Dexamethasone Suppression Test in Children with Major Depressive Disorder BORIS BIRMAHER, M.D., NEAL D. RYAN, M.D., RONALD DAHL, M.D., HARRIS RABINOVICH, M.D., PAUL AMBROSINI, M.D., DOUGLAS E. WILLIAMSON, B.A., HANA NOVACENKO, M.S., BEVERLY NELSON, R.N., EE SING LO, PH.D., AND JOAQUIM PUIG-ANTICH, M.D.
Abstract. The authors report a study of 24-hour serial cortisol detenninations, measured during baseline and after the administration of 0.25 and 0.5 mg of dexamethasone in a sample of predominantly outpatient children with major depressive disorder, nonaffective psychiatric controls, and nonnal controls. In this sample, 24-hour baseline cortisol and the dexamethasone suppression test (DST) do not discriminate between the three groups. In addition, the authors measured 24-hour serum dexamethasone levels. There were no significant between group differences in serum dexamethasone. These results raise questions as to the utility of this test in the diagnosis of affective disorders in children. Possible reasons for the discrepancies in the dexamethasone suppression test results between in- and outpatient studies are discussed. l. Am. Acad. Child Adolesc. Psychiatry, 1992, 31, 2:291-297. Key Words: children, cortisol, dexamethasone suppression test, serum dexamethasone levels, depression. There has been controversy in the role of the dexamethasone suppression test (DST) as a tool for the diagnosis of major depressive disorder (MOD) for both adults and children. Casat et al. (1989) reviewed the available evidence on the validity of the DST in children. They included three inpatient studies (N = 113) (Livingston et aI., 1984; Petty et aI., 1985; Weller et aI., 1985) and two outpatient (N = 32) studies (Geller et aI., 1983 Poznanski et aI., 1982). The review only included studies in which a prospective design had been used. The studies used research diagnostic criteria (ROC) or DSM-III criteria for diagnosis and included one or more control samples. All administered 0.5 mg of dexamethasone at 11:00 P.M. except Geller et al. (1983), who administered 20 Ilg/kg (mean dose, 0.64 mg), and all used the threshold of 5 Ilg/dL of cortisol to define nonsuppression. Casat et al. (1989) showed that 55 (69.6%) of the 79 children with MOD and 20 (30.3%) of 66 children with other psychiatric disorders were nonsuppressors (X2 = 22.26, df = 1, p < 0.0001). The pooled DST sensitivity and specificity for all the inpatient and outpatient population together were 69.6% and 69.7%, respectively. However, as described in the adult literature (American Psychiatric Association, 1987), significantly more inpatient children with MOD were nonsuppressors (81.7%) than MOD outpatients (31.6%) (X 2
Accepted March 28, i99i. Drs. Birmaher, Ryan, Dahl, Puig-Antich; Ms. Nelson and Mr. Williamson are from the Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric institute and Clinic, Pittsburgh, PA. Drs. Rabinovich and Ambrosini are from the Department of Psychiatry, Medical College of Pennsylvania, Eastern Pennsylvania Psychiatric institute, Philadelphia, PA. Ms. Novacenko and Dr. Lo are from the Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric institute, New York, NY. The authors would like to thank Tamera McLauglinfor her assistance in typing and preparing this manuscript. This paper is dedicated to the memory of loaquim Puig-Antich, M.D. Reprint requests to Dr. Birmaher, Room 585, Western Psychiatric institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA i52i3. 0890-8567/92/3102--Q291$03.00/0©1992 by the American Academy of Child and Adolescent Psychiatry.
l. Am. Acad. Child Adolesc. Psychiatry, 3i :2, Marchi992
= 17.12, df = 1, p < 0.00004). Recently, Pfeffer et al. (1989), administered two doses of dexamethasone (0.5 and 1.0 mg) to 51 prepubertal psychiatric (76.5% had affective disorders) inpatients. They found that the optimal criterion for cortisol nonsuppression was 5 IlgidL measured at 8:00 A.M. after the administration of 0.5 mg of dexamethasone. With this criterion the sensitivity and specificity were similar to the above inpatient reports. Previous outpatient studies with the DST contained very small samples of depressed children. The purpose of the current research was to clarify the role of the DST in the diagnosis of MOD by comparing a large sample of predominantly outpatient prepubertal children to a group of normal children and other controls with nonaffective psychiatric disorders. This is the first study in children measuring plasma cortisol levels for 24 hours during baseline and then again for 24 hours following the administration of two oral doses of dexamethasone, 0.25 and 0.50 mg. In addition, this is the first study in children measuring 24-hour plasma dexamethasone levels. Patients and Methods Patients were accepted for screening at the Child and Adolescent Depression Clinic, New York State Psychiatric Institute, if they were reported to appear sad, said they felt sad, or had suicidal ideation or behavior, were nervous or afraid, or displayed ritualistic behavior. After informed consent was obtained, each case was screened for appropriateness in a 10- to 14-day diagnostic evaluation that included, in the following order, the Schedule for Affective Disorders and Schizophrenia for School Age Children (Kiddie-SADSP) for the present episode (Chambers et aI., 1985), the Psychosocial Schedule (Lukens et al., 1983), a pediatric history and exam, including Tanner staging and 10 to 14 days later the Kiddie-SADS-P for the past week. The two KiddieSADS-P assessments were carried out blindly to each other. The diagnosis of MOD was made using unmodified adult ROC criteria. The diagnoses of nonaffective emotional disorders conformed to DSM-III criteria. 291
BIRMAHER ET AL.
Criteria for Inclusion All subjects were aged 6 to 12 years, and were determined by the pediatrician to be medically normal and Tanner stage I or II of sexual development (Marshall and Tanner, 1969, 1970). Depressed subjects were accepted into the study only if they fit RDC (Spitzer et aI., 1978) for MDD (at least probable) in both Kiddie-SADS-P evaluations. MDD was considered to be endogenous only if it fit RDC for definite endogenous subtype in both evaluations. If not, it was classified as nonendogenous. Nonaffective psychiatric controls met DSM-III criteria for any of the nonaffective disorders in both evaluations and did not meet criteria for any affective disorder. Criteria for Exclusion Children were excluded if they met any of the following criteria: (1) use of psychoactive medication that could affect hypothalamic-pituitary function; (2) significant physical illness, especially endocrinopathies or heart disease; (3) obesity (weight-for-height greater than 95% on the National Center for Health Statistics curve) or growth failure (height or weight less than third percentile); (4) clinically diagnosed seizures or other major neurological illness; (5) IQ less than 70; (6) DSM-III criteria for anorexia nervosa, autism, or schizophrenia; and (7) inordinate fear of hypodermic needles (needle phobia). Normal controls were recruited through word of mouth. The ages in the normal control group ranged from 8 to 12 years. The same inclusion criteria as enumerated above were used for this group. The criterion for inclusion was no current or past history of child psychiatric disorder, as determined by a single Kiddie-SADS-E assessment (mother and child interviewed independently). Dexamethasone Administration and Cortisol Measurement After the 2-week diagnostic protocol and acceptance to the study, children came to the SleeplNeuroendocrine Unit. The first morning at 8:30 A.M., an indwelling catheter was placed. The vein was kept open by a slow drip of heparinized saline. Blood draws (1.5 rnI) were done every hour for a full 24-hour period. Blood samples were immediately centrifuged and the plasma was separated then frozen. Blood samples for the 24-hour baseline determination of cortisol began at 9:00 P.M. on the first night. At 9:00 P.M. the second night, subjects received a single p.o. dose of dexamethasone (either 0.25 or 0.50 mg selected by randomization), and blood samples were taken hourly for the following 24 hours. The next day at 9:00 P.M. subjects went home and 7 days later returned to the sleep lab. Upon return, at 9:00 A.M., an indwelling catheter was again placed in an antecubital vein. At 9:00 P.M. subjects received the alternate dose of dexamethasone (either 0.50 or 0.25 mg), and blood samples were drawn for the next 24 hours. A small subgroup of subjects (N = 7) at the beginning of the study did not have the indwelling catheters and only had samples drawn at 8:00 A.M., 4:00 P.M., and 11:00 P.M. These subjects were excluded from the analyses looking at 24 hour data but were included in comparisons at those specific time points. 292
Plasma cortisol was analyzed by competitive proteinbinding radioassay with an intraassay coefficient of variation (CV) of 9.1 %,3.7%, and 2.4% at 2.5,12.4, and 20.2Ilg/dL, respectively; and interassay CV of 9.6%, 3.9%, and 4.8% at the same levels. Plasma dexamethasone levels were obtained in a subgroup of the subjects, after the administration of 0.25 and 0.5 mg of dexamethasone. The dexamethasone levels were obtained every hour for the first 4 hours and then every 2 hours for the remainder of the 24-hour period. Dexamethasone levels were analyzed by radioimmunoassay (Lo et aI., 1989). Intra- and interassay CVs were 2.1 % and 3.3% for plasma levels at 2.93 ng/mL and 2.3% and 7.2% for plasma levels at 0.88 ng/mL.
Statistical Analysis Subjects with more than three consecutive missing samples were excluded from all examinations of mean cortisol levels. Three or fewer consecutive missing samples in a single subject were interpolated. Levels of cortisol and dexamethasone were then examined for normality (using the W statistic of Shapiro and Wilk) and log transformed as necessary before testing using parametric techniques. If after transformation the measures were still significantly nonnormal, nonparametric techniques (e.g., the Kruskal-Wallace test) were used for between group comparisons. Spearman correlation coefficients were used to examine the relationship between dexamethasone and cortisol levels within individuals.
Sample Fifty-four children were accepted for the study: 30 MDD, 15 nonaffective psychiatric controls and nine normal controls (Table 1). Among the MDDs, 15 were MDD nonendogenous, six psychotic, and 18 had suicidal ideation with a definite plan or had made a suicide attempt (called suicidal below). Patients with nonaffective disorders had the following diagnosis: 12 separation anxiety, three general anxiety, 13 simple phobia, and two conduct disorder. There were five depressive inpatients; the rest of the sample consisted of outpatients, but all subjects came to the sleep/neuroendocrine unit for these studies. As described above, in seven subjects at the beginning of the protocol, indwelling catheters were not used. These subjects are not included in analyses examining 24-hour cortisol levels. Thus, 47 children (28 MDD, 10 nonaffected controls, and nine normal controls) participated in the complete version of the studies. After the administration of 0.25 mg of dexamethasone, three subjects from this sample had more than three missing data points and were excluded from analyses, leaving 44 subjects (26 MDD, 10 nonaffective controls, and eight normal controls). Following the 0.5-mg dose of dexamethasone, two subjects had greater than three missing data points, leaving 45 subjects (23 MDD, 13 nonaffective psychiatric controls, and nine normal controls). Plasma dexamethasone levels after the administration of 0.25 and 0.5 mg of dexamethasone were assayed for a subgroup of 38 subjects (20 MDD, 11 nonaffective controls, J. Am. Acad. Child Adolesc. Psychiatry, 31 :2, March 1992
DST IN CHILDREN WITH MDD TABLE
Item
Major Depressive Disorder (N = 30)
Age (yrs)
9.89± 1.71
Sex Male Female
18 12
10 5
Race White Black Hispanic
II 14 5
2 8 5
a
1. Demographics
Nonaffective Psychiatric Controls (N = 15)
Normal Controls (N = 9)
9.25 ± 1.90
0.5
4 5
Fischer's exact test
0.6
7
Fisher's exact test
0.3
7 I
Values for age are mean ± SD.
!J.g/dL; nonaffective controls: 4.7 ± 1.2 !J.g/dL; normal: 5.2 ± 0.9 !J.g/dL; F2.44 = 0.98, p < 0.38), (MDD: 14.3 ± 2.3 !J.g/ dL; nonaffective controls: 15.2 ± 3.8 !J.g/dL; normal: 14.9 ± 2.4 !J.g/dL; F2,44 = 0.45, p < 0.64, respectively). Further analysis of the hourly basal cortisol secretion yielded no statistically significant differences between groups. Within the MDD group, analysis of subgroups by endogenous subtype (F3,43 = 0.87, NS), severity of depression (F3,42 = 0.81, NS), and suicidality (F3,42 = 0.81, NS) found no significant differences in basal plasma cortisol. There were no significant between group differences in the time of nocturnal rise in cortisol as determined by the cluster analysis program (Veldhuis and Johnson, 1986) (MDD: 608.6 ± 105 minutes; nonaffective controls: 522 ± 206 minutes; normal: 613.3 ± 103 minutes; p < 0.3, NS).
seven normal controls) and 37 subjects (20 MDD, 10 nonaffective controls, seven normal controls), respectively. There were no significant differences across groups for the total and above reduced samples for age, sex, and race (Table 1). By adapting the method of Endicott et al. (1981), the authors extracted Hamilton depression rating scale (HDRS) scores from the Kiddie-SADS scores. The mean HDRS for patients with MDD was 20.93 ± 6.0 and for nonaffective disorders 12.4 ± 6.4 (F],43 = 19.5, p < 0.0001). The mean HDRS for MDD inpatients was 26.0 ± 4.47 and for MDD outpatients 19.92 ± 5.77 (F 1•28 = 4.98, p < 0.04). There was no statistical difference in the HDRS scores between MDD endogenous (20.9 ± 7.5) and MDD nonendogenous (20.9 ± 4.0) (F1,28 = 0, NS).
Postdexamethasone Cortisol Levels (Figs. 2 and 3)
Results
The order of administration of the two different doses of dexamethasone was not found to significantly affect cortisol secretion. Within the 0.25-mg dose, the overall mean cortisol
Basal Cortisol (Fig. 1) The mean 24-hour basal and peak: serum cortisol levels were found to be similar across groups (MDD: 5.3 ± 1.8
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