Hormonal Responses to Dextroamphetamine in Depressed and Normal Adolescents G. SCOTT WATERMAN, M.D., NEAL D. RYAN, M.D., JOAQUIM PUIG-ANTICH, M.D., VIVECA MEYER, M.D., PAUL J. AMBROSINI, M.D., HARRIS RABINOVICH, M.D., STACY STULL, B.S., HANA NOVACENKO, M.S., DOUGLAS E. WILLIAMSON, B.A., AND BEVERLY NELSON, R.N.

Abstract. Because of its neuroendocrine effects, amphetamine infusion has been used as a probe to investigate neurobiological correlates of depressive illness. In two separate studies, a total of 72 adolescents with major depressive disorder and 66 normal adolescents were given dextroamphetamine, 0.15 mg/kg, intravenously. Their cortisol, growth hormone, and prolactin responses were measured. These endocrine responses did not reliably distinguish adolescents with major depressive disorder from those without it, nor did they reliably delineate any specific depressive subgroup. These findings are compared with those from similar studies of adult depression. J. Am. Acad. Child Adolesc. Psychiatry, 1991, 30, 3:415-422. Key Words: adolescence, amphetamine, depression, neuroendocrine. The impediments to the direct investigation of central neurotransmitter and receptor abnormalities in psychiatric disease have led to the development of strategies that exploit peripheral measures that reflect central processes. The amphetamine challenge test is one such maneuver that has been used to study neurochemical correlates of depressive illness in adults. The effects of amphetamine are thought to be mediated by the neurotransmitters dopamine, norepinephrine, and serotonin (Dommisse et al., 1984). These substances, in turn, modulate the release into the circulation of peripherally measurable hormones, such as cortisol, growth hormone, and prolactin. Different neuroendocrine responses between depressed and normal subjects to amphetamine challenge have thus been interpreted as evidence for derangements in central neurotransmitter or receptor function in depression. When given to normal subjects intravenously, methamphetamine and dextroamphetamine stimulate cortisol release that peaks after approximately 30 minutes (Sachar et al., 1981). A significant cortisol response was achieved with 0.15 mg/kg but not with 0.1 mg/kg, and infusing amphetamine in the evening stimulated a larger rise in cortisol than giving it in the morning (Halbreich et al., 1981). When administered to depressed patients, however, methamphetamine produced a cortisol response that was significantly lower than when it was given to the same subjects in the Accepted August 21, 1990. Drs. Waterman, Ryan, Puig-Anticn (deceased), and Meyer, Ms. Stull, Mr. Williamson, and Ms. Nelson are with the Department of

recovered state (Checkley and Crammer, 1977). Dextroamphetamine suppressed elevated cortisol levels in depressed subjects while provoking a rapid rise in plasma cortisol in normals (Sachar et al., 1980, 1981). The cortisol response to methamphetamine was significantly lower in a group of endogenous depressives than in "reactive" depressives or in either of two nondepressed psychiatric control groups (Checkley, 1979). However, Feinberg et al. (1981) reported finding no difference between the cortisol responses to amphetamine of endogenous versus nonendogenous depressives, and Stewart et al. (1984) found that depressive subtype was not a reliable predictor of abnormal cortisol response to dextroamphetamine. Amphetamine serves also as a stimulus for growth hormone release when given intravenously (Langer et al., 1975) as well as orally (Dommisse et al., 1984). Langer et al. (1976) found that adult patients with endogenous depression showed a smaller growth hormone response to intravenous amphetamine than did normal control subjects. Schizophrenic and alcoholic controls did not differ from normals, but "reactive" depressives released more growth hormone compared with the control groups. In their study of methamphetamine stimulation, Check ley and Crammer (1977) reported that growth hormone response did not differ between depressed patients and the same subjects after recovery. Checkley (1979) also found that this test did not distinguish endogenous depressives from any of his three psychiatric control groups. In a reanalysis of Langer's data, Halbreich et al. (1980) concluded that if the endogenously

Psychiatry, University ofPittsburgh School ofMedicine, Western Psy-

depressed group was compared with normal control subjects

chiatric Institute and Clinic, Pittsburgh, Pennsylvania. Drs. Ambrosini and Rabinovich are with the Department of Psychiatry, Medical College ofPennsylvania, Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pennsylvania. Ms. Novacenko is with the Department of Psychiatry, Columbia University College ofPhysicians and Surgeons, New York State Psychiatric Institute, New York, New York. This work is dedicated to the memory ofJoaquim Puig-Antich, M.D. Correspondence should be directed to Dr. Waterman, Child and Adolescent Mood Program, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213. 0890-8567/9113003-0415$03 .001O© 1991by the American Academy of Child and Adolescent Psychiatry.

of similar age (over 42), their growth hormone responses were not different. His own study (Halbreich et al., 1982) found that, when age and sex were controlled for, the magnitude of growth hormone response to amphetamine stimulation did not distinguish endogenous depressives from normals, nor were endogenously depressed subjects different from "atypical" depressives. The authors note that these findings suggest the importance of age and/or menopausal status in amphetamine-stimulated growth hormone secretion.

J. Am. Acad. Child Adolesc. Psychiatry, 30:3, May 1991

415

WATERMAN ET AL. TABLE

1. Demographics: New York State Psychiatric Institute Major Depressive Disorder

Sample size Sex M F Race White Black Other Age Mean SD

2. Demographics: Western Psychiatric Institute and Clinic Major Depressive Disorder

Normal

45

32

22 23

19 13

29 4 12

15 9 8

15.0 1.8

15.1 t 1.6 P

X' P

X' P

0.50 NS 5.13 NS

-0.39 NS

Dommisse et al. (1984) found that orally administered dextroamphetamine produced a fall in prolactin that was not different from the effect of placebo. To the authors' knowledge, studies of amphetamine challenge in depression have not measured prolactin response. The present paper concerns data from two separate studies of hormonal response to dextroamphetamine infusion in adolescent major depressive disorder (MDD). One sample comes from the New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons. The other sample is from the Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. The current results will be compared with those found in such studies of depression in adults.

Method REFERRAL AND CLINICAL ASSESSMENT Adolescents were accepted for screening at both centers if they had symptoms or behaviors potentially indicative of depression. If the screening was suggestive of depression, adolescents were entered into a 2-week protocol consisting of psychiatric, psychosocial, and pediatric assessments, including physical examination, Tanner staging, and EKG. Psychiatric evaluation consisted of administration of the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present Episode (K-SADS-P) (Chambers et aI., 1985), and the K-SADS-E (the epidemiological version) for lifetime diagnoses (Orvaschel et al. , 1982). From 7 to 14 days after the initial evaluation, those subjects who met Research Diagnostic Criteria (RDC) (Spitzer et aI., 1978) for MDD on the first evaluation underwent a second K-SADS-P evaluation with a different clinician covering symptoms over the preceding week only. Normal control subjects were recruited by advertisement and were evaluated with the K-SADS-E and physical examination (including Tanner staging and EKG). CRITERIA FOR INCLUSION Subjects who had attained at least Tanner stage III of pubertal development and who were under 18 years of age were included in the depressed group if they met RDC criteria for MDD, at least probable, on both 416

TABLE

Sample size Sex M F Race White Black Other Age Mean SD

Normal

27

34

10 17

14 20

20

32

6 1

0 2

15.2

14.9 1.6

1.5

X' P

0.004 NS

Fisher's exact p < 0.05

P

0.83 NS

K-SADS-P evaluations and were determined by the pediatrician to be medically healthy. Subjects who met the above pubertal and age criteria were accepted into the normal group if they had no lifetime DSM-ll1 Axis I diagnosis, as determined by the K-SADS-E, and were medically healthy. Informed consent was obtained from the parents or guardians as well as from all adolescents. CRITERIA FOR EXCLUSION Subjects were excluded from the study if they met any of the following criteria: taking medication (a 2-week washout period was used); having significant medical illness; being obese (weight/height ratio greater than the 95th percentile on the National Center for Health Statistics curve) or severely, chronically malnourished (weight or height below the 3rd percentile); having clinical seizures or other major neurological illness; having an IQ below 70; meeting DSM-111 criteria for anorexia nervosa, autism, or schizophrenia; or being pregnant. SAMPLES The demographic data are shown in Tables 1 and 2. For the New York sample, there were no significant differences in the sex, race, or age distributions between the MDD and the normal groups. The Pittsburgh sample was also evenly balanced between the diagnostic groups for sex and age. There were, however, six black subjects in the MDD group and none in the normal group. In addition, the New York sample contained just four inpatients, while the Pittsburgh sample had 10 inpatients. PROCEDURE This study was part of a psychobiological protocol that included studies of sleep EEG, 24-hour serum cortisol, dexamethasone suppression test, thyrotropin-releasing hormone (TRH) stimulation test, clonidine stimulation of growth hormone, and insulin tolerance test. With the exception of one test (TRH stimulation), a period of several days separated the amphetamine test from prior studies. For many of the subjects, the TRH stimulation test preceded amphetamine administration by 7 hours. This short-lived peptide should l.Am.Acad. Child Adolesc.Psychiatry, 30:3, May 1991

DEXTROAMPHETAMINE IN ADOLESCENT DEPRESSION

have had no significant effect on the hormones measured for the present study. For those subjects who were inpatients at the time of the study, the protocol was carried out early in hospitalization and always before the initiation of any pharmacotherapy. On the day of this test, subjects were kept n.p.o. after 12 noon. An intravenous catheter was inserted at 3 P.M. Beginning 1/2 hour after the catheter was inserted, three blood samples were withdrawn at IS-minute intervals for determination of cortisol, growth hormone, and prolactin plasma levels. Immediately after the third sample was collected, dextroamphetamine (0.15 mg/kg) was administered intravenously over I minute. Five additional blood samples were then collected, also at IS-minute intervals, for hormone assays. ASSAYS

Cortisol New York. Plasma cortisol was measured by a solid phase radioimmunoassay using test tubes precoated with antibody specific for cortisol and 1251-labeled cortisol-3-derivative as a ligand. Samples were assayed in duplicate. The intra- and interassay coefficients of variation were 5.76% and 6.98% at 3.72 ng/mL, 3.10% and 4.60% at 12.48 ng/mL, and 3.30% and 5.30% at 21.29 ng/mL. Pittsburgh. Cortisol levels in plasma were determined from 25 f.1L samples assayed in duplicate. The procedure used was Diagnostic Products solid phase 1251 radioimmunoassay for cortisol. This method is sensitive to 1 u.g/dl, of cortisol. Patient samples, standards, and quality controls were pipetted in duplicate along with labeled antigen into tubes coated with a highly specific cortisol antibody. The Micromedics Automated Pipetting System was used for the pipetting steps to minimize error. The tubes were then incubated for 45 minutes at 37° C to enhance the competition between the labeled antigen and that of the patient for antibody sites on the tube. After this incubation, the tubes were decanted and washed to decrease nonspecific binding. The remaining percentage of bound antigen was then determined on a gamma spectrometer. The counts are inversely proportional to the amount of cortisol present in the curve. Patient sample duplicates exceeding as. 0 coefficient of variation were retested in duplicate. The intraassay percent variation of patient results over the study ranged from 1.28 to 2.69.

Pittsburgh. Human growth hormone levels were determined with 50 f.1L patient plasma samples. A modified version of the double antibody 1251 radioimmunoassay procedure developed by Diagnostic Products Corporation was used for these determinations. All patient samples, standards, and quality controls were pipetted in duplicate using the Automated Pipetting Station by Micromedics Systems. To increase the sensitivity of the assay to 0.5 ng/mL of growth hormone from that of the standard procedure, the amount of antibody was decreased, and a longer, sequential incubation of the antibody and radio-labeled antigen was used. There was an initial 2-hour room temperature incubation of the plasma with the primary human growth hormone antibody, followed by a I-hour room temperature incubation with the radio-labeled (1 251) compound. The separation of the bound and free phases was carried out using gamma globulin plus dilute polyethylene glycol solutions. The bound phase was then counted in a gamma counter. The counts are inversely proportional to the amount of growth hormone present in the patient sample as determined from the standard curve. Patient duplicates with a coefficient of variation exceeding 5.0 were retested. The range for the intraassay percent variation of patient samples over the study was 0.95 to 2.30. Prolactin

New York. Plasma human growth hormone was analyzed

New York. Plasma prolactin was measured by a double antibody radioimmunoassay. Prolactin standard (hPRI-RP1) and the primary antiserum were donated by the National Pituitary Agency. The 1251-labeled prolactin was purchased from New England Nuclear and repurified on the day of assay on a G-100 Sephadex column. Antirabbit globulin serum was used for separation of the bound and free fractions. Samples were assayed in duplicate. The intra- and interassay coefficients of variation were 6.37% and 6.86% at 3.76 ng/mL, 3.83% and 5.72% at 27.0 ng/mL, and 2.01 % and 3.49% at 46.26 ng/mL. Pittsburgh. The procedure used for this determination was a modified version of Becton Dickinson's 1251 radioimmunoassay for prolactin. The patient's prolactin level was determined on an 80 f.1L plasma sample. All patient samples, standards, and quality controls were pipetted in duplicate using the Micromedics Automated Pipetting System. A more specific prolactin antibody, supplied by the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases, replaced Becton Dickinson's antibody in the assay. To improve the sensitivity of the procedure, a sequential 37°C incubation of reagents was used. An assay sensitivity

by a double antibody radioimmunoassay. Human growth

of I ng/mL of prolactin was obtained by incubating a pa-

hormone standard (hGH-RP-I) and the primary antiserum were donated by the National Pituitary Agency. The 1251_ labeled human growth hormone was purchased from New England Nuclear and repurified on the day of assay on a G-IOO Sephadex column. Antirabbit globulin serum was used for separation of the bound and free fractions. Samples were assayed in duplicate. The intra- and interassay coefficients of variation were 9.62% and 12.38% at 1.54 ng/ mL, 3.17% and 3.75% at 7.47 ng/mL, and 2.63% and 3.86% at 33.14 ng/mL.

tient's plasma with primary antibody for 4Y2 hours followed by a 1Y2-hour incubation of this complex with labeled antigen. Bound and unbound prolactin were then separated using a second precipitating antibody. Upon centrifugation, the bound phase was pelleted in the tube, and the radioactivity present in the pellet was determined by gamma counter. The level of radioactivity bound is inversely related to the concentration of the antigen in the patient sample or standard. A standard curve was plotted and the concentration of prolactin in the patient sample was determined from the

Growth Hormone

l.Am.Acad. Child Adolesc.Psychiatry, 30:3, May 1991

417

WATERMAN ET AL. TABLE

3. Cortisol Response to Amphetamine (u.gldl., Mean ± SD)

Major Depressive Disorder New York State Psychiatric Institute Delta 3.34 Peak 5.45 Western Psychiatric Institute and Clinic Delta 5.12 Peak 5.74

Normal

Statistic

± 3.81 ± 4.13

2.50 ± 2.75 4.91 ± 3.38

t = 1.12 t = 0.60

± 2.68 ± 4.66

6.45 ± 2.40 5.75 ± 2.87

t t

standard curve. Patient sample duplicates with a coefficient of variation exceeding 5.0 were retested. The range of intraassay percent variation of patient samples over the study was 1.08 to 2.86. ANALYSIS

The MDD and normal groups were compared using two different indices of hormonal response to dextroamphetamine. One index (mean delta) consists of the difference between the mean hormone plasma level for the five postamphetamine infusion determinations and that for the three preinfusion ones. The other index (peak) represents the highest postinfusion hormone level minus the level immediately before the administration of amphetamine. These two parameters (mean delta and peak) were calculated for each subject, and the two diagnostic groups were compared. The distributions of these parameters were tested for normality using the Shapiro-Wilk's statistic. The groups were then compared using Student's t-test when the distributions were approximately normal, and the Mann-Whitney U test was employed for comparisons of nonnormal distributions. Data from the two samples (New York and Pittsburgh) were analyzed separately.

-0.27 -0.01

= =

NS NS

Cortisol Response to Amphetamine

N.Y.S.P.I.

W.P.I.C.

16

16

14



MDD(n-45)



!iorll)aL(n=-32)

12



MDD (n-26)



!i0rll)aL(n=-34)

12

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Hormonal responses to dextroamphetamine in depressed and normal adolescents.

Because of its neuroendocrine effects, amphetamine infusion has been used as a probe to investigate neurobiological correlates of depressive illness. ...
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