BIOL PSYCHIATJ~ ~" ] 992;32: ! 09- ! 26

109

The Dexamethasone Suppression Test in Children and Adolescents: A Review and a Controlled S udy Ronald E. Dahl, Joan Kaufman, Neal D. Ryan, James Perel, Mayadah A1-Shabbout, Boris Birmaher, Beverly Nelson, and Joaquim Puig-Antich

Dexamethasone Suppression Test (DST) studie~ conducted in children and adolescents are reviewed, together with factors hypothesized to explain discrepancies in rates of DST nonsuppression across studies, These factors are then examined in a controlled study of 27 adolescents with major depressive disorder (MDD) and 34 normal controls (NC). Subjects were given 1 mg of dexamethasone at 11:00 I,M, and the following day serum samples for cortisol were collected each hr from 8 AM to 11 PM through an indwelling catheter. There were no significant differences found between the MDD and NC subjects on any postdexamethasone cortisol measure. 1.urther, cortisol suppressors and nonsuppressors were not distinguished by any of the hypothesized factors identified from the review, including inpatient status, presence of suicidalily, endogenous features, psychotic symptoms, or prior history of MDD. Questions abou~ the appropriateness of the 1 mg do.~e of dexamethasone (currently the standard dose used with adolescents) are raised, to~,ether with a discussion of the effects of stress on DST findings.

Introduction Physiological measures of stcess have occupied a central role in studies of the biological correlates of depression across the age span. Assessments of the hypothalamic-pituitaryadrenal (HPA) axis functioning have been at the core of this research, with the Dexamethasone Suppression Test (DST) the measure of HPA axis functioning that has been used most extensively in child and adolescent samples. The purpose of this article is to: (1) review the studies of the DST that have been conducted with children and adolescents; (2) highlight the factors that may explain discrepancies in rates of DST nonsuppression reported across studies; and (3) present data from a controlled investigation in which these factors are examined systematically.

From the Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Department of Psychiatry, Pittsburgh, PA Address reprint requests to Ronald E. Dald, M.D., Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Department of Psychiatry, 3811 O'Hara Street, Pittsburgh, PA 15213. Received July 30, 1991; revised February 10, 1992. © 1992 Society of Biological Psychiatry

0006-3223/92/$05.00

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DST in Children and Adolescents in 1989, Casat et al reviewed all the studies of the DST that had been conducted in child and adolescent samples. Their review was based on 11 studies of children (three inpatiert studies, eight outpatient), and eight studies of adolescents (all inpatients). Based on the review of these investigations, it was concluded that (1) the sensitivity of the DST was higher among children than among adolescents with major depressive disorder (MDD) (70% versus 47%); (2) children in inpatient settings are more likely to be nonsuppressors than children in outpatient settings (82% versus 32%); and (3) the specificity of the DST appears to be superior in aaolescent samples (80% versus 70%). Since that publication by Casat et al, the number of published reports of the DST in children and adolescents have more than doubled. These studies, grouped by age and inpatient status, are summarized in Table 1. Ten studies of children from inpatient settings, 4 studies of children from outpatient settings, 11 studies of adolescents from inpatient settings, and 2 studies of adolescents from outpatient settings are presented. The criteria used to diagnose subjects, the dose of dexamethasone administered, the method of serum collection and cortisol determination, the number of nonsuppressors, and the sensitivity and specificity estimates of the DST derived in each study are outlined in the Table. Whenever authors provided sufficient data, estimates of specificity were computed separately for the different diagnostic groups used as psychiatric controls. Throughout this manuscript, sensitivity is used to denote the number of true-positives (depressed children classified as depressed based on results of the DST), and specificity is used to denote the number of true-negatives (nondepressed children correctly classified as not depressed based on results of the DST). All the studies presented in Table 1 used information from both parents and children to derive subjects' diagnoses. Approximately half the studies utilized standard research diagnostic procedures. The number, times, and method of serum collection and cortisol determination varied somewhat flora one investigation to another. Most studies utilized venipunctures to obtain the serum sl~ecimens, but two studies used an indwelling catheter. In addition, most studies used radi3immunoassay (RIA) methodologies for cortisol determination, but five studies used competitive protein binding (CPB) techniques. Beyond these differences, however, there war considerable procedural consistency across studies. Most child studies gave subjects a 0 5 mg dose of dexamethasone, most adolescent studies used a 1 mg dose, and all studies defined postdexamethasone values of greater than 5 I~g/dl as evidence of DST nonsuppression. When cortisol specimens were collected at more than one time (e.g., 8 AM, 4 P~, and 11 PM), a postdexamethasone value greater than 5 ~g/dl at any point in time was sufficient for nonsuppressor status. The general findings in Table I regarding the sensitivity and specificity of the DST are consistent with the conclusions of Casat et ai. The sensitivity of the DST appears to be higher among children than among adolescents (58% versus 44%), higher in subjects from inpatient settings than subjects in outpatient settings (61% versus 29%), and more specific in adolescent samples (84% versus 74%). The sensitivity and specificity data are now presented for inpatient and outpatients separately by age. Among depressed children, the sensitivity of the DST is 74% (N = 156) for inpatients, and 36% (N = 109) for outpatients. The specificity in samples of child psychiatric controls was 74% (N = 198) for inpatients and 85% (N = 59) for outpatients. With adolescents, the sensitivity rates were 51% (N = 196) for inpatients, and 14% (N = 44) for outpatients. The specificity in samples of adolescent psychiatric controls is 86%

DST in Adolescents

BIOLPSYCHIATRY 1992~32:109-126

111

(N = 365) for inpatients, and 100% (N = 8) for outpatients. When investigators provided sufficientlydetailed diagnostic information about the psychiatric control groups to compute specificity estimates separately foe different disorders, few differences were found in rates of nonsuppression for the different psychiatric conditions. Examining the data across studies, for child inpatients with dysthymia disorder (N = 25), schizophrenia-spectrum disorders (N = 15), and anxiety disorders (N = 34), the specificity of the DST was approximately 60%. For adolescent inpatients with dysthymia disorder (N = 78), conduct disorder (N = 88j, and schizophrenia spectrum disorders (N = 20), the specificity of the DST was approximately 84%. These findings suggest that false-positives are common across many diagnostic groups, but more likely to occur in child samples. A number of factors beyond age (child versus adolescent) and clinical status (inpatient versus outpatient) have been hypothesized to explain variation in DST nonsuppression rates across studies. These include the presence of particular clinical symptoms, depression subtype, and history of previous psychiatric illness. Increased rates of DST nonsuppression have been associated with concurrent suicidal behavior (Pfeffer et al 1991; Robbins and Alessi 1985), and subsequent suicidal lethality (Robbins and Alessi 1985), the endogenous subtype (Robbins et al 1983), the psychotic subtype (Freeman et al 1985), and a prior history of major depressive illness (Klee and Garfinkel 1984). There are also procedural factors that may account for differences in DST nonsuppression rates across studies. Among the four studies with DST sensitivity rates below 20% (Birmaher et al 1992a, 1992b; Pfeffer et al 1989; Steigard et ai 1990), one study (Pfeffer et al 1989) reported low sensitivity when a high dose/kg body weight of dexamethasone was administered, two studies with low sensitivity rates used an indwelling catheter (in contrast to repeated venipunctures) to collect serum for cortisol determination (Birmaher 1992a, 1992b), and two studies were performed using outpatient depressed subjects (Birmaher et al 1992b; Steingard et al 1990). Thus, the dose of dexamethasone, characteristics of depressed subjects, and methods of blood sampling may influence DST results; however, the relative contributions of these factors ~_,'eimpossible to disentangle by retrospective review. This manuscript reports DST findings in a sample of adolescents (inpatients and outpatients) and normal controls in which postdexamethasone cortisol specimens were obtained through an indwelling c~theter. Many of the factors identified in the review that have been hypothesized to account for variation in rates of nonsuppression are examined in the data set. Specifically, it was hypothesized that higher postdexamethasone cortisol secretion values and higher rates of nonsuppression would be predicted by (1) inpatient status, (2) a history of suicidal behavior, (3) psychotic and endogenous depressive subtypes, and (4) a prior history of MDD. In addition to examining these hypotheses, the rates of nonsuppression obtained in this study (using an indwelling catheter) in both inpatients and outpatients are compared with rates obtained in other studies using venipunctures to collect cortisol specimens.

Subjects and Methods Recruitraent Procedures Subjects in the MDD group were recruited from the outpatient and inpatient units at Western Psychiatric Institute and Clinic, and controls were recruited through newspaper advertisements and personal contacts. Prospective subjects participated in a 10-day to

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Table 1. Review of DST Studies with Children and Adolescents Citation

Sample

Studies ,vith Children from Inpatient Settings Livingston et ai 3 MDD 1984 3 CD 6 ANX I SCHZ-S 2 MISC

Diagnostic procedure

Dexamethasone dose (rag)

6-12

Clinical interviews DSM-III

0 . 5 @ 11 PM

Clinical interviews DSM-II! Kiddie-SADS DSM-IF&RDC Kiddie-SADS DSM-lll

0.5 @ IIPM

Ages

Weller et al 1984

20 MDD

6-12

Freeman et al 1985

5 MDD

6-12

Petty et al 1985

7 MDD 6 DD 6 SCHZ-S 3 CD 2 ANX 6 MISC 50 MDD 18 BD 18 NC 34 MDD 19 DD 6 ADDM 15 ANX 4 CD 8 SCHZ-S 7 MISC 8 MDD 12 ANX 12 BD

5-12

Weller et al 1985

Doherty et al 1986

Livingston ct al 1987

Pfeffer et al 1989° Pfeffer et al 1989"

Fristad et al 1989

Naylor et al 1990

Birmaher et al 1992ab

DICA DSM-III

0 . 5 @ !1 PM

0 . 5 @ il PM

I mg @ ! ! PM

3-16

Kiddie-SADS RDC&DSM-ili

6-12

DICA DSM-II!

20 MDD 31PC 19 MDD 31PC

6-12

Kiddie-SADS DSM-Ill Kiddie-SADS DSM-III

63 MDD 14 BD 21 NC 25 MDD + DD 48 PC

6--12

DICA DSM-Ill

0 . 5 r a g @ I IPM

5-14

Clinical interviews DSM-III

0.5 if bw < 36 kg I mg if bw > 36 kg @ II PM

6-12

Kiddie-SADS RDC Criteria Kiddie-SADS RDC&DS M-Ill Clinical interviews DSM. If! Kiddie-SADS DSM-III

0 . 5 r a g @ IIPM

Studies with Children from Outpatient Settings Pozanski et al 9 MDD 1982 9PC GeUer et al 1983 14 MDD Steingard et al, 1990 Birmaher et al 1992ab

6-12

0.5 @ !1 PM

56 MDD 22 ADHD 26 MDD 10 PC 8 NC 23 MDD 13 PC 9 NC

6-12

5-12 4-16 8-12

8-12

Kiddie-SADS DSM-III

0 . S m g @ 11 PM

0.5mg@

II aM

0.1mg@

II aM

201tg/kg @ ! 1:30 PM Mean dose = 0.56 mg 17 ttg/kg @ I I PM 0.25 m g @ 9 PM

0.5 mg @ 9 PM

(Continued)

T a b l e !.

Citation

Sample

Diagnostic procedure

Ages

Dexamethasone dose (rag)

Studies with Adolescents from Inpatient Settings Robbins et al 1982 4 MDD 5PC

15-18

SADS RDC

I mg @ 11:30 PM

Extein et al 1982

15 MDD 12 PC

13-18

Clincial interviews DSM-III

1 m g @ 12 AM

Klee et al 1982

20 MDD 13 PC

11-17

Kiddie-SADS DSM-III

i m g @ I 1 I'M

Targum and Capodanno 1983

17 MDD 38 DD 47 CD 15 SCZ-S 9 MDD-E 7 MDD-NE 12PC 22 MDD 4 DD 16 PC

13-19

Clinical interviews DSM-III

! mg @ 11:30 PM

Robbins et al 1983

Ha et al 1984

Emslie et al 1987

33 MDD 18 DD

13-18

)S

13-17

Kiddie-SADS RDC

I mg @ ! i : 3 0

6-.18 (64 Tanner >~3)

Clinical interviews DSM-III

0.5 g for children 1 g adolescents @ 11 PM

10-16

Clinical interviews DSM-ll!

1 g @ 11 PM

13-17

Clinical interviews DSM-III

1 g @ 11 PM

12-19

Clinical interviews DSM-Ill Kiddie-SADS RDC

1 m g @ ! I I'M

Clinical interviews DSM.m Kiddie-SADS RDC

I g @ i I PM

8 BP Woodside et al 1987

Khan 1987

Evans et al 1987 Appelbloom-Fondu et al 1988

1 mg @ !1 PM

,~DS

35 PC 10 MDD 17 ADDM 18 CD 2 BP 6 MISC 33 MDD 22 CD 7 DD 5 ADIID 18 MISC 20 MDD 32 PC 6 MDD 8 DD

Studies with Adolescents from Outpatient Settings Brambilla et al 8 DD 1989 Birmaher et al 44 MDD 1992b~ 38 NC

12-20

9-16 11-18

1 mg @ 9 PM

I g @ I I PM

Diagnostic Codes: ADDM = adjustment disorder with depressed mood; ADHD = attention deficit hyperactivity disorder, ANX = anxiety disorders; BD = behavior disorders (oppositional defiant disorder, attention deficit disorder with hyperactivity, conduct disorder); CD = conduct disorder; DD = dysthymia; MDD = major depressive disorder; MDD-E = MDD, endogenous; MDD-NE = MDD, Nonendogenous; MISC = diagnoses repotted infrequently (e.g., borderline, anorexia, pervasive developmental disorders, post.tranmatic stress disorder, labile personality disorder, substance abuse); NC = normal controls; PC = psychiatric controls; SCHZ-S = schizophrenia specL-umdisorders. Cortisol determination codes: CPB = competitive protein binding; NR = not reported; RIA = radioimmunoassy. aThe sensitivity and specificity rates reported in the Pfeffer et al 1989 study were computed for each cortisoi collection. The value in the table reflects rates of nonsuppression determined by the 8 AM cortisol levels. All other studies in the table that collected cortisoi at more than one point in time classified subjects as nonsuppressors if they had cortisol values greater than 5 ~g/dl at any point in time. bThe Birmaher et al citations represent a single study in children. Using two different doses of dexamethasone; data from results at each dose are shown separately in this table. Sensitivity and specificity tares were computed using evidence of nonsuvression at either 8 AMor 4 i'M. CThe study of adolescents by Birmaher et al, 1992b, computed sensitivity and specificity rates using evidence of nonsuppression at either 8 AM, 4 PM, or 11 PM,

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Table I.

(Continued)

R.E. Dalai et al

Cortisol collection (method and times)

Cortisol determination method

No. dex nonsuppressors

Sensitivity %

Specificity %

Venipuncture 4 PM postdex

RIA

2/3 MDD 0/3 CD 4/6 ANX I/1 SCHZ-S 0/2 MISC

67

100 CD 33 ANX 0 SCHZ-S 100 MISC

Venipuncture 8 AM, 4 PM, postdex Venipuncture 4 PM postde~: Venipuncture 4 I,M, II PM postdex

RIA

14/20 MDD

70

NR

4/5 MDD

80

RIA

6/7 MDD 5/6 DD 5/6 SCHZ-S 2/3 CD I/2 ANX 1/6 MISC 40/50 MDD 5/18 BD 2/18 NC 15/34 MDD 4/19 BD 2/6 ADDM 1/15 ANX 0/4 CD 0/8 SCHZ-S 017 MISC 8/8 M D D 8/12 A N X 1/12 BD 11/20 MDD 4/31 PC

86

17 DD 17 SCHZ-S 33 CD 50 ANX 83 MISC

80

72 BD 89 NC

44

79 DD 67 ADDM 93 ANX 100 CD 100 SCHZ-S 100 MISC

100

33 ANX 92 BD

Venipuncture 8 AM, 4 PM predex 8 AM, 4 PM postdex Venipuncture 8 AM, 4 PM, 11 PM postdex

RIA

RIA

Vcnipunclure 4 PM postdcx

RIA

Venipuncture 8 AM, 4 PM, I 1 PM predex 8 AM, 4 PM, I I PM postdex Venipuncture 8 AM, 4 PM, I 1 PM predex 8 AM, 4 PM, I 1 PM postdex Venipuncture 8 AM, 4 PM, I 1 PM postdex

RIA

Venipuncture 1! I'M predex 4 PM, postdex Venipuncture 4 PM postdex Venipuncture 4 PM postdcx Venipuncturc 4 PM postdex Indwelling catheter 24 hourly samples predex 24 hourly samples postdex Indwelling catheter 24 hourly samples predex 24 hourly samples postdex

RIA

2/19 MDD 1/31 PC

RIA

42/63 MDD !/17 BD 2/21 NC 18/25 MDD + DD 11148 PC

CPB

CPB RIA RIA CPB

CPB

55°

87

I I=

97

67

94 BD 90 NC

72

77

5/9 MDD !/9 PC 2/14 MDD

56

89

19/56 MDD 5/22 ADHD 11/26 MDD 2/10 PC 6/8 NC 4•23 MDD 0/15 PC 5/8

34

77

42

80 PC 25 NC

17

100 PC 37 NC

14

DST in Adolescents

Table I.

BIOL PSYCHIATRY 1992;32:109-126

! 15

(Continued)

Cortisoi collection (method and times)

Cortisol determination method

Studies with Adolescents from Inpatient Settings Venipuncture RIA ! I PM predex 8 AM, 4 P~,, postdex Venipuncture RIA 8 AM, 4 PM, 12 AM predex 8 AM, 4 PM, 12 AM postdex Venipuncture RIA 8 AM, predex 8 AM, 4 PM, 1! PM poslOex Venipuncture RIA 4 PM, I ! :30 PM postdex

No. dex nonsuppressors

Specificity %

2/4 MDD 0/5

50

100

8/15 MDD 1/12 PC

53

92

8/20 MDD 1/13 PC

40

92

7/17 MDD 7/38 DD 7•47 CD 4115 SCZ.S 4/9 MDD-E 0/7 MDD-NE 0/12 PC 7/22 MDD 2/4 DD 3/16

41

82 DD 85 CD 73 SCZ-S

25

100 PC

32

50 DD 81 PC

18/33 MDD 4/18 DD 3/8 BP 4/35 PC 8/10 MDD 3/17 ADDM 2/18 CD 2/2 BP 2/6 MISC 23/33 MDD 3/22 CD 1/7 DD I/5 ADHD 3/I 8 MISC 10/23 MDD 5•32 PC 4/6 MDD 0/8 DD

55

78 DD 63 BP 89 PC.

80

82 ADDM 89 CD 0 BP 67 MISC

70

86 CD 86 DD 80 ADHD 83 MISC

43

84

67

100 DD

Venipuncture 8 AM, 4 eM, II PM postdex

CPB

Venipuncture 4 PM, 11 PM postdeg

CPB

Venipuncture 4 PM, postdex

RIA

Venipuncture 4 PM, I I PM postdeK

RIA

Venipuncture 4 PM, I 1 PM postdex

NR

Venipuncture 4 PM, 11 PM postdex Venipuncture 2 PM, 9 PM postdex

RIA

Venipuncture 4 PM postdex Indwelling catheter 24 hourly samples predex 16 houdy samples postdex

RIA

0/8 DD

CPB

6/44 MDD 1/38 NC

RIA

Sensitivity %

100 DD 14

97 PC

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2-week diagnostic screening protocol which included administration of the epidemiological version of the Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS-E)(Chambers et al 1985), and a pediatric examination with Tanner staging (Marshall and Tanner 1969, 1970). Subjects in the MDD group were also administered the present episode version of the diagnostic instrument, the K-SADS-P, two times, approximately 2 weeks apart, to evaluate the stability of current symptomatology. Only symptoms experienced during the preceding week were recorded at the second interview which was conducted by a diagnostician blind to the results of the first KSADS-P evaluation. All symptom ratings ~ver,~ made by interviewing the parent(s), then interviewing the adolescent. Final diagnoses were made by a child psychiatrist who reviewed the data obtained from the two K-SADS-P interviews, and met briefly with the subject to confirm all positive symptoms. A diagnosis of MDD was made using Research Diagnostic Criteria (RDC)(Spitzer et al 1978), and a diagnoses of nonaffective disorders were made using DSM-lll/Criteria (American Psychiatric Association).

Criteria for Inclusion All research participants were at least Tanner stage II1 of pubertal development and determined to be medically healthy by a pediatrician. Depressed patients were accepted if they fit unmodified RDC criteria for MDD at both psychiatric evaluations, and normal controls (NCs) were accepted if they had no current or previous history of any psychiatric disorder. Informed censent to participate in the study was obtained from all adolescents and one of their parents or a legal guardian, and the NC subjects were paid for their participation in the study.

Criteria for Exclusion The following were criteria for exclusion: (1) any medications (excep, Tylenol) within 2 weeks of the study; (2) significant medical illnesses; (3) obesity (weight greater than 150% of ideal body weight) or severe growth failure (weight or height less than 3% on the National Health Statistic Curve); (4) meeting DSM-III criteria for mania, anorexia uervosa, autism, schizophrenia, or schizoaffective disorder; (5) an IQ score of less than 70; and (6) pregnancy.

Sample The sample consisted of 61 adolescents, including 27 patients with the diagnosis MDD and 34 NCs with no history of psychiatric illness. By design, all subjects in each group were at least Tanner stage III of sexual maturation, but less than 18 years of age. There were no significant group differences in subjects' gender (MDD 11 males, 16 females; NC 14 males, 20 females; X-'=0.02, df= 1, n.s.) or mean age (MDD 15.3 ± 1.5; NC 14.8 _ 1.6; t(61) = 1.05, p > 0.10)(The age range was 11 years 11 months to 17 years 8 months in the NC group; 12 years 8 months to 17 years 3 months in the MDD group). There were significant race differences (MDD 20 white, 7 black, 0 biracial; NC 32 white, 0 black, 2 biracial; X'= 10.80, dr= 2, p < 0.005). Of the 27 adolescents with MDD, !3 were inpatients and 14 were outpatients. The majority (82%) of the adolescents fit RDC criteria for endogenous depression, and approximately one-fifth (19%) had psychotic symptoms. In addition, almost half of the

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MDD sample (48%) had significant suicidel symptomatology, receiving a score of 4 or greater on the K-SADS item for suicidality, indicating the presence of a definite suicidal plan or history of a recent suicide attempt. There was considerable comorbidity in the MDD sample, with many adolescents meeting criteria for more than one additional diagnosis. There were 13 (48%) depressed adolescents with dysthymia, 11 (41%) with phobias, 7 (26%) with generalized anxiety disorder, 3 (11%) with conduct disorder, 4 (15%) with separation anxiety disorder, and 1 (4%) with obsessive-compulsive disorder. Hamilton Depression Rating Scale (HDRS) scores were extracted from the K-SADS-P data using an adaptation (WiUiamson et al 1992) of the method developed by Endicott et al (1981). The mean extracted HDRS score for this MDD adolescent sample was 24.2 + 6.5.

Dexamethasone Administration and Cortisol Assessment Procedures Subjects that met study criteria were admitted to the Child and Adolescent Sleep Laboratory at Western Psychiatric Institute and Clinic for 3 consecutive nights (Part A of the protocol), and then returned approximately l week later for 2 additional days of study (Part B of the protocol). Part A of the protocol included 3 nights of polysomnography and 24-hr baseline cortisol data collection. The methodology a~ld findings of Part A of the protocol are described in detail elsewhere (Dahl et al 1990, 1991). For Part B of the protocol, an indwelling catheter was reinserted at 8 AM when subjects returned to the Child and Adolescent Sleep Laboratory, and it remained in place for 48 hr. On day 1 of Part B of the protocol, subjects were given a Thyroid Releasing Hormone Test (500 Ixg) from 8:30 to 10:30 AM, and a d-amphetamine challenge test (0.15 mg/kg) from 3:00 to 5:30 PM. At 11 PM that day, subjects received a 1.0 mg PO dose of dexamethasone. On day 2, beginning at 8 AM, blood samples for postdexamethasone cortisol determination were taken through the indwelling catheter each hr for 16 consecutive hr. Blood samples were immediately centrifuged and the plasma was then frozen until assayed. Plasma cortisol was determined by radioimmunoassay (RIA) with an intraassay coefficient of variation (CV) of 1.28-2.69% from 1.0 to 22.0 ttg/di, and interassay CV of 6.26% at 14 ttg/dl. Postdexamethasone cortisol secretion values of less than 1 Ixgtdl were assigned the value of 0.5 I~g/dl, the lowest detectable limits of the assay.

Statistical Analyses Problems with missing data were minimal. Of the original 62 subjects, 56 had all 16 postdexamethasone cortisol blood samples drawn. On~" subject had seven consecutive missing data points and was dropped from the study. The remaining five adolescents with incomplete ~ata had only one or two missing specimens, and linear interpolations were conducted to fill in missing values. For all variables, Shapiro-Wilk's test (Shapiro 1965) for normality was performed. The baseline and postdexamethasone cortisol values were not normally distributed, and multiple transformations failed to normalize cortisol values. Consequently, nonparametric Mann Whitney tests were utilized to examine between-group differences. The following summary -~,ariableswere computed: (1) mean 16-hr postdexamethasone cortisol secretioa (the area under the curve was also calculated and comparable results were obtained regardless of which postdexamethasone summary variable was utilized); (2) peak secretion determined by the maximum postdexamethasone cortisol concentration; and (3) postdex-

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Table 2. Postdexamethasone Cortisol Values (Ixg/dl) in Major Depressive Disorder (MDD) and Normal Control (NC) Groups

Cortisol value 8 AM 9 AM l0 AM II AM 12 PM I PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM I I PM Mean cortisol value Peak cortisol value

MDD(n = 27) Mean ± SD !.3 1.1 0.8 0,7 0,6 1,2 !,3 1.3 1.6 1,4 1,5 1,3 1.1 0,8 1.1 1.0 1. !

± ± ± ± ± ± ± ± ± ± --. ± ± ± ± ± --.

3.1 2.6 0.9 0.5 0.4 1,8 2.2 !,9 2.9 1,7 2.6 1.7 1,2 0.7 1.2 1.1 I, 1

3,4 ± 4,0

NC(n = 34) Mean ± SD

Mann-Whitney value

p-value

0.6 0.6 0.7 0.9 0.7 0.9 1.2 1.5 1.8 1.9 1.6 1,5 I.! 1,0 0.9 0.9 !. !

± 0.4 ± 0.4 ± 0.7 ± 1.6 ± 0.8 ± !.2 --. 2.1 ± 2,7 - 2.7 --. 2.3 ± i.7 ± !.5 .4- 1.1 ± 1,0 ± 1.3 --- 1. ! ± !. I

471.0 455.5 471.0 471.0 453.0 466.0 438.5 407.0 416,5 413.5 387.0 438.5 430.0 437.0 505,5 460,0 462.0

0.74 0.91 0.74 0.74 0.87 0.88 0.66 0.33 0.44 0.44 0.19 0.73 0.61 0.87 0.37 0,98 0.96

2,9 ± 3.5

485,0

0.69

amethasone suppression status (nonsuppressor status was assigned to patients that had postdexamethasone cortisol values greater than 5 p.g/dl at either 8 AM, 4 PM, or 11 aM). For the MDD versus NC comparisons, group differences were initially examined for each hourly cortisol assessment and the three summary variables. Subsequent analyses comparing the different subgroups of MDD patients were only performed for the summary variables and postdexamethasone cortisoi values at the "standard draws" (8 AM, 4 r'M, 11 aM). Spearman Rank Correlation Coefficients were used to examine associations between sets of continous variables, including an examination of the relationship between postdexamethasone cortisol values and the baseline 24-hr cortisol data collected during Part A of the protocol, and the preamphetamine and postamphetamine challenge test cortisol values.

Results Postdexamethasone Cortisol Values and Rates of Nonsuppression: MDD versus NC Figure 1 depicts the pattern of postdexamethasone cortisoi secretion for the MDD and NC adolescents. Table 2 shows the means, SDs, Mann-Whitney values, and significance levels of all between-group comparisons on the cortisol measures. The pattern of cortisol secretion in the two groups was similar across the 16-hr period that was assessed. There were no significant differences between the MDD group and the NCs on any of the summary cortisol values examined including mean 16-hr cortisol secretion levels, peak

D S T in Adolescents

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! 19

Table 3. Postdexamethasone Cortisol Values (ttg/dl) in Subgroup Comparisons within the MDD Subjects" Subgroup

N

lnpatients Outpatients Suicidal Nonsuicidal Endogenous Nonendogenous Psychotic Nonpsychotic Previous episode First episode

13 14 13 14 23 4 5 22 5 22

16-hr mean (Mean -+ SD) !.0 i.2 i.4 0.9 !.2 0.7 0.7 1.2 1.4 1.0

.4_ -+ ± ± ± ± ± ±

1.0 1.2 1.4 2.5 1.2 0.3 0.3 1.2 1.8 0.9

Peak (Mean ± SD) 3.4 3.4 4.1 2.7 3.6 1.9 2.2 3.6 3.4 3,3

-- 4.6 ± 3.6 .4- 5.2 ± 2.5 ± 4.3 ± 2.1 - !.6 ± 4.4 -4-_5.1 - 3.8

8 AM x alue (Mean ± SD) 1.7 0.9 1.7 0.9 1.5 0,5 0,5 1,5 0,6 1.4

± ± ± ± ± ± ± ± -

4.2 1.6 4,2 1,6 3.4 0,0 0,0 3,4 0,3 3.4

4 PM V'dtlue (Mean ± SD) 1.7 1.5 1,7 0.9 1.8 0.5 0.9 1.8 2.9 1.3

± 2.6 -4- 3.2 ± 2.3 ± 1.5 ± 3.1 .4- 0.0 +- 0,6 -+ 3.1 --- 5,3 ± 2.0

11 PM value (Mean ± SD) 0.8 1.0 0.9 1,0 0,9 1,4 0.6 1,1 1,6 0,~

± 1.0 ± 1.1 +- 1.1 -+ 1.1 ± 0.9 ± 1.9 -+ 0.1 4- 4.4 ± 1.6 ± 0.9

*All subgroup comparisons were examined with the Mann-Whitney nonparametric statistic. For all comparisons, p > 0,10,

value, or cortisol level at any of the 16 collection times from 8 AM to 11 PM (Mann Whitney, p > 0.10). No effects of gender or race were detected on any of the following measures: mean 16-hr postdexamethasone cortisol concentrations, peak value or any of the "standard" (8 AM, 4 PM, or 11 PM) draws. Age was significantly correlated with the 11 PM draw (Spearman Rho - 0.31, N - 61; p < 0.02), but the coefficients for the correlation of age with the other four cortisol values examined approached zero (the Spearman Rho correlation coefficients ranged from - 0 . 0 2 , to -0.06). When the data were examined categorically, very few subjects in either group had postdexamethasone values greater than 5 p,g/dl at any of the three standard draws. Only four (15%) MDDs and three (9%) NCs met this criteria for DST nonsuppression (X2 = 0.46, df = 1, p > 0.10). These rates of nonsuppression convert to sensitivity and specificity estimates of 15% and 91%, respectively. When postdexamethasone cortisol values of greater than 5 I~g/dl at any of the 16 draws were used to determine nonsuppressor status, 6 (22%) MDDs and 8 (24%) NCs were DST nonsuppressors (X2 -- 0.04, df = 1, p > 0.10). To allow for comparability with other published studies, in all of the remaining analyses nonsuppression is defined as postdexamethasone values greater than 5 ~g/dl at any of the three standard draws (8 AM, 4 PM, or 11 PM).

inpatients versus Outpatients Table 3 depicts the results of all the subgroup analyses that were conducted to examine the factors that were hypothesized to account for variation in rates of nonsuppression. There were no differences between the inpatients and the outpatients on the mean 16-hr postdexamethasone cortisol secretion levels, peak cortisol value after dexamethasone was administered, or any of the standard draws. Two of the four MDD nonsuppressors were inpatients, and 11 of the 23 MDD suppressors were inpatients (×2 = 0.46, df = 2, p > 0.10).

Effects of Suicidality The MDD group was dichotomized into suicidal and nonsuicidal subgroups, with subjects scoring 4 or greater on the K-SADS item for suicidality assigned to the suicidal group. Scores of 4 or greater indicate a definite suicidal plan or actual suicidal attempt. This

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cutoff was used in previous reports (Ryan et al 1988; Dalai et al 1990, 1991.) Using this classification, approximately half (48%) the MDD subjects were classified suicidal. Suicidal MDD subjects did not differ from nonsuicidai subjects on the mean 16-hr postdexamethasone cortisol secretion levels, peak cortisol value after dexamethasone was administered, or any of the standard draws (see Table 3). Three of the four MDD DST nonsuppressors were classified suicidal, as were 11 of the 23 MDD DST suppressors (Xa = 1.17, df = 1, p > 0.10).

MDD Subtypes The majority (82%) of the MDD adolescents in the study met criteria for endogenous depression. Comparison with the small group of nonendogenously depressed subjects (N = 4) revealed no significant differences on any of the postdexamethasone cortisol measures (see Table 3). All four of the MDD nonsuppressors had endogenous depressions, but this finding was not statistically significant (X2 = 0.82, df = 1, p > 0.10). In terms of psychotic features, five adolescents (19%) in the study endorsed the presence of psychotic symptoms. Those patients with psychotic symptoms did not differ from those without psychotic symptoms on any of the postdexamethasone cortisol values (see Table 3) or rates of nonsuppression (×2 = 0.16, df -- 1, p > 0.10).

Prior Affective Illness Five adolescents in the study had a previous episode of major depressive illness. Those patients with a prior history of depression did not differ from the first episode cases in terms of any of the postdexamethasone eortisol values (see Table 3). Of the five adolescents with a prior history of MDD, only one was a DST nonsuppressor (X2 = 0.16, df = 1, p > 0.10).

Relationships Between 24-Hr Baseline and Postdexamethasone Cortisol Values Twenty-four-hour baseline cortisol data had been collected on day 3 of Part A of the protocol (see Dahl et al 1991 for discussion of baseline findings). Baseline cortisol data were available for 58 of the 61 adolescents that received the DST. Spearman Rho Correlations were computed to examine the relationship between the 24-hr baseline and postdexamethasone cortisol secretion values. Mean baseline 24-hr cortisol values showed significant positive correlations with several measures of postdexamethasone cortisol secretion, including mean postdexamethasone 16-hr cortisol values (Spearman Rho = 0.33, N = 58, p < 0.02), the peak postdexamethasone value (Spearman Rho = 0.32, N = 58, p < 0.02), and the 4 PM cortisol value (Spearman Rho = 0.36, N = 58, p < 0.02). The correlation with the !1 aM cortisol specimen also approached significance (Spearman Rho = 0.22, N = 58, p < 0.10). As these correlations were all positive, they suggest that adolescents with higher baseline cortisol ate more likely to secrete higher cortisol after dexamethasone.

Relationship beaveen Pre- and Postamphetamine Cortisol and Postdexamethasone Cortisol Values A d-amphetamine challenge test (0. i5 mg/kg) was conducted from 3:00 to 5:30 PM the afternoon prior to dexame~asone administration (see Waterman et al 1991, for discussion of amphetamine challenge data). Three baseline cortisol specimens were collected every

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12I

15 min prior to d-amphetamine IV infusion, and five additional specimens were collected on 15-min intervals after the infusion. Amphetamine challenge data were available for 57 of the 61 adolescents that received the DST, and Spearman Rho Correlations were again utilized to examine the relationship between the different cortisol measures. Mean baseline (pre-amphetamine) cortisol values were significantly correlated with the mean 16-hr postdexamethasone cortisol (Spearman Rho = 0.48, N = 57, p < 0.0001 and the l I aM cortisol values (Spearman Rho = 0.47, N = 57, p < 0.0003). The mean postamphetamine cortisol values, however, were not significantly correlated with any of the postdexamethasone values, including the mean 16-hr cortisol value (Spearman Rho = 0.19, N = 57, p = n.s), peal: postdexamethasone response (Spearman Rho = 0.15, N = 57, p = n.s), or any of the standard draws (8 AM: Spearman Rho = 0.09; 4 PM: Spearman Rho = 0.12; and II pM = 0.18, p = n.s, for all coefficients). As the mean postamphetamine cortisol values were normally distributed, group differences between DST suppressors (DST-S) and nonsuppressors (DST-NS) on this measure were examined with an analysis of variance (ANOVA). There was no difference in the mean postamphetamine cortisol secretion of DST suppressors and nonsuppressors (F(1,56) = 0.59, p = n.s.; DST-S: 14.6 ± 6.1, DST-NS: 14.6 -+ 5.4). These results suggest that subjects' response to the amphetamine challenge test did not significantly influence their response to the DST.

Discussion Overall, there were no group differences found between the MDD an,; NC subjects on any of the postdexamethasone cortisol measures, and none of the factors that were hypothesized to account for variation in DST rates distinguished the suppressors from the nonsuppressors in this study. In fact, only four adolescents in the MDD group and three in the NC group were DST nonsuppressors. What factors can account for this low rate of DST nonsuppression? The low rate of DST nonsuppression in this investigation is not apt to be attributable to the subjects' hospitalization status. In this and previous reviews (Casat et al 1980), inpatients were found to have greater rates of DST nonsuppression than outpatients. However, this MDD group consisted of equal numbers of inpatients and outpatients, and the inpatients were no more likely to fail to suppress cortisol than the outpatients in the study. The low rate of nonsuppression in this study is also unlikely to be related to the clinical characteristics of the sample. Previous studies have reported increased rates of nonsuppression in samples of endogenously depressed (Robbins et al 1983) and/or suicidal adolescents (Pfeffer et al 1991; Robbins and Alessi 1985). As the majority of the MDD sample in this study met RDC criteria for endogenous depression, and approximately half the sample reported significant suicidal ideation, high rates of DST nonsuppression would have been expected. In this study, the rates of nonsuppression were uniformly low across all subgroups of depressives. Postdexamethasone cortisol values did not differ significantly for any subgroup, whether defined by the presence of suicidality, endogenous features, psychotic symptomatology, or history of prior episode of major affective illness. However, the number of subjects in some subgroup analyses (such as psychotic, nonendogenous, and prior history of affective disorder) were small, thus the lack of group differences on these splits must be interpreted with caution. The administration of the amphetamine challenge test prior to the administration of • e DST must also be considered. There was no relationship between postamphetamine

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cortisol response and postdexamethasone cortisol levels. Further, the DST suppressors did not respond differently to the amphetamine challenge test than the DST nonsuppressors. The possibility of nondetected effects, however, cannot be completely ruled out, and highlight the need to consider design factors when interpreting experimental data. The results of this study must also be considered in the larger context of studies of HPA axis abnormalities in major depression. Subjects with depression are hypothesized to have an abnormality in cortisol regulatory mechanisms, with a tendency to hypersecrete cortisol in response to stressful stimuli (Gold et al 1988). The DST represents one method of examining this system by testing the sensitivity of the HPA axis to feedback inhibition. Cortisol values following the administration of dexamethasone represent a physiological balance between two opposing sets of factors: one set suppresses secretion(e.g., cortisol and dexamethasone), and one set stimulates secretion (e.g., exogenous stressors). Factors on each side of this balance will affect postdexamethasone cortisol values and thus influence the sensitivity and specificity of the DST to HPA axis abnormalities. Therefore, consideration of DST results should address factors of steroid availability to inhibitory centers as well as the presence of exogenous stressors experienced by the subjects in the DST protocol. With regard to steroid availability, it is possible that the dose of dexamethasone used in this study was too high, causing uniform suppression of cortisoi, regardless of clinical status. In studies of preadolescents, Pfeffer et al (1989) reported that the 0.5-mg dose was more sensitive than the l-rag dose for children this age, and Birmaher et al (1992a) reported that the 0.25-rag dose provided better sensitivity than the 0.5-rag dose. There are no dosage studies in adolescents. As the dose of dexamethasone used in this study was the same as the dose used in all other studies of adolescents, the very low rate of nonsuppressor status repuited here is unlikely to be due solely to dose effects. However~ as stated in the introduction, adolescent DST studies (all with I-rag doses) report lower sensitivities than child DST studies. In addition to dosage, availability of dexamethasone is also influenced by variance in absorption and metabolism. Several studies of adults with MDD have reported a significant negative correlation between postdexamethasone cortisol values and plasma dexamethasone levels (Arana et al 1955; Berger et al 1984; Cart et al 1986). Plasma dexamethasone levels were not measured in this study and present an important limitation of the study. Although a relationship between nonsuppressor status and plasma dexamethasone levels has not been consistently reported in child samples (Naylor et al 1990; Birmaher et al 1992a), careful attention m the pharmacokinetics of dexamethasone may also help to explain variation in DST nonsuppression rates in depressed and nondepressed samples. In determining the sensitivity and specificity of the DST to HPA axis abnormalities, one must also consider the other side of the equation from the inhibitory effects of steroid availability: the amount of exogenous stress experienced by the subject. Stress has a profound effect on DST results. When experimental conditions are sufficiently stressful, such as collecting cortisol specimens after an engagement of public speaking, even normal control subjects are found to have a high rate (44%) of DST nonsuppression (Baumgartner et al 1985). Within samples of MDD inpatients, nonsuppression rates have been found to be two times greater (71% versus 33%) when the DST is administered within the first 2 days of hospitalization than when it is administered later in the hospital stay (Coccaro et a! 1984). The "dose of stress" associated with the administration of the DST, like the dose of dexamethasone, must also be considered in the interpretation of DST results. If the dose of stress is too high, even normal controls will be nonsuppressors. If it is too low, the DST may fail to discriminate between different diagnostic groups.

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The sleep/neuroendocrine laboratory where these adolescent subjects in this study were tested is a very low stress environment. All subjects had spent 4 prior days in the laboratory and were well acclimated to the place, procedures, and staff by the time of the DST study. The laboratory, is furnished with many age-appropriate materials, including books, art supplies, board games, entertainment videos, and computer games. In addition, subjects are given considerable one-to-one attention from staff who have years of experience running biological studies in children and adolescents. Many subjects express a liking for the laboratory environment, reporting a strong preference for the laboratory over the inpatient unit. It is important to emphasize that even the "inpatients" left the general hospital unit and came to the sleep lab for the days and nights of the biologic studies. The issue of catheter draws (versus repeated venipunctures) should also be considered. Although indwelling catheters might appear more stressful initially, we have found that once children and adolescents have adapted to the catheter, they subjectively report the catheters to be lest stressful than repeated venipunctures. Most subject.~;are completely unaware of blood drawing through the catheter and continue with their current activity (e.g., computer games, watching television, board games). Once the catheter is in place, the subject knows the rest of the protocol will be free of any further painful procedures, whereas with the usual DST, the child or adolescent is anticipating at least one to three additional needle sticks. The lower rate of DST nonsuppression obtained in this study using an indwelling catheter is consistent with the findings of other studies that used similar methodologies with children (Birmaher et al 1992a), adolescents (Birmaher et al 1992b), and adults (Pfohl et al 1985). It is possible that the environment and methods in which the data were collected may not have contained sufficient stressors to elicit a differential stress response from the depressed subjects in this study. These DST findings must also be considered in comparison with the 24-hr baseline cortisol results from Part A of the protocol (Dahl et al 1991). These results showed elevated cortisol near sleep onset (a time when cortisol is physiologically suppressed) in the suicidal group of MDD adolescents compared with nonsuicidal MDD subjects (and compared with the NC adolescents). It is possible that this approach (24-hr baseline sampling including the physiological nadir in cortisol secretion) may be a more sensitive measure of a tendency toward cortisol hypersecretion than the DST. The possibility must also be considered that a lower dose of dexamethasone (at least in a setting with relatively low exogenous stress~, may also be more sensitive to HPA abnormalities associated with adolescent depression. Future studies should investigate the appropriate dose of dexamethasone for adolescent studies, and systematically examine the impact of exogenous stressors within the context of the DST protocol. Issues of age, development, and cognitive undelstanding of the procedures may also be important to consider in these studies.

Conclusions Consistent with previous analyses, the current review based on a considerably larger number of studies suggests th~_t ~1) the DST is more sensitive in children than in adolescents; (2) subjects from inpatient samples are more likely to be nonsuppressors than subjects from outpatient samples; and (3) greater specificity is achieved with the DST in adolescent samples. In this review, specificity rates were also computed separately for the different diagnostic psychiatric control groups. Within samples of child inpatients, approximately 40% of children with dysthymia, anxiety disorders, or schizophrenia spectrum disorders were DST nonsuppressors. Within adolescent inpatient samples, approx-

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imately 16% of all psychiatric control subjects, regardless of diagnosis, were DST nonsuppressors. The data presented in this study raise important questions regarding the administration of the DST. The results raise concerns about the appropriateness of the current dose of dexamethasone standardly used with adolescents, and the need to consider the "quantity of stress" associated with the administration of the DST. Dr. Joaquim Puig-Antichperformed a central role in designingand conductingthis study. All data analysis, interpretation,and manuscriptpreparationwerecompletedsubsequentto his unt!~'nelydeath in December, 1989. This article is dedicatedto his memory.

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The dexamethasone suppression test in children and adolescents: a review and a controlled study.

Dexamethasone Suppression Test (DST) studies conducted in children and adolescents are reviewed, together with factors hypothesized to explain discrep...
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