduct disorder
2/2
I/I
317
!/2
Anxiety disorder
4/26
7/38
Psychotic disorder
Normal controls
2/8 0/2 4/18
7/47
6/22 8/20 2/3 6/7 36/50 1 i/26 18/33 8/20
I/2 4/5
23/33 8i8 8,/10
I/6
173/317 54.6%
17/71 23.9%
I/I
4/6 I/2
!/! 2/3 1/18
4/18
2/5 3/8
0/4
! 15 7/14
3/22 3/13 2/18
17/22
11/24 45.8%
31/156 19.9%
23/45 51. ! %
10/39 25.6%
1/18 5.6%
31/156 19.9%
23/45 51. !%*
10/39 25.6%
1/18 5.6%
16/51
25/74 33.8%
! 6/5 ! 31.4% 17/71 23.9%
10/19 52.6%*
0/6
0/7
2/2 10/19 52.6%
1/15
!/3
5/9 1/9 19/56
198/391 50.6%*
I/4 8/I !
27/75 36%*
1/i
*By Fisher exact test (two-tailed) vs. DST rates in normal controls, p < 0.05. -~Reponreflects only 4 PM DST results. bReport reflects S AM, 4 eM, and | 1 PM DST results. ~Results reported for only I mg of dexamethasone.
psychiatric control group did not permit adequate statistical comparisons between all diagnostic groups. Though the rate of abnormal DST found in children with MDD is consistent with DST findings reported in outpatient samples of adults with MDD (APA Task Force 1987), it was striking to find a 22.7% rate of dexamethasone nonsuppression in an outpatient sample of children with ADDH. Several competing explanations can be considered in accounting for similarities in rates of DST results between ADDH and MDD. High rates of postdexamethasone nonsuppression in children with ADDH may suggest that the DST lacks specificity for mood disorders. Abnormalities in the DST are thought to reflect abnormalities in the limbic system, which is involved in regulating a wide range of human behaviors and functions
198
BIOL PSYCHIATRY 1090,28:193-202
R. Steingardet al.
(i.e., sleep, appetite, psychomotor activity, hedonic capacity, reward and reinforcement, motivation, memory, anger, and rage) (Carroll et al. 1976; Greden 1985). Therefore, it is not surprising to find DST abnormalities in a variety of psychopathological states and not only in MDD. In fact, abnormal DST results have also been reported in elderly patients (Fogel et al. 1985), in patients with alcoholism (Khan et ai. 1984), in patients with recent weight loss (Fichter and Pirke 1980), as well as in patients with schizophrenia (Tandon et al. 1989), anorexia (Brambilla et al. 1985), and bulimia (Mitchell et al. 1984). Our findings, therefore, may add to the unc~rtai~ntyof the role of the DST as a discriminatory tool in the diagnosis of mood disorders (Hirschfeld eta!. 1983) and shpport the claim that the in~oduction of the DST for this specific purpose may have been premature (Nierenberg and Feinstein 1988). However, lack of specificity is not without clinical relevance. DST studies in both adults and children have consistently reported higher rates of DST abnormalities in inpatients compared with outpatients, suggesting that the DST may be an index of clinical severity. If so, despite lack of specificity, the DST may be a potentially usefill laboratory aid in the assessment of severity of psychopathology. The use of nonspecific laboratory tests is common in medical practice. For example, despite lack of specificity, an elevated erythrocyte sedimentation rate can alert the physician to a potentially serious clinical problem or the need for further clinical evaluation. This clinical aspect is particularly relevant for child psychiatry. The differential diagnosis between an adjustment disorder and an incipient serious psychiatric dis~:~rdercan pose important clinical dilemmas. Such a dilemma can develop in the evaluation of juveniles with ADDH and associated depressive symptoms in the differential diagnosis between demoralization and major depression. In light of recent findings indicating that the comorbidity of ADDH and MDD may be a significant risk factor for adolescent suicide (Brent et al. 1988), the availability of a laboratory test, such as the DST, that can aid the clinician in assessing the severity of the clinical picture has clinical relevance. One component of clinical severity is the presence of comorbid disorders. Until recently, issues of comorbidity had received little attention in the evaluation of research and clinical findings in child psychiatry. Comorbidity has been found to be highly prevalent in clinical (Biederman et al. 1990; Munir et al. 1987) and epidemiological (Anderson et ai. 1987; Bird et al. 1988) samples of children. For example, symptomatic and diagnostic overlaps have been reported between attention deficit disorder (ADD) and conduct disorder, between ADD and affective disorders, between ADD and anxiety disorders, between depressive disorder and anxiety disorders, and between conduct disorder and substance abuse (Anderson et al. 1987; Biederman and Faraone 1988; Biederman and Faraone 1989; Bird et al. 1988; Rutter 1989). Zimmerman et al. (1986) have suggested that diagnostic heterogeneity may have contributed to the apparent lack of specificity of the DST in adults with MDD. DST studies in children have not adequately addressed comorbidity in accounting for DST results. In our sample, the nonmutually exclusive diagnostic groups of any ADDH and any MDD attained relatively higher rates of dexamethasone nonsuppression than those found in either ADDH or MDD alone. This finding reflects the inclusion of patients with comorbid MDD + ADDH, who exhibited the highest rate of dexamethasone nonsuppression (37.9%). Given the high rates of comorbidity found in clinical and epidemiological samples of children (Bird et al. 1988; Munir eta!. 1987), these findings further underscore the importance of assessing comorbidity in clinic and study populations in attempting to evaluate DST results.
Comorbidity in the DST in Juveniles
BIOL PSYCHIATRY 1990;28:193-202
199
We have reexamined the literature on available studies of DST in juveniles. This review also indicates that the presence Of comorbidity may be highly relevant in accounting for reported DST findings. As previously noted, comparable DST results were found in children with maior affective disorders, ADD, ~ d anxiety disorders which were significalltly higher than the 5.6% rate found in normal controls (Table 2). Although the available DST studies are limited by small sample size, our review of the literature indicates that, on the aggregate, inpatients with ADDH have a 46% rate of abnormal DST. This rate ~s as high as that found in inpatients with MDD. Our present findings provide further support for similarities in DST results between ADDH and MDD in outpatients by showing that the rate of DST abnormalities in some outpatient children with ADDH is as high as that found among outpatients with MDD. Our findings of high rates of nonsuppression in MDD and ADDH may also suggest that ADDH and MDD share a common pathophysiology. The possibility of a shared etiology is consistent with the recent findings suggesting an association between ADDH and MDD. Studies of high risk children of parents with affective disorders have found high rates of ADDH in the offspring (Orvaschel 1989). Family-genetic studies of ADDH children have found a significantly higher risk for affective disorders in ADDH children and their relatives compared with control children and their relatives (Biederman and Faraone 1988). Family studies of adopted children diagnosed with ADDH showed high rates of MDD in the probands and their biological relatives compared with their adoptive relatives and biological i~elatives of a normal control group (Deutsch et al. 1982). Recent case reports describe individuals with a childhood history of ADDH who subsequently developed major affective disorders (Dvoredsky and Stewart 1981). Based on concepts proposed by Pauls et al. (1986), Biederman and Faraone (1988) recently examined familial relationships between ADDH and MDD. Results of this analysis are consistent with the hypothesis that MDD and ADDH may share common genetic vulnerabilities. Specifically, this study found that (1) the rate of MDD among the relatives of ADDH children was significantly higher than the rate in relatives of a normal control group; (2) the rate of MDD was similar among the relatives of ADDH children with comorbid MDD and the relatives of ADDH chil&en without comorbid MDD; (3) ADDH and MDD did not cosegregate within families. Although not available to us at the time of our study, several methodological techniques have been recommended k help improve the implementation and interpretation or DST studies in clinical populatic..s. Those include the use of serum dexamethasone levels (APA Task Force 1987; Ritchie 1985), etandardization of assay techniques (Arana 1985; Maguire 1987), the use of new analytic approaches such as receiver operating characteristic analysis (Hsiao et al. 1989; Mossman and Somoza 1989a; Mossman and Somoza 1989b), and the use of a controlled low-stress environment (Puig-Antich et al. 1989). Studies that incorporate these techniques off,'- the potential of enhancing and refining the applicability of the DST as a research and cdnical tool in psychiatry. In summary, we found comparable rates of postdexamethasone nonsuppression in pediatric outpatients who met DSM-III criteria for MDD, ADDH, and comorbid MDD + ADDH. A review of the literature regarding DST results in juveniles also indicates comparable DST findings in MDD and ADDH patients. Several competing explanations can be considered in accounting for these findings: (i) the DST lack~ specificity for mood disorders; (2) ADDH and MDD share a common pathophysio!-~:',~: ~:-?~ r~ D ~'~ may be an index of clinical severity. Therefore, despite its limitat:,OnSo. ~.: ~-~~_ ~ ~°:, ~ro~i ~e potentially useful clinical and research information regarding the 7 -'~ ~"~ ':-~" ~"
200
BIOL PSYCHIATRY 1990;28:193-202
R. Steingard et al.
certain psychiatric disorders, and may alert clinicians to the presence of serious psychiatric disorders. The findings also stress the relevance of assessing comorbidity in interp~,fing DST results.
References Anderson JC, Williams S, McGee R, Silva PA (1987): DSM-III Disorders in preadolescent chil&en: Prevalence in a large sample from the general population. Arch Gen Psychiatry 44:69-76. APA Task Force (1987): The dexamethasoi~e suppression test: An overview of its current status in psychiatry. The APA Task Force on Laboratory Tests in Psychiatry. Am J Psychiatry 144:12531262. Arana GW, Baldessarini RJ, Omsteen M (1985): The dexamethasone suppression test for diagnosis and prognosis in psychiatry: Commentary and review. Arch Gen Psychiatry 42:1193-1204. Biederman J, Faraone S (1988): Evidence of familial association between attention deficit disorder and major depressive disorder. American Psychiatric Association Annual Meeting, Montreal. Biederman J, Faraone S (1989): Familial association between attention deficit disorder and anxiety disolders. American Psychiatric Association Annual Meeting, San Francisco. Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT (1990): Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder. J Am Acad Child Adolesc Psychiatry (in press). Biederman J, Munir K, Knee D, et al (1987): High rate of affective disorders in probands with attention deficit disorder and in their relatives: A controlled family study. Am J Psychiatry 144:330o333. Bird HR, Canino G, Rubio-Stipec M, et al (1988): Estimates of the prevalence of childhood maladjustment in a community survey in Puerto Rico. Arch Gen Psychiatry 45:1120-1126. Bohline DS (1985): lntel]lectual and affective characteristics of attention deficit disordered children. J Learn Dis 18:604-608. Brambilla F, Cavagnini F, Invitti C, et al (1985): Neuroendocrine and psychopathological measures in anorexia nervosa: Resemblances to primary affective disorders. Psychiatry Res 16:165-176. Brent DA, Perper JA, Goldstein CE, et al (1988): Risk factors for adolescent suicide. A comparison of adolescent suicide v~ctims with suicidal inpatients. Arch Gen Psychiatry 45:581-588. Brown RT, Borden KA, Clingerman SR, Jenkins P (1988)" Depression in attention deficit-disordered and normal children and their parents. Child Psychiatry Hum Dev 18:119-132. Can'oll BJ, Curtis GC, Mendels J (1976): Neuroendocrine regulation in depression. I. Limbicadrenocortical dysfunction. Arch Gen Psychiatry 33:1039-1044. Casat CD, Arana GW, Powell KP (1989): The DST in children and adolescents with major depressive disorder. Am J Psychiatry 146:503-507. Crumley FE, Clevenger J, Steinfink D, Oldham D (1982): Preliminary report on the Dexamethasone Suppression Test for psychiatrically disturbed adolescents. Am J Psychiatry 139:1062-1064. Deutsch CK, Swanson JM, Bruell JM, Cantwell DP, Weinberg F, Baren M (1982): Overrepresentation of adoptees in children with the attention deficit disorder. Behav Genet 12:231-238. Doherty MB, Madansky D, Kraft J, Carter-Ake LL, Rosenthal PA, Coughlin BF (1986): Cortisol dynamics and test pe~,~rraancc of the dexamethasone suppression test in 97 psychiatrically hospitalized children aged 3-16 years. J Am Acad Child Adolesc Psychiatry 25:400-408. Dvoredsky A, Stewart M (1981): Hyperactivity followed by manic depressive disorder: Two case reports. J Clin Psychiatry 42:212-214. Emslie GJ, Weinberg WA, Rush AJ, Weissenburger J, P&-kin FL (1987): Depression and dexamethasone suppression testing in children and adolescents. J Child Neurol 2:31-37. Evans DL, Nemeroff CB (1987): The clinical use of the dexamethasone suppression test in DSMiii affective disorders: Correlation with the severe depressive subtypes of melancholia and psychosis. J Psychiatr Res 21:185-194.
Comorbidity in the DST in Juveniles
BIOLPSYCHIA'iRY 1990;28:193-202
201
Extein I, Rosenberg G, Pottash AL, Gold MS (1982): The dexamethasone suppression test ill depressed adolescents. Am J Psychiatry 139:1617-1619. Fichter MM, Pirke KM (1986): Effect of experimental and pathological weight loss upon the hypothalamo-pituital3,.adrenal axis. Psychoneuroendocrinology I 1:295-305. Fogel BS, Satel SL, Levy S (i985): Occurrence of high concentrations of postdexamethasone cortisol in elderly psychiatric inpatients. Psychiatry Re~ 15:85-90. Geller B, Rogol AD, Knitter EF (1983): Preliminary data on the dexamethasone suppression test in children with majo~ depressive disorder. Am J Psychiat~ 140:620-622. Greden JF (1985): Laboratory Tests in Psychiatry. In Kaplan HI, Sadock BJ (eds), Comprehensive Textbook of Psychiatry (ed 4). Baltimore: Williams and Wilkins, 2028-2033. Ha H, Kaplan S, Foley C (1984): The dexamethasone suppression test in adolescent psychiatric patients. Am J Psychiatry 141:421-423. Hirschfeld RM, Koslow SH, Kupfer DJ (1983): The clinical utility of the dexamethasone suppression tes~ in psychiatry: Summary of a National Institute of Mental Health workshop. JAMA 250:21722174. Hsiao JK, Bartko JJ, Potter WZ (1989): Diagnosing diagnoses: Receiver operating characteristic methods and psychiatry. Arch Gen Psychiatry 46:664-667. Hsu LK, Molcan K, Cashman MA, Lee S, Lohr J, Hindmarsh D (1983): The dexamethasone suppression test in adolescent depression. J Am Acad Child Adolesc Psychiatry 22:470--473. Jensen JB, Burke N, Garfinkel BD (1988): Depression and symptoms of attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 27:742-7. Khan A (1987): Biochemic~ profile of depressed adolescents. J Am Acad Child Adolesc Psychiatry 26:873-878. Khan A, Ciraulo DA, Nelson WH, Becker JT, Nies A, Jaffe JH (1984): Dexamethasone supp~ssion test in recently detoxified alcoholics: Clinical implications. J Clin Psychopharmacol 4:94-97. Klee SH, Garfinkel BD (1984): Identification of depression in chi!&en and adolescents: The role of the dexamethasone suppression test. J Am Acad Child Adolesc Psychiatry 23:410-415. Livingston R, Martin CC (1987): Depression, anxiety and the dexamethasone suppression test in hospitalized prepubertal children. Hillside J Clin Psychiatry 9:55-63. Livingston R, Reis CJ, Ringdahl IC (1984): Abnormal dexamethasone suppression test results in depressed and nondepressed children. Am J Psychiatry 141:106-108. Maguire KP, Schweitzer I, BiddJe N, Bridge S, Tiller JW (1987): The dexamethasone suppression test: Importance of dexamethasone concentrations. Biol Psychiatry 22:957-967. Mitchell JE, Pyle RL, Hatsukami D, Boutacoff LI (1984): The dexamethasone suppression test in patients with bulimia. J Clin Psychiatry 45:508-511. Mossman D, Somoza E (1989a): Assessing improvements in the dexamethasone suppression test using receiver operating characteristics enalysis. Biol Psychiatry 25:159-173. Mossman D, Somoza E (1989b): Maximizing diagnostic information from the dexamethasone suppression test. Arch Gen Psychiatry 46:653-660. Munir K, Biederman J, Knee D (i987): Psychiatric comorbidity in patients with attention deficit disorder: A controlled study. J Am Acad Child Adolesc Psychiatry 26:844-~48. Nierenberg AA, Feinstein AR (1988): How to evaluate a diagnostic marker test. Lessons from the rise and fall of dexamethasone suppression test. JAMA 259:1699-1702. Orvaschel H (1989): Comorbidity of attention deficit disorder and depress,on. Regional Meeting of the World Federation of Societies of Biological Psychiatry, Jerusalem, Israel. Pauls DL, Leckman JF, Towbin KE, Zalmer GE, Cohen DJ (1986): A possible genetic relationship exists between Tourette's syndrome and obsessive-compulsive disorder. Psychopharmacol BuU 22:730-733.
202
BIOLPSYCHIATRY 1990;28:193-202
R. Steingard et al.
Petty LK, Asamow JR, Carlson GA, Lesser L (1985): The dexamethasone suppression test in depressed, dysthymic, and nondepressed children. Am J Psychiatry 142:631-633. Poznanski EO, Carroll BJ, Banegas MC, Cook SC, Grossman JA (1982): The dexamethasone suppression test in prepubertal depressed children. Am g Psychiatry 139:321-324. Puig-Antich J, Dahl R, Ryan N, et al (1989): Cortisol secretion in prepubertal children with majoc depressive disorder: Episode and recovery. Arch Gen Psychiatry 46:801-809. Ritchie JC, Carroll BJ, Olton PR. et al ~1985): Plasma cortisol determination for the dexamethasone suppression test: Comparison of competitive protein-binding and commercial radioimmunoassay methods. Arch Gen Psychiatry 42:493--497. Robbins DR, Alessi NE, Yanchyshyn GW, Colfer MV (1983): The dexamethasone suppression test in psychiatrically hospitalized adolescents. J Am Acad Adolesc Child Psychiatry 22:467469. Rutter M (1989): Isle of Wight Revisited: Twenty-five years of child psychiatric epidemiology. J Am Acad Child Adolesc Psychiatry 28:633-653. Tandon R, Silk KR, Greden IF, et al (1989): Positive and negative symptoms in schizophrenia and the dexamethasone suppression test. Biol Psychiatry 25:788-792. Targum SD, Capodanno AE (1983): The dexamethasone suppression test in adolescent psychiatric inpatients. Am 3 Psychiatry 140:589-591. Weinberg WA, McLean A, Snider RL, Nuckols AS, Rintelmann ~0~t,Erwin PR (1989): Depression, learning disability and school behavior problems. Psychol Rep 64:275-283. Weller EB, Weller RA, Fristad MA, Preskom SH, Teare M (1985): The dexamethasone suppression test in prepubertal depressed children. J Clin Psychiatry 46:511-5!3. Woodside DB, Brownstone D, Fisman S (1987): _'~ae dexamethasone suppression test and the Children's Depression Inventory in psychiatric disorders in children. Can J Psychiatry 32:2-4. Zimmerman M, Coryell W, Pfohl B (1986): Validity of familial subtypes of primary unipolar depression. Arch Gen Psychiatry 43:1090-1096.
